TW202337896A - Methods for treating or preventing sars-cov-2 infections and covid-19 with anti-sars-cov-2 spike glycoprotein antibodies - Google Patents

Abstract

The present invention provides methods for preventing and treating SARS-CoV-2 infections, COVID-19, or symptoms thereof. The methods of the invention feature the administration of one or more antigen-binding molecules (e.g., antibodies) that bind a surface protein of SARS-CoV-2 (e.g., spike protein).

Description

Methods to treat or prevent SARS-CoV-2 infection and COVID-19 with anti-SARS-CoV-2 spike glycoprotein antibodies

The present invention belongs to the medical field and relates to the administration of antigen-binding molecules that bind to surface proteins of SARS-CoV-2 (for example, anti-SARS-CoV-2 spike glycoprotein antibodies and antigen-binding fragments thereof, or such antibodies or antigens). Combinations of binding fragments) to treat SARS-CoV-2 infection and COVID-19, and methods and pharmaceutical compositions.

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

In December 2019, pneumonia of unknown cause was identified in the patient. A novel mantle RNA beta coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was later identified in these patients, and the disease caused by SARS-CoV-2 infection was subsequently named 2019 by the World Health Organization. coronavirus disease (COVID-19). As of November 2022, nearly 633 million confirmed COVID-19 cases have been reported globally. The rapidly spreading global outbreak has prompted the World Health Organization to declare COVID-19 a pandemic and public health emergency of international concern.

Patients with COVID-19 are at risk for a variety of respiratory conditions, ranging from relatively mild respiratory symptoms to severe respiratory failure and death. In hospitalized patients, intensive care and/or oxygen supplementation (eg, mechanical ventilation) is often required, and higher mortality rates are reported. Among the 44,500 confirmed infections reported by the Chinese Centers for Disease Control and Prevention, nearly 20% of patients presented with advanced respiratory symptoms (14% with dyspnea, hypoxia, or >50% lung damage on imaging; 5% with respiratory failure) , shock or multiple organ failure). Another analysis of patients with COVID-19 in China found that of 1,099 hospitalized patients, 5% were admitted to the intensive care unit (ICU), 2.3% required invasive mechanical ventilation, and 1.4% died. Among patients reported in China with advanced disease on admission (defined as pneumonia, hypoxemia, and shortness of breath), these negative outcomes rose to 19%, 14.5%, and 8.1%, respectively. Reports of 2,634 hospitalized patients with COVID-19 in the United States identified similar clinical outcomes: 14.2% were admitted to the 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 enhanced care for respiratory support.

Coronaviruses have an RNA genome encapsulated in a nucleocapsid (N) protein surrounded by an outer envelope. The mantle contains membrane (M) protein and mantle (E) protein that participate in virus assembly, and spike (S) protein that mediates entry into host cells. The S protein forms larger trimer protrusions that provide the characteristic crown appearance of coronaviruses. The S protein trimer binds to host receptors and mediates host-viral membrane fusion after initiation by cellular proteases. The S protein appears to be important for the viral infectivity of SARS-CoV-2. The SARS-CoV-2 S protein binds to the host receptor angiotensin-converting enzyme 2 (ACE2) with high affinity, and in cell analysis and animal models, ACE2 can be used as a functional receptor for host cell entry. body.

In view of the possible key role of the S protein in the pathogenesis of SARS-CoV-2, many efforts have been made to develop antibodies and vaccines targeting this protein.

The present disclosure provides methods for improving one or more clinical parameters of COVID-19. In some cases, the methods comprise administering to a subject in need thereof a therapeutic composition, 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 symptoms of COVID-19. In some cases, one or more COVID-19 symptoms include fever, cough, or shortness of breath.

In some embodiments, the subject is selected from the group consisting of: (a) human COVID-19 patients requiring low flow oxygen supply; (b) human COVID-19 patients requiring high intensity oxygen therapy without mechanical ventilation patients; and (c) human COVID-19 patients requiring mechanical ventilation. In some cases, subjects are hospitalized due to one or more symptoms of COVID-19. In some cases, the subjects are outpatients (that is, patients treated on an outpatient basis).

The disclosure also provides methods for preventing SARS-CoV-2 infection or COVID-19 in a subject. In some cases, methods include administering to the subject a prophylactic composition, wherein the prophylactic composition includes at least one antigen-binding molecule that binds a surface protein of SARS-CoV-2 (eg, SARS-CoV-2 spike protein).

In some embodiments, the subject is an uninfected subject at high risk for SARS-CoV-2 infection. In some embodiments, the subject at high risk for SARS-CoV-2 infection is a health care worker, a first responder, or a household member of a subject who tests positive for SARS-CoV-2 infection.

In some embodiments, the therapeutic or prophylactic composition comprises a first antigen-binding molecule that binds to a first epitope on a surface protein of SARS-CoV-2, and a second antigen-binding molecule that binds to a surface protein of SARS-CoV-2. A second antigen-binding molecule of epitope, wherein the first epitope and the second epitope do not overlap in structure.

In some embodiments, the therapeutic or prophylactic composition further comprises a third antigen-binding molecule that binds to a third epitope on a surface protein of SARS-CoV-2, wherein the third epitope is structurally identical to the first epitope. The epitope and the second epitope do not overlap.

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

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

In some embodiments, the antigen-binding molecule is an anti-SARS-CoV-2 spike glycoprotein antibody or an antigen-binding fragment thereof, which includes a heavy chain variable region (HCVR) and a light chain variable region (LCVR) amino acid sequence pair Containing six complementarity determining regions HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3, the amino acid sequence pair includes an amino acid sequence selected from the group consisting of: SEQ ID NO: 2/10, 22/ 30, 42/50 and 73/81. In some cases, the anti-SARS-CoV-2 spike protein antibody or antigen-binding fragment includes six complementarity determining regions HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3, each of which includes an amine group selected from the group consisting of: Acid sequence: SEQ ID NO: 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 protein antibody or antigen-binding fragment includes an HCVR/LCVR amino acid sequence pair, which includes an amino acid sequence selected from the group consisting of: SEQ ID NO: 2/ 10, 22/30, 42/50, and 73/81. In some embodiments, the anti-SARS-CoV-2 spike protein antibody comprises a human IgG heavy chain constant region. In some cases, anti-SARS-CoV-2 spike protein antibodies comprise a heavy chain constant region of an IgG1 or IgG4 isotype. In some cases, the anti-SARS-CoV-2 spike protein antibody comprises a heavy chain and light chain amino acid sequence pair selected from the group consisting of: SEQ ID NO: 18/20, 38/40, 56/58 , and 89/91.

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 an HCVR/LCVR amino acid sequence pair. The amino acid sequence pair includes an amino acid sequence selected from the group consisting of: SEQ ID NO: 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 pair of heavy chain and light chain amino acid sequences, the heavy chain and the light chain amino acid sequence pair is selected from the group consisting of: SEQ ID NO: 18/20, 38/40, 56/58 and 89/91.

In some embodiments, the first antigen-binding molecule is six complementarity determining regions HCDR1-HCDR2-HCDR3-LCDR1 contained within a heavy chain variable region (HCVR) and light chain variable region (LCVR) amino acid sequence pair. -The first anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment thereof of LCDR2-LCDR3, the amino acid sequence pair includes the amino acid sequence of SEQ ID NO: 2/10, and the second antigen-binding molecule is The second anti-SARS-CoV-containing six complementarity determining regions HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 contained within the heavy chain variable region (HCVR) and light chain variable region (LCVR) amino acid sequences 2. A spine glycoprotein antibody or an antigen-binding fragment thereof, the amino acid sequence pair comprising the amino acid sequence of SEQ ID NO: 22/30. In some cases, the first anti-SARS-CoV-2 spike protein antibody or antigen-binding fragment comprises six complementarity determining regions HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3, which respectively comprise SEQ ID NO: 4-6- 8-12-14-16 amino acid sequence, and the second anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment contains six complementarity determining regions HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3, which are respectively Contains the amino acid sequence of SEQ ID NO: 24-26-28-32-34-36. In some cases, the first anti-SARS-CoV-2 spike protein antibody or antigen-binding fragment includes: an HCVR/LCVR amino acid sequence pair including the amino acid sequence of SEQ ID NO: 2/10, and the second antibody The SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment includes: an HCVR/LCVR amino acid sequence pair including the amino acid sequence of SEQ ID NO: 22/30. In some embodiments, the first anti-SARS-CoV-2 spike protein antibody and the second anti-SARS-CoV-2 spike protein antibody comprise a human IgG heavy chain constant region. In some cases, the first anti-SARS-CoV-2 spike protein antibody and the second anti-SARS-CoV-2 spike protein antibody comprise a heavy chain constant region of an IgG1 or IgG4 isotype. In some cases, the first anti-SARS-CoV-2 spike protein 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 includes: a heavy chain including the amino acid sequence of SEQ ID NO: 38 and a light chain including the amino acid sequence of SEQ ID NO: 40.

In some embodiments, the first antigen-binding molecule is a first anti-SARS-CoV-2 spike glycoprotein antibody having the same binding and/or blocking properties as a reference antibody comprising the HCVR/LCVR amino acid sequence pair or its Antigen-binding fragment, the HCVR/LCVR amino acid sequence pair includes the amino acid sequence of SEQ ID NO: 2/10, and the second antigen-binding molecule is the same as the reference antibody including the HCVR/LCVR amino acid sequence pair. A second anti-SARS-CoV-2 spike glycoprotein antibody or an antigen-binding fragment thereof with binding and/or blocking properties, the HCVR/LCVR amino acid sequence pair comprising the amino acid sequence of SEQ ID NO: 22/30. In some embodiments, the first antigen-binding molecule is a first anti-SARS-CoV-2 spike glycoprotein antibody or an antigen-binding thereof that has the same binding and/or blocking properties as a reference antibody comprising a heavy chain and a light chain pair. Fragment, the heavy chain and light chain pair comprise the amino acid sequence of SEQ ID NO: 18/20, and the second antigen-binding molecule has the same binding and/or blocking as the reference antibody comprising the heavy chain and light chain pair A first anti-SARS-CoV-2 spike glycoprotein antibody or an antigen-binding fragment thereof, the heavy chain and light chain pair comprise the amino acid sequence of SEQ ID NO: 38/40.

In some embodiments, the antigen-binding molecule is an anti-SARS-CoV-2 spike glycoprotein antibody or an antigen-binding fragment thereof, which includes: a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 42 and The light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO: 50 contains six complementarity determining regions HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3. In some cases, the anti-SARS-CoV-2 spike protein antibody or antigen-binding fragment includes six complementarity determining regions HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3, which respectively include SEQ ID NO: 44-46-48- Amino acid sequence 52-34-54. In some cases, the anti-SARS-CoV-2 spike protein antibody or antigen-binding fragment includes: HCVR including the amino acid sequence of SEQ ID NO: 42 and LCVR including the amino acid sequence of SEQ ID NO: 50. In some embodiments, the anti-SARS-CoV-2 spike protein antibody comprises a human IgG heavy chain constant region. In some cases, anti-SARS-CoV-2 spike protein antibodies comprise a heavy chain constant region of an IgG1 or IgG4 isotype. In some cases, the anti-SARS-CoV-2 spike protein 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.

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 an HCVR/LCVR amino acid sequence pair. The amino acid sequence pair includes the amino acid sequence of SEQ ID NO: 42/50. In some embodiments, the antigen-binding molecule is an anti-SARS-CoV-2 spike glycoprotein antibody with the same binding and/or blocking properties as a reference antibody comprising a heavy chain and a light chain pair. Contains the amino acid sequence of SEQ ID NO: 56/58.

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. In some cases, the therapeutic or prophylactic composition includes about 1.2 g of mAb10933 and about 1.2 g of mAb10987. In some cases, the therapeutic or prophylactic composition contains about 1.2 g of mAb10985. In some cases, the therapeutic or prophylactic composition includes about 4.0 g of mAb10933 and about 4.0 g of mAb10987. In some cases, the therapeutic or prophylactic composition includes about 150 mg of mAb10933 and about 150 mg of mAb10987. In some cases, the therapeutic or prophylactic composition contains about 150 mg of mAb10985. In some cases, the therapeutic or prophylactic composition includes about 300 mg of mAb10933 and about 300 mg of mAb10987. In some cases, the therapeutic or prophylactic composition contains about 300 mg of mAb10985. In some cases, the therapeutic or prophylactic composition includes about 600 mg of mAb10933 and about 600 mg of mAb10987. In some cases, the therapeutic or prophylactic composition includes about 600 mg of mAb10985. In some cases, the therapeutic or prophylactic composition includes 150 mg to 1200 mg of mAb10933 and 150 mg to 1200 mg of mAb10987. In some cases, the therapeutic or prophylactic composition further includes 150 mg to 1200 mg of mAb10985. In some cases, the therapeutic or prophylactic composition contains about 1.2 g of mAb10989.

In some embodiments, a therapeutic or prophylactic composition is administered to a 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 can be co-administered simultaneously, for example, by combining the antibodies in an intravenous bag prior to a single infusion, or by combining the antibodies into a syringe prior to a single injection. Alternatively, both antibodies can be administered as two separate subcutaneous injections. In the above embodiments, the subject may be at high risk for clinical complications.

In any of the various embodiments, following administration of the therapeutic composition, the subject exhibits one or more efficacy parameters selected from the group consisting of: (a) SARS-CoV-2 viral shedding relative to Reduction from baseline; (b) improvement in clinical status by at least 1 point using a 7-point ordinal scale; (c) reduction or elimination of the need for supplemental oxygen; (d) reduction or elimination of the need for mechanical ventilation; (e) prevention of COVID- 19-related deaths; (f) prevention of all-cause mortality; and (g) changes in serum concentrations of one or more disease-related biomarkers. In some cases, the 7-point ordinal scale is: [1] Death; [2] Hospitalization, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation; [3] Hospitalization, requiring non-invasive ventilation or high-flow oxygen device; [ 4] Hospitalization, supplemental oxygen required; [5] Hospitalization, supplemental oxygen not required - ongoing medical care required (COVID-19 related or otherwise); [6] Hospitalization, supplemental oxygen not required - ongoing medical care no longer required; and [7] no hospitalization. In some cases, one or more efficacy parameters are measured 21 days after administration of the first dose of the therapeutic composition. In some cases, reduction in SARS-CoV-2 viral shedding relative to baseline was 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-associated biomarkers is a change in c-reactive protein, lactate dehydrogenase, D-dimer, or ferritin.

In any of the various embodiments, the subject exhibits fewer than 5 COVID-19 related medical visits, telemedicine visits, hospitalizations, and/or intensive care unit (ICU) admissions following administration of the therapeutic composition . In some cases, the subject exhibits fewer than 5 COVID-19 related medical visits, telemedicine visits, hospitalizations, and/or intensive care unit (ICU) admissions within 29 days after administration of the first dose of the therapeutic composition. Admission. In some cases, subjects exhibited less than 4, less than 3, less than 2, or less than 1 COVID-19-related medical visits, telemedicine visits, hospitalizations, and/or intensive care unit (ICU) admissions .

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

In some embodiments, the method further comprises administering to the subject an additional therapeutic agent. 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 steroids. 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 concurrently with the therapeutic composition. In any of the various embodiments of the methods discussed above or herein, the subject can be seronegative for SARS-CoV-2 infection.

In one aspect, the present disclosure provides a method for improving one or more clinical parameters of SARS-CoV-2 infection, the method comprising administering a therapeutic composition to a subject suffering from SARS-CoV-2 infection, The therapeutic composition includes a first anti-SARS-CoV-2 spike glycoprotein antibody or an antigen-binding fragment thereof, which includes a heavy chain variable region (HCVR) and a light chain variable region (LCVR) amino acid sequence pair. Three heavy chain complementarity determining regions (HCDR) and three light chain complementarity determining regions (LCDR), the amino acid sequence pair includes the amino acid sequence of SEQ ID NO: 2/10; and the second anti-SARS-CoV -2 Spiny glycoprotein antibody or antigen-binding fragment thereof, which contains three HCDRs and three LCDRs contained in an amino acid sequence pair of HCVR and LCVR, and the amino acid sequence pair contains the amino group of SEQ ID NO: 22/30 An acid sequence, wherein the therapeutic composition reduces at least one symptom of SARS-CoV-2 infection more rapidly when administered to a population of seronegative subjects than to a comparable population of seronegative subjects administered placebo.

In one aspect, the present disclosure provides a method for improving one or more clinical parameters of SARS-CoV-2 infection, wherein the method includes administering a therapeutic composition to a subject suffering from SARS-CoV-2 infection , wherein the therapeutic composition includes a first anti-SARS-CoV-2 spike glycoprotein antibody or an antigen-binding fragment thereof, which includes a heavy chain variable region (HCVR) and a light chain variable region (LCVR) amino acid sequence pair Containing three heavy chain complementarity determining regions (HCDR) and three light chain complementarity determining regions (LCDR), the amino acid sequence pair includes the amino acid sequence of SEQ ID NO: 2/10; and the second anti-SARS- CoV-2 spine glycoprotein antibody or antigen-binding fragment thereof, which contains three HCDRs and three LCDRs contained in the HCVR and LCVR amino acid sequence pairs, and the amino acid sequence pair contains the amine of SEQ ID NO: 22/30 A amino acid sequence, wherein the therapeutic composition reduces at least one symptom of SARS-CoV-2 infection more rapidly when administered to a population of seronegative subjects compared to a comparable population of seropositive subjects.

In one aspect, the present disclosure provides a method for improving one or more clinical parameters of SARS-CoV-2 infection, the method comprising administering a therapeutic composition to a subject suffering from SARS-CoV-2 infection, The therapeutic composition includes a first anti-SARS-CoV-2 spike glycoprotein antibody or an antigen-binding fragment thereof, which includes a heavy chain variable region (HCVR) and a light chain variable region (LCVR) amino acid sequence pair. Three heavy chain complementarity determining regions (HCDR) and three light chain complementarity determining regions (LCDR), the amino acid sequence pair includes the amino acid sequence of SEQ ID NO: 2/10; and the second anti-SARS-CoV -2 Spiny glycoprotein antibody or antigen-binding fragment thereof, which contains three HCDRs and three LCDRs contained in an amino acid sequence pair of HCVR and LCVR, and the amino acid sequence pair contains the amino group of SEQ ID NO: 22/30 An acid sequence, wherein the therapeutic composition reduces the viral load of the subject population 7 days after administration (Day 7) compared to the day of administration (Day 0).

In some embodiments, after treatment with 0.6 g of a first anti-SARS-CoV-2 spike protein antibody and 0.6 g of a second anti-SARS-CoV-2 spike protein antibody, compared to a comparable population of subjects treated with placebo. Among patients, the time-weighted mean change in nasopharyngeal (NP) viral load on day 7 from baseline was a greater reduction of at least 0.86 log10 copies/ml in the seronegative subject population (p<0.0001).

In some embodiments, after treatment with 1.2 g of a first anti-SARS-CoV-2 spine glycoprotein antibody and 1.2 g of a second anti-SARS-CoV-2 spine glycoprotein antibody, compared to a comparable population of subjects treated with placebo. Among patients, the change from baseline in nasopharyngeal (NP) viral load on day 7 was a greater reduction of at least 1.04 log10 copies/ml in the seronegative subject population (p<0.0001).

In some embodiments, after treatment with 0.6 g of a first anti-SARS-CoV-2 spike protein antibody and 0.6 g of a second anti-SARS-CoV-2 spike protein antibody, compared to a comparable population of subjects treated with placebo. Among patients, the mean change from baseline in nasopharyngeal (NP) viral load at day 7 in the subject population was a greater reduction of at least 0.71 log10 copies/ml (p<0.0001).

In some embodiments, after treatment with 1.2 g of a first anti-SARS-CoV-2 spine glycoprotein antibody and 1.2 g of a second anti-SARS-CoV-2 spine glycoprotein antibody, compared to a comparable population of subjects treated with placebo. Among patients, the mean change from baseline in nasopharyngeal (NP) viral load at day 7 in the subject population was a greater reduction of at least 0.86 log10 copies/ml (p<0.0001).

In one aspect, the present disclosure provides a method for improving one or more clinical parameters of SARS-CoV-2 infection, the method comprising administering a therapeutic composition to a subject suffering from SARS-CoV-2 infection, The therapeutic composition includes a first anti-SARS-CoV-2 spike glycoprotein antibody or an antigen-binding fragment thereof, which includes a heavy chain variable region (HCVR) and a light chain variable region (LCVR) amino acid sequence pair. Three heavy chain complementarity determining regions (HCDR) and three light chain complementarity determining regions (LCDR), the amino acid sequence pair includes the amino acid sequence of SEQ ID NO: 2/10; and the second anti-SARS-CoV -2 Spiny glycoprotein antibody or antigen-binding fragment thereof, which contains three HCDRs and three LCDRs contained in an amino acid sequence pair of HCVR and LCVR, and the amino acid sequence pair contains the amino group of SEQ ID NO: 22/30 An acid sequence, wherein the therapeutic composition reduces the viral load in the subject population.

In some embodiments of the methods discussed above or herein, administering the therapeutic composition comprises administering 0.6 g of a first anti-SARS-CoV-2 spike protein antibody and 0.6 g of a second anti-SARS-CoV-2 Spiny glycoprotein antibodies, and wherein the administration results in an average viral load reduction of at least 3.00 log10 copies/ml on day 7 post-administration compared to the baseline viral load measured on day 0 prior to administration. In some cases, this reduction is at least 3.50 log10 copies/ml. In some cases, this reduction is at least 3.90 log10 copies/ml.

In some embodiments, administering the therapeutic composition comprises administering 1.2 g of a first anti-SARS-CoV-2 spike glycoprotein antibody and 1.2 g of a second anti-SARS-CoV-2 spike glycoprotein antibody, and wherein The administration produced an average viral load reduction of at least 3.50 log10 copies/ml on day 7 post-dose compared to the baseline viral load measured on day 0 before dosing. In some cases, this reduction is at least 3.75 log10 copies/ml. In some cases, this reduction was at least 4.09 log10 copies/ml.

In one aspect, the present disclosure provides a method for improving one or more clinical parameters of SARS-CoV-2 infection, the method comprising administering a therapeutic composition to a subject suffering from SARS-CoV-2 infection, The therapeutic composition includes a first anti-SARS-CoV-2 spike glycoprotein antibody or an antigen-binding fragment thereof, which includes a heavy chain variable region (HCVR) and a light chain variable region (LCVR) amino acid sequence pair. Three heavy chain complementarity determining regions (HCDR) and three light chain complementarity determining regions (LCDR), the amino acid sequence pair includes the amino acid sequence of SEQ ID NO: 2/10; and the second anti-SARS-CoV -2 Spiny glycoprotein antibody or antigen-binding fragment thereof, which includes three HCDRs and three LCDRs contained in the HCVR and LCVR amino acid sequence pair, which includes the amino acid sequence of SEQ ID NO: 22/30, wherein Compared with a comparable subject group treated with placebo, 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- The therapeutic composition reduced the time to symptom remission (defined as symptoms becoming mild or non-existent) in a group of subjects treated with CoV-2 spike protein antibody and 1.2 g of a second anti-SARS-CoV-2 spike protein antibody. Median 4 days. In some embodiments, the subject and/or population of subjects includes subjects who are not hospitalized for COVID-19.

In one aspect, the present disclosure provides a method of reducing the risk of contracting a symptomatic SARS-CoV-2 infection, the method comprising administering to a subject a combination of at least two antibodies that bind to the SARS-CoV-2 spike protein, wherein the combination of at least two antibodies reduces the subject's risk of contracting a symptomatic SARS-CoV-2 infection for at least two months following administration of a single dose of the combination of at least two antibodies.

In some embodiments of the methods discussed above or herein, the method continues for at least 3 months, at least 4 months, at least 5 months, at least 6 months after administration of a single dose of the combination of at least two antibodies. Month, or at least 7 months to reduce the risk of the subject. In some embodiments, the method reduces the subject's risk for at least 8 months after administration of a single dose of the combination. In some embodiments of the methods discussed above or herein, the method continues for up to 3 months, up to 4 months, up to 5 months, up to 6 months after administration of a single dose of a combination of up to two antibodies. Month, or at most 7 months to reduce the subject’s risk. In some embodiments, the method reduces the subject's risk for up to 8 months after administration of a single dose of the combination. In some embodiments of the methods discussed above or herein, the method continues for at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks after administration of a single dose of the combination of at least two antibodies. weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 20 weeks, at least 21 weeks, At least 22 weeks, at least 23 weeks, at least 24 weeks, at least 25 weeks, at least 26 weeks, at least 27 weeks, at least 28 weeks, at least 29 weeks, at least 30 weeks, at least 31 weeks, at least 32 weeks, at least 33 weeks, at least 34 weeks week, at least 35 weeks, at least 36 weeks, at least 37 weeks, at least 38 weeks, at least 39 weeks, or at least 40 weeks to reduce the subject's risk. In some embodiments, the method reduces the subject's risk for 2 to 32 weeks after administration of a single dose of the combination. In some embodiments, the method reduces the subject's risk for at least 32 weeks after administration of a single dose of the combination. In some embodiments of the methods discussed above or herein, the method continues for up to 5 weeks, up to 6 weeks, up to 7 weeks, up to 8 weeks, up to 9 weeks after administration of a single dose of a combination of up to two antibodies. weeks, up to 10 weeks, up to 11 weeks, up to 12 weeks, up to 13 weeks, up to 14 weeks, up to 15 weeks, up to 16 weeks, up to 17 weeks, up to 18 weeks, up to 19 weeks, up to 20 weeks, up to 21 weeks, Up to 22 weeks, Up to 23 weeks, Up to 24 weeks, Up to 25 weeks, Up to 26 weeks, Up to 27 weeks, Up to 28 weeks, Up to 29 weeks, Up to 30 weeks, Up to 31 weeks, Up to 32 weeks, Up to 33 weeks, Up to 34 weeks week, up to 35 weeks, up to 36 weeks, up to 37 weeks, up to 38 weeks, up to 39 weeks, or up to 40 weeks to reduce the subject's risk. In some embodiments, the method reduces the subject's risk for 2 to 32 weeks after administration of a single dose of the combination. In some embodiments, the method reduces the subject's risk for up to 32 weeks after administration of a single dose of the combination.

In some embodiments of the methods discussed above or herein, the spine glycoprotein is a wild-type SARS-CoV-2 spine glycoprotein comprising the amino acid sequence of SEQ ID NO: 92. In some embodiments of the methods discussed above or herein, the spine glycoprotein is a variant SARS-CoV-2 spine glycoprotein comprising the amino acid sequence of SEQ ID NO: 93. An exemplary spike protein sequence is given as SEQ ID NO: 92; a variant spike protein sequence containing the E484K mutation is given as SEQ ID NO: 93.

In some embodiments of the methods discussed above or herein, each of the at least two antibody species is administered at a dose of 1 g to 10 g. In some cases, each of the at least two antibodies is administered at a dose of 1.2 g.

In some embodiments of the methods discussed above or herein, the risk is reduced by at least 80% relative to a subject who is not administered a combination of at least two antibodies.

In some embodiments of the methods discussed above or herein, the combination includes an antibody that binds to SARS-CoV-2 spike protein and includes the amino acids of SEQ ID NO: 4, 6, and 8, respectively. The sequences are three heavy chain complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and three light chain CDRs LCDR1, LCDR2, and LCDR3 respectively comprising the amino acid sequences of SEQ ID NO: 12, 14, and 16.

In some embodiments of the methods discussed above or herein, the combination includes an antibody that binds to SARS-CoV-2 spike protein and includes the amino acids of SEQ ID NO: 24, 26, and 28, respectively. The sequences are three heavy chain complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and three light chain CDRs LCDR1, LCDR2, and LCDR3 respectively comprising the amino acid sequences of SEQ ID NO: 32, 34, and 36.

In some embodiments of the methods discussed above or herein, the combination comprises: (a) a first antibody that binds to SARS-CoV-2 spike protein and comprising SEQ ID NO: 4, respectively. The three heavy chain complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3 of the amino acid sequences of SEQ ID NOs: 12, 14, and 16 respectively, and the three light chains of the amino acid sequences of SEQ ID NOs: 12, 14, and 16 respectively. CDR LCDR1, LCDR2, and LCDR3; and (b) a second antibody that binds to the SARS-CoV-2 spike protein and includes the amino acid sequences of SEQ ID NO: 24, 26, and 28 respectively. Three heavy chain complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and three light chain CDRs LCDR1, LCDR2, and LCDR3 respectively comprising the amino acid sequences of SEQ ID NO: 32, 34, and 36.

In some cases, the first antibody comprises: a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 10 ), and the second antibody includes: HCVR including the amino acid sequence of SEQ ID NO: 22 and LCVR including the amino acid sequence of SEQ ID NO: 30. In some cases, the first antibody, the second antibody, or both the first antibody and the second antibody comprise human IgGl of a human IgG4 heavy chain constant region.

In some embodiments of the methods discussed above or herein, administering a single dose of the combination comprises administering a single dosage form containing at least two antibodies. In some embodiments, administering a single dose of the combination includes administering each of the at least two antibodies in separate dosage forms within 24 hours of each other.

In one aspect, the present disclosure provides a method of reducing the risk of contracting a symptomatic SARS-CoV-2 infection, the method comprising administering to a subject a combination of two antibodies that bind to the SARS-CoV-2 spike protein, wherein the combination Reducing the subject's risk for at least two months after administration of a single dose of a combination comprising: (a) a first antibody that binds to the SARS-CoV-2 spike protein and comprising each of SEQ. Three heavy chain complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3 of the amino acid sequences of ID NOs: 4, 6, and 8, and the amino acid sequences of SEQ ID NOs: 12, 14, and 16 respectively The three light chain CDRs LCDR1, LCDR2, and LCDR3; and (b) a second antibody that binds to the SARS-CoV-2 spike protein and includes SEQ ID NOs: 24, 26, and 28 respectively. The three heavy chain complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3 of the amino acid sequences, and the three light chain CDRs LCDR1, LCDR2, and the amino acid sequences of SEQ ID NOs: 32, 34, and 36 respectively. and LCDR3.

In some embodiments of the methods discussed above or herein, the first antibody comprises: a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2 and an amine group comprising SEQ ID NO: 10 A light chain variable region (LCVR) having an acid sequence, and the second antibody includes: an HCVR comprising the amino acid sequence of SEQ ID NO: 22 and an LCVR comprising the amino acid sequence of SEQ ID NO: 30. In some cases, the first antibody, the second antibody, or both the first antibody and the second antibody comprise human IgGl of a human IgG4 heavy chain constant region.

In some embodiments of the methods discussed above or herein, the spike protein is a wild-type SARS-CoV-2 spike protein comprising the amino acid sequence of SEQ ID NO: 92, or the spike protein is a spike protein comprising SEQ ID NO: 93 Variations in the amino acid sequence of SARS-CoV-2 spike protein.

In some embodiments of the methods discussed above or herein, each of the two antibodies is administered at a dose of 1.2 g. In some embodiments, administering a single dose of the combination includes administering a single dosage form containing both antibodies.

In some embodiments of the methods discussed above or herein, the risk is reduced by at least 80% relative to a subject not administered the combination.

In some embodiments of the methods discussed above or herein, the method reduces the subject's risk for at least eight months following administration of a single dose of the combination.

In some embodiments of the methods discussed above or herein, the combination of antibodies is in a pharmaceutical composition formulated for subcutaneous administration. In some embodiments, the antibody system is administered subcutaneously to the subject. In some cases, the antibody is administered to the subject in four subcutaneous injections.

In some embodiments of the methods discussed above or herein, the subject is immunocompromised.

In some embodiments of the methods discussed above or herein, each of the two antibodies is administered at a dose of 600 mg.

In one aspect, the present disclosure provides a method for long-term COVID-19 prevention, the method comprising administering to a subject a combination of at least two antibodies that bind to SARS-CoV-2 spike glycoprotein, wherein upon administration of a single The combination of at least two antibodies reduces the subject's risk of symptomatic SARS-CoV-2 infection for at least two months after the first dose.

In some embodiments of the methods discussed above or herein, the method continues for at least 3 months, at least 4 months, at least 5 months, at least 6 months after administration of a single dose of the combination of at least two antibodies. Month, or at least 7 months for COVID-19 prevention targets.

In some embodiments of the methods discussed above or herein, the method prevents COVID-19 in the subject for at least 8 months after administration of a single dose of the combination.

In some embodiments of the methods discussed above or herein, the spine glycoprotein is a wild-type SARS-CoV-2 spine glycoprotein comprising the amino acid sequence of SEQ ID NO: 92. In some embodiments of the methods discussed above or herein, the spine glycoprotein is a variant SARS-CoV-2 spine glycoprotein comprising the amino acid sequence of SEQ ID NO: 93.

In some embodiments of the methods discussed above or herein, each of the at least two antibody species is administered at a dose of 1 g to 10 g. In some cases, each of the at least two antibodies is administered at a dose of 1.2 g.

In some embodiments of the methods discussed above or herein, the risk is reduced by at least 80% relative to a subject who is not administered a combination of at least two antibodies.

In some embodiments of the methods discussed above or herein, the combination includes an antibody that binds to SARS-CoV-2 spine glycoprotein and includes an amine group comprising SEQ ID NOs: 4, 6, and 8, respectively. The three heavy chain complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3 of the acid sequence, and the three light chain CDRs LCDR1, LCDR2, and LCDR3 of the amino acid sequences of SEQ ID NO: 12, 14, and 16 respectively. .

In some embodiments of the methods discussed above or herein, the combination includes an antibody that binds to SARS-CoV-2 spine glycoprotein and includes an amine group comprising SEQ ID NOs: 24, 26, and 28, respectively. The three heavy chain complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3 of the acid sequence, and the three light chain CDRs LCDR1, LCDR2, and LCDR3 of the amino acid sequences of SEQ ID NO: 32, 34, and 36 respectively. .

In some embodiments of the methods discussed above or herein, the combination comprises: (a) a first antibody that binds to SARS-CoV-2 spike protein and comprising SEQ ID NO: 4, respectively. The three heavy chain complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3 of the amino acid sequences of SEQ ID NOs: 12, 14, and 16 respectively, and the three light chains of the amino acid sequences of SEQ ID NOs: 12, 14, and 16 respectively. CDR LCDR1, LCDR2, and LCDR3; and (b) a second antibody that binds to the SARS-CoV-2 spike protein and includes the amino acid sequences of SEQ ID NO: 24, 26, and 28 respectively. Three heavy chain complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and three light chain CDRs LCDR1, LCDR2, and LCDR3 respectively comprising the amino acid sequences of SEQ ID NO: 32, 34, and 36.

In some cases, the first antibody comprises: a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 10 ), and the second antibody includes: HCVR including the amino acid sequence of SEQ ID NO: 22 and LCVR including the amino acid sequence of SEQ ID NO: 30.

In some embodiments of the methods discussed above or herein, the antibodies are administered subcutaneously to the subject. In some embodiments, the antibody is administered to the subject in four subcutaneous injections.

In some embodiments of the methods discussed above or herein, the subject is immunocompromised.

In some embodiments of the methods discussed above or herein, each of the two antibodies is administered at a dose of 600 mg.

Any of the various methods discussed above or herein may be reformulated (i) for the treatment and/or prevention of SARS-CoV-2 infection and/or COVID-19, and/or for the treatment, prevention and antigen-binding molecules or antibodies in methods for mitigating the severity or progression of SARS-CoV-2 infection and/or COVID-19, or symptoms thereof, and/or for reducing the risk of contracting symptomatic SARS-CoV-2 infection (and antigen-binding fragments), or (ii) antigen-binding molecules or antibodies (and antigen-binding fragments) in the manufacture of for the treatment and/or prevention of SARS-CoV-2 infection and/or COVID-19, and/or for the treatment of , prevent and reduce the severity or progression of SARS-CoV-2 infection and/or COVID-19, or its symptoms, and/or use in pharmaceuticals to reduce the risk of contracting symptomatic SARS-CoV-2 infection. In particular, the present disclosure includes the use of antigen-binding molecules that bind to the surface protein of SARS-CoV-2, including the anti-SARS-CoV-2 spike protein antibodies or antigen-binding fragments thereof discussed herein, for the prevention and treatment of SARS- CoV-2 infection and COVID-19 and/or for the treatment, prevention and reduction of the severity or progression of SARS-CoV-2 infection and/or COVID-19, or its symptoms, and/or for the reduction of symptomatic SARS-CoV infection -2 risk of infection. The present disclosure also includes the use of antigen-binding molecules that bind to the surface protein of SARS-Co-2, including the anti-SARS-CoV-2 spike glycoprotein antibodies or antigen-binding fragments thereof discussed herein, for manufacture and use in prevention and treatment SARS-CoV-2 infection and COVID-19 and/or for the treatment, prevention and reduction of the severity or progression of SARS-CoV-2 infection and/or COVID-19, and/or for the reduction of symptomatic SARS-CoV-2 infection Medications that reduce the risk of infection. Where methods are discussed herein with reference to a combination of two anti-SARS-CoV-2 spike protein antibodies, such combinations include a first such antibody or antigen-binding fragment thereof for use in producing a combination with a second such antibody or antigen-binding fragment thereof (or a third or fourth such antibody or antigen-binding fragment), and the use of a second such antibody or antigen-binding fragment thereof (or a third or fourth such antibody or antigen-binding fragment) Use for the manufacture of a medicament for use in combination with a first such antibody.

In various embodiments, any features or components of the embodiments discussed above or herein may be combined, and such combinations are within the scope of the present disclosure. Any specific value discussed above or herein may be combined with another related value discussed above or herein to describe a range, where such values represent the upper and lower ends of the range, and such ranges are encompassed by the scope of the disclosure within.

Other embodiments will become apparent from the review of the embodiments that follows.

Federal awards for research or development

This invention was accomplished with government support under agreement HHSO100201700020C granted by the U.S. Department of Health and Human Services. The government has certain rights in this invention. reference sequence listing

This application incorporates a computer-readable sequence listing in ST.26 XML format, titled 11117WO01_Sequence, created on November 6, 2022, and containing 133,780 bytes.

Before the present invention is described, it is to be understood that this invention is not limited to the 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, as the scope of the invention will be limited only by the scope of the appended claims.

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, when used with reference to a particular recited numerical value, the term "about" means that the value may differ by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values therebetween (eg, 99.1, 99.2, 99.3, 99.4, etc.).

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 by reference in their entirety. Virus

The present invention includes methods for treating or preventing viral infection in a subject. The term "virus" includes any virus whose infection in a subject is treatable or preventable by administration of an anti-SARS-CoV-2-S antibody or antigen-binding fragment thereof (e.g., in which at least part of the infectivity of the virus strongly dependent on the SARS-CoV-2 spike protein). In one embodiment of the invention, "virus" is any virus expressing SARS-CoV-2 spike protein (eg, CoV-S). "Viral infection" refers to the invasion and proliferation of viruses in a subject's body.

Coronavirus virions are spherical virus particles with a diameter of approximately 125 nm. The most prominent feature of coronaviruses is the spherical spines protruding from the surface of the virus particles. These spines are a defining feature of the virion and give it a corona-like appearance, giving it the name coronavirus. Inside the virion envelope is the nucleocapsid. Coronaviruses have helical symmetry nucleocapsids, which are uncommon among sense RNA viruses, while antisense RNA viruses are much more common. SARS-CoV-2 belongs to the coronavirus family. The initial connection between virions and host cells is initiated through the interaction between the S protein and its receptor. The position of the receptor binding domain (RBD) in the S1 region of the coronavirus S protein varies depending on the virus, and some of them have an RBD at the C-terminus of S1. The S protein/receptor interaction is a major determinant of host species infected by coronaviruses and also controls the tissue tropism of virions. Many coronaviruses utilize peptidases as their cellular receptors. After receptor binding, the virus must then enter the host cell cytoplasm. This is typically accomplished by acid-dependent proteolytic cleavage of the S protein by cathepsins, TMPRRS2, or another protease, followed by fusion of viral and cellular membranes.

The SARS-CoV-2 coronaviruses described herein also include variant coronaviruses, which in some embodiments are classified as "variants of interest" or "variants of concern" by the World Health Organization (WHO) variants of concern)”. Mutated coronaviruses can have mutations in their spike glycoproteins, which can change viral properties, such as the severity or infectivity of COVID-19. WHO defines variants of concern as variants associated with one or more of the following changes from wild type to a degree of global public health significance: 1) Increased infectivity or adverse changes in the epidemiology of COVID-19 ; 2) Increased virulence or changes in clinical disease manifestations; or 3) Reduced effectiveness of public health and social measures, including available therapeutics, vaccines, and diagnostics. Variants of concern are defined by WHO as SARS-CoV-2 viruses that: 1) have genetic changes that are predicted or proven to affect viral properties, including immune escape, treatment escape, diagnostic escape, infectivity, and disease severity; and 2) It has been identified as causing significant community transmission or multiple COVID-19 clusters in multiple countries, with an increase in relative prevalence and number of cases over time, or other epidemiological impacts indicating new global public health risks . As of October 14, 2022, WHO classified a variant of concern (Ο), which includes the BA.1, BA.2, BA.3, BA.4, and BA.5 lineages and their descendants, as well as BA.1 /BA.2 reorganization form). As used herein, this variant may be interchangeably referred to as SARS-CoV-2 variant O, variant O SARS-CoV-2, SARS-CoV-2 O, and the like. Previously circulating variants of concern include alpha, beta, gamma and delta variants. Each variant can be defined by mutations in its spine protein compared to wild-type spine glycoprotein. For example, the O variant classified as B.1.1.529 contains the following mutations in its spine glycoprotein: A67V, Δ69-70, T95I, G142D/Δ143-145, Δ211/L212I, ins214EPE, G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y505H, T547K, D614G, H655Y, N679K, P681H, N764K, D796Y, N856 K, Q954H, N969K, and L981F (full length ΟSpinoglycoprotein: SEQ ID NO: 1072). Additionally, variants may have additional lineages covering a group of related viruses. In some embodiments, the antibodies and antigen-binding fragments thereof described herein can bind to any of these variants and/or lineages. In other embodiments, antibodies and antigen-binding fragments thereof can neutralize such variants and/or lineages. Methods to prevent and treat SARS-CoV-2 infection and COVID-19

The invention provides for prevention and treatment by administering one or more antigen-binding molecules that bind to surface proteins of SARS-CoV-2, including anti-SARS-CoV-2 spike glycoprotein antibodies or antigen-binding fragments thereof as discussed herein. Methods for SARS-CoV-2 infection and COVID-19 in those in need. In some cases, the subjects are hospitalized COVID-19 patients. In some cases, subjects are outpatients (i.e., ambulatory patients) who test positive for SARS-CoV-2 infection. In some cases, subjects are human patients with laboratory-confirmed SARS-CoV-2 and one or more symptoms of COVID-19, such as fever, cough, or shortness of breath. In some cases, the subjects are (a) human COVID-19 patients who require low-flow oxygen supply; (b) human COVID-19 patients who require high-intensity oxygen therapy but not mechanical ventilation; or (c) human COVID-19 patients who require mechanical ventilation. Human COVID-19 patients. In some cases, subjects are non-hospitalized humans with symptomatic COVID-19. In some cases, the subject is an uninfected human, such as an uninfected human in a group at high risk of exposure (such as health care workers or first responders) or a subject who has been closely exposed to a person infected with SARS-CoV-2 uninfected humans (such as roommates or family members who have been infected with COVID-19). In some cases, subjects are at high risk for COVID-19 complications or more likely to be infected with SARS-CoV-2, such as the elderly, immunocompromised people, and people who typically do not respond well to vaccines. In some embodiments, the present invention provides methods for treating, preventing, and reducing the severity or progression of SARS-CoV-2 infection and/or COVID-19.

In some embodiments, mAb10933 and mAb10987 (casirivimab and imdevimab, respectively) may be used in methods of prevention (e.g., pre-exposure prophylaxis or post-exposure prophylaxis) against symptomatic COVID-19. Cast to the object. In some embodiments, the subject is immunocompromised, eg, has an immunodeficiency, such as a primary or secondary immunodeficiency. In some embodiments, the subject has not responded effectively to COVID-19 vaccination. Illustrative criteria related to immune insufficiency include: active or recent treatment for solid tumors and hematologic malignancies; receipt of solid organ or recent hematopoietic stem cell transplantation; severe primary immunodeficiency; advanced or untreated HIV infection; Aggressive treatment with immunosuppressive or immunomodulatory high-dose corticosteroids, alkylating agents, antimetabolites, tumor necrosis (TNF) blockers, and other biologic agents; and chronic medical conditions, such as asplenia and chronic kidney disease, among others Some patients with these conditions may be associated with varying degrees of immune deficiency. In some embodiments, the subject meets ≥ 1 of the following criteria: a. Solid organ transplant (SOT) or hematopoietic blood cell transplant (HSCT) recipients receiving any immunosuppressive drugs b. Active hematological malignancy or treatment has been completed within 3 months c. Solid organ malignancies receive active treatment using T cell or B cell immunosuppressive therapy d. Moderate or severe primary immunodeficiency (such as hypogammaglobulinaemia, common variable immunodeficiency, severe combined immunodeficiency) e. HIV and CD4 <200 cells/microliter f. Patients with rheumatic diseases, autoimmune diseases, or multiple sclerosis receive immunosuppressive therapy to modulate Th1, Th17, or B cell responses g. Receiving any of the following immunosuppressive medications for more than 3 weeks: - T-cell inhibitors (e.g., ≥5 mg prednisone equivalent/day for >3 weeks), proteasome inhibitors (such as bortezomib, lenalidomide), alen monoclonal antibody (alemtuzumab), antithymocyte globulin, CAR-T therapy, calcineurin inhibitor) - Alkylating agent - Purine analogs such as fludarabine or cladribine - B cell depleting agents, such as rituximab and ocrelizumab - mTOR inhibitors - Anti-metabolites such as mycophenolate mofetil - JAK inhibitors.

The present invention also includes the use of antigen-binding molecules that bind to the surface protein of SARS-CoV-2, including the anti-SARS-CoV-2 spike glycoprotein antibodies or antigen-binding fragments thereof discussed herein, for the prevention and treatment of SARS-CoV. -2 infection and COVID-19 and/or used to treat, prevent and reduce the severity or progression of SARS-CoV-2 infection and/or COVID-19, or its symptoms. The present invention also includes the use of antigen-binding molecules that bind to the surface protein of SARS-Co-2, including the anti-SARS-CoV-2 spike protein antibodies discussed herein or antigen-binding fragments thereof, for use in prevention and treatment SARS-CoV-2 infection and COVID-19 and/or agents used to treat, prevent and reduce the severity or progression of 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 a first such antibody or antigen-binding fragment thereof for use in producing a combination with a second such antibody or antigen-binding fragment thereof The use of a medicament for use in combination, and the use of a second such antibody or antigen-binding fragment thereof for the manufacture of a medicament for use in combination with the first such antibody.

As used herein, a therapeutic or prophylactic agent (e.g., an anti-SARS-CoV-2 spike protein antibody) that "prevents" a disease or condition refers to a reduction in the number of treated agents in a statistical sample relative to an untreated control sample. A compound that delays the onset of a disorder or condition in a sample, or delays the onset of a disorder or condition relative to an untreated control sample. As used herein, the term "treating" includes ameliorating or eliminating a condition once established. In either case, prevention or treatment can be discerned in the diagnosis provided by a physician or other health care provider and the expected results of administering the therapeutic or preventive agent.

Generally, treatment or prevention of a disease or condition as described in this disclosure is accomplished by administering an effective amount of one or more anti-SARS-CoV-2 spike protein antibodies or antigen-binding fragments thereof. The effective amount of a pharmaceutical agent refers to the amount that is effective in achieving the desired therapeutic or preventive results at the necessary dose and time period. The therapeutically effective amount of an agent of the present disclosure may vary depending on factors such as the disease condition, age, gender, and weight of the individual, as well as the ability of the agent to elicit the desired response in the individual. The prophylactically effective amount refers to the amount that effectively achieves the desired preventive results at the necessary dose and time period.

In some embodiments, anti-SARS-CoV-2 spike protein antibodies or antigen-binding fragments thereof can be used to treat, prevent, or mitigate progression of SARS-CoV-2 infection or COVID-19. In some cases, anti-SARS-CoV-2 spike protein antibodies or antigen-binding fragments thereof block the interaction of the spike protein receptor binding domain (RBD) with angiotensin-converting enzyme 2 (ACE2), allowing infection of host cells. Sexuality is reduced. Blocking viral entry results in reduced SARS-CoV-2 RNA replication and shedding of the corresponding virus in infected tissues. Thus, in some embodiments, anti-SARS-CoV-2 spike protein antibodies or antigen-binding fragments thereof will reduce viral shedding in the upper respiratory tract. In some embodiments, 7 to 29 days after initiating dosing (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days after initiating dosing) , 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or 29 days) to measure viral shedding in samples collected from the patient’s upper respiratory tract. In some cases, reduction in SARS-CoV-2 viral shedding relative to baseline was determined by RT-qPCR in nasopharyngeal swab samples, nasal samples, or saliva samples.

In some cases, anti-SARS-CoV-2 spike protein antibodies or antigen-binding fragments thereof improve the clinical status of patients (e.g., patients diagnosed with SARS-CoV-2 infection or COVID-19). In some embodiments, improvement in clinical status is based on a 7-point ordinal scale for assessing changes in clinical status (grading clinical status from death [1] to non-hospitalization [7]). The use of an ordinal scale that incorporates multiple clinical outcomes of interest (e.g., death, mechanical ventilation, etc.) ranked by their clinical importance is used to assess efficacy in trials with severe and/or critically ill patients with COVID-19. appropriate measures. In some cases, administration of an anti-SARS-CoV-2 spike protein antibody or antigen-binding fragment thereof improved the patient's clinical status by at least 1 or 2 points. In some cases, administration of anti-SARS-CoV-2 spike glycoprotein antibodies or antigen-binding fragments thereof resulted in reduced mortality and/or oxygen therapy utilization, and/or increased ventilator-free days in such patients. As discussed above, the following ordinal scale can be used to assess improvement in clinical status: [1] Death [2] Hospitalization requiring invasive mechanical ventilation or ECMO [3] Hospitalization requiring non-invasive ventilation or high-flow oxygen device [4] Hospitalized, requiring supplemental oxygen [5] Hospitalization, no supplemental oxygen required - Continuous medical attention required (COVID-19 related or otherwise) [6] Hospitalization, no supplemental oxygen required - no longer requiring ongoing medical care [7] Not hospitalized.

In some cases, subjects experienced fewer than 5 COVID-19-related medical visits, telemedicine visits, hospitalizations, and/or intensive care visits after administration of anti-SARS-CoV-2 spike glycoprotein antibodies or antigen-binding fragments thereof Admission to the ward (ICU). In some cases, the subject exhibits less than 5 (e.g., less than 5, less than 4, less than 3, less than 2, or less than 1) COVID-19-related medical visits, telemedicine visits, hospitalizations, and/or intensive care units ( ICU) admission. In some embodiments, the subject exhibits fewer than 5 COVID-19 related visits during the 29-day period following administration of the first dose. In some cases, subjects presented with fewer than 4 COVID-19-related medical visits, telemedicine visits, hospitalizations, and/or intensive care unit (ICU) admissions. In some cases, subjects presented with fewer than 3 COVID-19-related medical visits, telemedicine visits, hospitalizations, and/or intensive care unit (ICU) admissions. In some cases, subjects presented with fewer than 2 COVID-19-related medical visits, telemedicine visits, hospitalizations, and/or intensive care unit (ICU) admissions. In some cases, subjects presented with no more than 1 COVID-19-related medical visit, telemedicine visit, hospitalization, and/or intensive care unit (ICU) admission.

In some cases, following administration of an anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment thereof, the subject becomes resistant to SARS-CoV-2 within 2 days to 3 weeks after the first administration of the therapeutic composition. Tested negative. In some cases, negative tests for SARS-CoV-2 were determined by RT-qPCR in nasopharyngeal swab samples, nasal samples, or saliva samples.

In any of the various embodiments discussed above or herein (e.g., prophylactic or therapeutic administration of the combination of mAb 10933 and mAb 10987), one or more anti-SARS-CoV-2 spike protein antibodies are administered. The results can be any one or more of the following: (a) Time-weighted mean reduction in viral shedding (log ₁₀ copies/ml) from baseline, as measured by RT-qPCR in nasopharyngeal (NP) swabs ; (b) Time-weighted mean viral shedding (log ₁₀ copies/ml) reduction from baseline, as measured by RT-qPCR in nasal swabs; (c) Time-weighted mean viral shedding (log ₁₀ copies/ml) ) Reduction from baseline, as measured by RT-qPCR in saliva samples; (d) At least 1 point improvement in clinical status from baseline using a 7-point ordinal scale; (e) COVID-19 related medical visits Decrease relative to controls (COVID-19 related medical visits are defined as follows: hospitalization, emergency room (ER) visit, urgent care visit, physician office visit, or telemedicine visit where the primary reason for the visit is COVID -19); (f) Reduced time to negative RT-qPCR in NP swabs in the absence of subsequent positive RT-qPCR relative to controls; (g) Reduced incidence of hospitalization or number of days in hospital relative to controls ; (h) Relative to controls, the incidence of ICU admission or days spent in ICU is reduced; (i) Relative to controls, the incidence of mechanical ventilation or time spent on mechanical ventilation is reduced; (j) Relative to controls, COVID- 19 Reduction in duration of symptoms; (k) In the absence of subsequent positive RT-qPCR in any test sample (nasopharyngeal swab, nasal swab, saliva), the number of negative RT-qPCR in all test samples relative to the control Reduction in time; (l) Reduction in the incidence of subsequent development of signs or symptoms of SARS-CoV-2 infection (strictly or broadly); (m) Reduction in time-weighted average daily viral load (e.g., by day 7 A decrease of 0.4 or more log10 copies/ml, a decrease of 0.5 or more log10 copies/ml by day 7, or a decrease of 0.6 or more log10 copies/ml by day 7, or a decrease of 0.5 or more log10 copies/ml by day 11 copies/ml, a reduction of 0.6 or more log10 copies/ml by day 11, or a reduction of 0.7 or more log10 copies/ml by day 11); and (n) reduction in time-weighted average viral load from baseline (log10 copies/ml).

In some embodiments, administration of anti-SARS-CoV-2 spike glycoprotein antibodies can be compared to subjects who do not have effective amounts of existing anti-SARS-CoV-2 antibodies in their blood ("seronegative" subjects). The impact is greater in subjects with effective amounts of existing anti-SARS-CoV-2 antibodies ("seropositive" subjects). In the example provided here, serostatus (i.e., seronegative, seropositive, or undetermined) was determined by assessing the presence of serum anti-SARS-CoV-2 antibodies: anti-Echinacea [S1] IgA (Euroimmun IgA test) , anti-thorn [S1] IgG (Euroimmun IgG test) and anti-nucleocapsid IgG (Abbot IgG test). Study participants were analyzed by grouping seronegative (if all available tests were negative), seropositive (if any test was positive), or seroconclusive (missing or indeterminate results). If the antibodies in the sample are below the test's lower limit of quantitation, the test is classified as negative. As described herein, the methods described herein may have differential effects (e.g., greater viral load reduction, faster time to symptom relief, fewer drug administrations) in seronegative subjects relative to a comparable population of seropositive subjects. post-medical visit). Antigen-binding molecules and anti-SARS-CoV-2 spike glycoprotein antibodies

The methods and uses of the present invention utilize antigen-binding molecules that bind surface proteins of SARS-CoV-2. In some embodiments, the antigen-binding molecule is an anti-SARS-CoV-2 spike protein antibody or an antigen-binding fragment thereof.

The amino acid and nucleotide sequences of the variable regions, CDRs, and heavy 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 for the 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 are suitable for use in the methods described herein are found in U.S. Patent No. 10,787,501, which is incorporated herein by reference in its entirety. [Table 1 ]: Amino acid sequence identifier SEQ ID NO Antibody name HCVR HCDR1 HCDR2 HCDR3 LCVR LCDR1 LCDR2 LCDR3 HC LC mAb10933 2 4 6 8 10 12 14 16 18 20 mAb10987 twenty two twenty four 26 28 30 32 34 36 38 40 mAb10989 42 44 46 48 50 52 34 54 56 58 mAb10985 73 75 77 79 81 83 85 87 89 91 [Table 2 ]: Nucleic acid sequence identifier SEQ ID NO Antibody name HCVR HCDR1 HCDR2 HCDR3 LCVR LCDR1 LCDR2 LCDR3 HC LC mAb10933 1 3 5 7 9 11 13 15 17 19 mAb10987 twenty one twenty three 25 27 29 31 33 35 37 39 mAb10989 41 43 45 47 49 51 33 53 55 57 mAb10985 72 74 76 78 80 82 84 86 88 90

In various embodiments, an anti-SARS-CoV-2 spike protein antibody or antigen-binding fragment for use in the methods or uses discussed herein is six CDRs comprising any one or more of the antibodies listed in Table 1 (HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) antibody or antigen-binding fragment. In some cases, an anti-SARS-CoV-2 spike protein antibody or antigen-binding fragment includes a CDR pair of a heavy chain variable region (HCVR) and a light chain variable region, the heavy chain variable region (HCVR) and the light chain variable region The variable region pair includes an amino acid sequence selected from the group consisting of SEQ ID NO: 2/10, 22/30, 42/50 and 73/81. Methods and techniques for identifying CDRs within the 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, for example, the Kabat definition, the Chothia definition, and the AbM definition. In general, the Kabat definition is based on sequence variability, the Chothia definition is based on the position of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia methods. See, for example, Kabat, "Sequences of Proteins of Immunological Interest", National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et al., J Mol Biol 273 :927-948 (1997); and Martin et al., PNAS (USA) 86:9268-9272 (1989). Public databases can also be used to identify CDR sequences within antibodies.

In some embodiments, the anti-SARS-CoV-2 spike protein antibody or antigen-binding fragment comprises HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 domains, each of which domains are selected from the group consisting of SEQ ID NO: 4-6-8 -Amino groups of the group consisting of 12-14-16, 24-26-28-32-34-36, 44-46-48-52-34-54, and 75-77-79-83-85-87 acid sequence.

In some embodiments, the anti-SARS-CoV-2 spike protein antibody or antigen-binding fragment comprises an HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NO: 2/10, 22/30, 42/50, And the amino acid sequence of the group consisting of 73/81.

In some embodiments, the anti-SARS-CoV-2 spike protein antibody comprises a heavy chain (HC) and a light chain (LC) pair selected from the group consisting of SEQ ID NO: 18/20, 38/40, 56/58, and the amino acid sequence of the group consisting of 89/91.

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

In some embodiments, the anti-SARS-CoV-2 spike protein antibody is mAb10933. In some embodiments, the anti-SARS-CoV-2 spike protein antibody is mAb10987. In some embodiments, the anti-SARS-CoV-2 spike protein antibody is mAb10989. In various embodiments, the anti-SARS-CoV-2 spike protein antibody is an antibody comprising the CDRs, HCVR and LCVR or heavy and light chains of mAb10933 (eg, the amino acid sequences shown in Table 1). In various embodiments, the anti-SARS-CoV-2 spike protein antibody is an antibody comprising the CDRs, HCVR and LCVR or heavy and light chains of mAb10987 (eg, the amino acid sequences shown in Table 1). In various embodiments, the anti-SARS-CoV-2 spike protein antibody is an antibody comprising the CDRs, HCVR and LCVR or heavy and light chains of mAb10989 (eg, the amino acid sequences shown in Table 1). Antibodies provided herein may be interchangeably identified as "mAb" followed by a number or "REGN" followed by a number. For example, mAb10933 and REGN10933 refer to the same antibody (amino acid sequence provided in Table 1 and nucleic acid sequence provided in Table 2). Similarly, mAb10987 and REGN10987 are equivalent, mAb10989 and REGN10989 are equivalent, and mAb10985 and REGN10985 are equivalent. Additionally, mAb10933 may be referred to as casirumab and mAb10987 may be referred to as idelimumab. The combination of casirumab and idelimumab is called REGEN-COV.

In some embodiments, the methods and uses discussed herein include compositions comprising a first antigen-binding molecule (eg, an antibody) that binds a first epitope on a surface protein of SARS-CoV-2, and that binds SARS-CoV-2. - a second antigen-binding molecule (such as an antibody) for a second epitope on the surface protein of CoV-2, wherein the first epitope and the second epitope do not overlap structurally. In some embodiments, the methods and uses discussed herein include combinations of two or more anti-SARS-CoV-2 spike glycoprotein antibodies or antigen-binding fragments thereof. In some cases, two antibodies or antigen-binding fragments used in combination bind to structurally non-overlapping epitopes of the RBD. In some embodiments, the combination includes mAbl0987 and mAb10933. In some embodiments, the combination includes mAbl0987 and mAbl0989. In some embodiments, the combination includes mAbl0933 and mAbl0987 and mAbl0985. In various embodiments, the combination includes a first anti-SARS-CoV-2 spike glycoprotein antibody that is a CDR, HCVR and LCVR or heavy and light chain comprising mAb10933 (e.g., the amino acid sequence shown in Table 1 ); and a second anti-SARS-CoV-2 spike protein antibody, which is an antibody comprising the CDR, HCVR and LCVR or heavy chain and light chain of mAb10987 (e.g., the amino acid sequence shown in Table 1) ; and optionally a third anti-SARS-CoV-2 spike glycoprotein antibody that includes the CDR, HCVR and LCVR or heavy and light chains of mAb10985 (e.g., the amino acid sequence shown in Table 1) antibody. In various embodiments, the combination includes a first anti-SARS-CoV-2 spike protein antibody that is a CDR, HCVR and LCVR or heavy and light chain comprising mAb10989 (e.g., the amino acid sequence shown in Table 1 ); and a second anti-SARS-CoV-2 spike protein antibody, which is an antibody comprising the CDR, HCVR and LCVR or heavy chain and light chain of mAb10987 (e.g., the amino acid sequence shown in Table 1) . In some embodiments, combinations of antigen-binding molecules (e.g., antibodies such as mAbl0987 and mAbl0933, mAbl0987 and mAbl0989, or mAb10987, and mAb10933 and mAbl0985) can reduce the risk of escape mutants (eg, having one or more mutations in the S protein SARS-CoV-2 virus, which reduces the efficacy of treatment, for example by weakening the binding of antibodies to the S protein) frequency. Identification of escape variants after two passages in cell cultures of recombinant VSV encoding SARS-CoV-2 spike protein in the presence of mAb10933 (casirimab) or mAb10987 (idelimab) alone, but Escape variants were not identified after two passages in the presence of both casirimab and idelimumab. This antibody combination is also effective against mutated SARS-CoV-2 viruses. For example, the combination of mAb10933 and mAb10987 was evaluated for their ability to neutralize pseudotyped VSV manifesting a SARS-CoV-2 variant known as B.1.1.7, also known as the "UK variant." This variant amplifies rapidly and may have different effects than wild-type SARS-CoV-2, including more severe symptoms than wild-type virus and potential resistance to vaccines and/or therapeutics. They are classified in part by the following mutations in the spike protein: HV 69-70 deletion, Y144 deletion, N501Y, A570D, P681H, T716I, S982A, and D1118H. The combination of casirumab and idelimumab was shown to effectively neutralize the virus (Figure 29). Indeed, casirimab and idelimab, individually and together, retain protection against pseudoviruses exhibiting all spike protein substitutions found in the B.1.1.7 lineage (UK origin) and against B.1.1.7 and other circulating lineages Only the neutralizing activity of the pseudovirus N501Y was found. Casirimab and idelimumab together retain neutralizing activity against pseudoviruses exhibiting all spike protein substitutions or individual substitutions K417N, E484K or N501Y found in the B.1.1351 lineage (South African origin), and against P.1 Neutralizing activity of K417T+E484K found in the lineage (Brazilian origin), although casirumab alone, but not idelimumab, had reduced activity against pseudoviruses expressing K417N or E484K, as indicated above. The E484K substitution was also found in the B.1.526 lineage (New York origin).

[surface 3A ]: Casirimab and idelimab alone and together retain the efficacy against B.1.427/B.1.429 Found in Pedigree (California Origin) L452R Substituted neutralizing activity. mAb10933 mAb10987 mAb10933 + mAb10987 variant Refer to the IC50 reduction factor of SARS-CoV-2 D614G UK B.1.1.7 0.98 0.70 1.04

[Table 3B ]: Pseudovirus neutralization data of SARS-CoV-2 variant substitutions together with casirimab and idelimumab Lineages containing spike protein substitutions The key to testing susceptibility reduction factor B.1.1.7 (British origin) N501Y ^a No ^changec B.1.351 (South African origin) K417N, E484K, N501Y ^b No ^changec P.1 (Brazilian origin) K417T + E484K No ^changec B.1.427/B.1.429 (California origin) L452R No ^changec B.1.526 (New York origin) ^d E484K No ^{changec a} Test for a pseudovirus showing the entire mutant spike protein. Among the variants, the following mutations from wild-type spike protein were found: del69-70, del145, N501Y, A570D, D614G, P681H, T716I, S982A, and D1118H. ^b Test the pseudovirus showing the entire mutant spike protein. The following changes from wild-type spike protein were found in the variants: D80Y, D215Y, del241-243, K417N, E484K, N501Y, D614G, A701V. ^c No change: Susceptibility decreases <2 times. ^dNot all isolates of the New York lineage carry the E484K substitution (as of February 2021).

Certain variants exhibit reduced susceptibility to casirimab alone, including those with acanine amino acid substitutions K417E (182-fold), K417N (7-fold), K417R (61-fold), Y453F (>438-fold) , L455F (80 times), E484K (25 times), F486V (>438 times), and Q493K (>438 times). Variants showing reduced susceptibility to idelimumab alone include substitutions K444N (>755-fold), K444Q (>548-fold), K444T (>1,033-fold), and V445A (548-fold). Casirimab and idelimumab together demonstrated reduced susceptibility to substitutions with K444T (6-fold) and V445A (5-fold). In a neutralization analysis of VSV pseudotypes using 39 different spike protein variants identified in circulating SARS-CoV-2, variants with reduced susceptibility to casirimab alone included those with Q409E (4-fold ), G476S (5-fold) and S494P (5-fold) substitutions, and variants with reduced susceptibility to idelimab alone include variants with the N439K (463-fold) substitution. Additional substitutions tested in pseudovirus assays that reduced activity against casirimab alone included E484Q (9-fold) and Q493E (446-fold). Casirimab and idelimumab 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 SARS-CoV-2 is a variant SARS-CoV-2, e.g., comprising 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 that only one variant (G446V) was present in alleles at a frequency of ≥15% and was detected in 3/66 subjects with nucleotide sequencing data, each in Single time point (both at baseline in subjects from the placebo and 2,400 mg casirumab and idelimumab groups, and in subjects from the 8,000 mg casirimab and idelimumab groups one on the 25th day). In a VSV pseudoparticle neutralization assay, the G446V variant was 135-fold less susceptible to idelimumab compared with wild type, but retained sensitivity to casirimab alone and casirimab plus idelimumab. Anti-all susceptibility.

In some embodiments, the methods and uses discussed herein include compositions comprising a first antigen-binding molecule (eg, an antibody) that binds a first epitope on a surface protein of SARS-CoV-2, and that binds SARS-CoV-2. - A second antigen-binding molecule (such as an antibody) for a second epitope on the surface protein of CoV-2, wherein the first antigen-binding molecule and the second antigen-binding molecule can simultaneously bind to the surface protein of SARS-CoV-2.

In certain embodiments, one, two, three, four or more antibodies or antigen-binding fragments thereof may be administered in combination (eg, simultaneously or sequentially). Exemplary combinations include mAb10933 and mAb10987, mAb10989 and mAb10987, mAb10933 and mAb10989, mAb10933 and mAb10987 and mAb10985.

As used herein, "antibody that binds SARS-CoV-2 spike protein" or "anti-SARS-CoV-2 spike protein antibody" or "anti-SARS-CoV-2 spike protein antibody" includes antibodies that bind SARS-CoV-2 spike protein. Antibodies and their antigen-binding fragments are soluble fragments of the protein and can also bind to epitopes within the receptor binding domain (RBD) of spike protein. Other antibodies that may be used alone or in combination with each other or with one or more of the antibodies disclosed herein for use in the methods of the present disclosure include, for example, 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).

The term "antibody" means any antigen-binding molecule or molecular complex that contains at least one complementarity-determining region (CDR) that specifically binds to or interacts with a specific antigen (eg, SARS-CoV-2 spike protein). The term "antibody" includes immunoglobulin molecules containing four polypeptide chains (two heavy (H) chains and two light (L) chains) interconnected by disulfide bonds, as well as multimers thereof (e.g., IgM) . Each heavy chain includes a heavy chain variable region (abbreviated herein as HCVR or _VH ) and a heavy chain constant region. The heavy chain constant region contains three domains, _CH1 , _CH2 and _CH3 . Each light chain includes a light chain variable region (abbreviated herein as LCVR or _VL ) and a light chain constant region. The light chain constant region contains one domain ( _CL 1). The _VH and _VL regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs), interspersed with more conservative regions called framework regions (FRs). Each V _H and V _L consists of three CDRs and four FRs arranged in the following order from the amine end to the carboxyl end: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments of the present invention, the FR of the anti-SARS-CoV-2 spike protein antibody (or the antigen-binding portion thereof) may be identical to the human germline sequence or may be naturally or artificially modified. Amino acid consensus sequences can be defined based on the side-by-side analysis of two or more CDRs.

As used herein, the term "antibody" also includes antigen-binding fragments of intact antibody molecules. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and similar terms include any naturally occurring substance that specifically binds an antigen to form a complex. , Polypeptides or glycoproteins that can be obtained, synthesized or genetically engineered by enzymatic methods. Antigen-binding fragments of an antibody may be derived, for example, from intact antibody molecules using any suitable standard technique, such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding the antibody variable domains and, optionally, constant domains. Such DNA is known and/or readily purchased from, for example, commercial sources, DNA libraries (including, for example, phage-antibody libraries), or may be synthesized. DNA can be sequenced and manipulated chemically or by using molecular biology techniques, such as arranging one or more variable domains and/or constant domains into a suitable configuration, or introducing codons to produce cysteine residues , modify, add or delete amino acids, etc.

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) a dAb fragment; and (vii) a minimal recognition unit consisting of 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 restricted FR3- CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, bifunctional antibodies, trifunctional antibodies, tetrafunctional antibodies, minibodies, nanobodies (e.g., monovalent Nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceutical (SMIP) and shark variable IgNAR domains are also included in the expression "antigen-binding fragment" as used herein.

Antigen-binding fragments of antibodies will typically contain at least one variable domain. The variable domains may be of any size or amino acid composition and will generally contain at least one CDR adjacent or in frame with one or more framework sequences. In an antigen-binding fragment having a _{VH domain} associated with a VL domain, the _VH and _VL domains may be positioned relative to each other in any suitable arrangement. For example, the variable region can be dimeric and contain VH- _VH , _VH - _{VL ,} or _VL - _VL dimers. Alternatively, antigen-binding fragments of antibodies may contain monomeric _VH or _VL domains.

In certain embodiments, an antigen-binding fragment of an antibody can 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 the antigen-binding fragments of the antibodies of the invention include: (i) _VH - _CH1 ; (ii) VH-CH2; (i) _VH - _CH2 ; iii) V _H -C _H 3; (iv) V _H -C _H 1-C _H 2; (v) V _H -C _H 1-C _H 2-C _H 3; (vi) V _H -C _H 2 -C _H 3; (vii) V _H -C _L ; (viii) V _L -C _H 1; (ix) V _L -C _H 2; (x) V _L -C _H 3; (xi) V _L - CH _{1 -CH} 2; (xii) V _{L -CH} 1 _-CH 2 _-CH 3; (xiii) V _{L -CH} 2 -CH ₃ ; and (xiv) V _L -C _L . In any configuration of variable and constant domains, including any of the illustrative configurations listed above, the variable and constant domains may be directly connected to each other or may be connected by a complete or partial hinge region or area connection. The hinge region may consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids in adjacent variable domains and/or constants in a single polypeptide molecule. Flexible or semi-flexible connections are created between domains. Furthermore, antigen-binding fragments of the antibodies of the invention may comprise homodimers or heterodimers (or other multimers) of any of the variable domain and constant domain configurations listed above, which are mutually exclusive. and/or non-covalently associated with one or more monomeric _VH or _VL domains (e.g., via disulfide bonds (S)).

Like intact antibody molecules, antigen-binding fragments can be monospecific or multispecific (eg, bispecific). Multispecific antigen-binding fragments of an antibody will typically comprise at least two different variable domains, where 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 the antigen-binding fragments of the antibodies of the invention using routine techniques available in the art.

In certain embodiments of the invention, the anti-SARS-CoV-2 spike protein of the antibody of the invention is a human antibody. As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the invention may include, for example, amino acid residues in CDRs and in particular CDR3 that are not encoded by human germline immunoglobulin sequences (e.g., induced by random or site-specific mutagenesis in vitro or by in vivo Mutations introduced by somatic mutations in vivo). However, as used herein, the term "human antibody" 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.

In some embodiments, the antibodies of the invention can be recombinant human antibodies. As used herein, the term "recombinant human antibody" is intended to include all human antibodies prepared, expressed, produced or isolated by recombinant means, such as antibodies expressed using recombinant expression vectors transfected into host cells (described further below); Antibodies isolated from recombinant combinatorial human antibody libraries (described further below); antibodies isolated from animals (e.g., mice) that are transgenic for human immunoglobulin genes (see, e.g., Taylor et al., Nucl Acids Res 20: 6287-6295 (1992)) or by any other means involving splicing of human immunoglobulin gene sequences to other DNA sequences, antibodies prepared, expressed, produced or isolated. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies can be subjected to in vitro mutagenesis (or in vivo somatic mutagenesis when transgenic animals using human Ig sequences are used), and therefore the _V of the recombinant antibody Although the amino acid sequences of the and _VL regions are derived from and related to human germline _VH and _VL sequences, they may not be sequences naturally present in the germline antibody library of human antibodies in vivo.

Human antibodies can exist in two forms related to hinge heterogeneity. In one form, the immunoglobulin molecule contains a stable four-chain construct of approximately 150-160 kDa, in which dimers are held together by interchain heavy chain disulfide bonds. In the second form, the dimers are not linked via interchain disulfide bonds and form a molecule of approximately 75-80 kDa (a half-antibody) consisting of covalently coupled light and heavy chains. These forms have been extremely difficult to isolate, even after affinity purification.

The frequency of occurrence of the second form in the various intact IgG isotypes is due to, but is not limited to, structural differences associated with the hinge region isotype of the antibody. Single amino acid substitutions in the hinge region of the human IgG4 hinge can significantly reduce the occurrence of the second form (Angal et al. Molecular Immunology 30:105 1993) to the amount observed using the human IgG1 hinge. The invention encompasses antibodies having one or more mutations in the hinge, _CH2 or _CH3 region, which may be desirable, for example, in production to increase the yield of the desired antibody form.

Antibodies of the invention may be isolated antibodies. As used herein, "isolated antibody" 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 is isolated or removed from at least one component of an organism or from a tissue or cell in which the antibody is naturally present or naturally produced is an "isolated antibody" for the purposes of this invention. Isolated antibodies also include antibodies in situ within recombinant cells. An isolated antibody is an antibody that has undergone at least one purification or isolation step. According to certain embodiments, isolated antibodies may be substantially free of other cellular material and/or chemicals.

The present invention includes neutralizing and/or blocking anti-SARS-CoV-2 spike protein antibodies. As used herein, "neutralizing" or "blocking" antibodies are intended to refer to antibodies that bind to the SARS-CoV-2 spike protein and have the following effects: (i) Inhibits the activity of the protein to any detectable extent, such as inhibiting the ability of SARS-CoV-S to bind to a receptor (such as ACE2), be cleaved by a protease (such as TMPRSS2), or mediate viral entry into a host cell or viral replication in a host cell .

The anti-SARS-CoV-2 spike protein antibodies disclosed herein may include one or more amine groups in the framework and/or CDR regions of the heavy and light chain variable domains compared to the corresponding germline sequences of the derived antibodies. Acid substitutions, insertions and/or deletions. Such mutations can be readily determined by comparing the amino acid sequences disclosed herein with germline sequences purchased from, for example, public antibody sequence databases. The invention includes antibodies and antigen-binding fragments thereof derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework regions and/or CDR regions are mutated to a derivative The corresponding residues of the germline sequence of the antibody are either mutated to the corresponding residues of another human germline sequence, or are mutated to conservative amino acid substitutions of the corresponding germline residues (such sequence changes are collectively referred to herein as " germline mutations"). One of ordinary skill in the art can readily generate a variety of antibodies and antigen-binding fragments containing one or more individual germline mutations or combinations thereof, starting from the heavy and light chain variable region sequences disclosed herein. In certain embodiments, all framework and/or CDR residues within the _VH and/or _VL domains are mutated back to residues found in the original germline sequence of the derived antibody. In other embodiments, only certain residues are mutated back to the original germline sequence, such as only the mutated residues found within 8 amino acids before FR1 or 8 amino acids after FR4, or only CDR1, CDR2, or Mutated residues found within CDR3. In other embodiments, one or more of the framework and/or CDR residues are mutated to the corresponding residues of a different germline sequence (ie, a germline sequence that is different from the germline sequence from which the antibody was originally derived). In addition, the antibodies of the invention may contain any combination of two or more germline mutations within the framework and/or CDR regions, for example, in which certain individual residues are mutated to the corresponding residues of a specific germline sequence, but not Certain other residues in the original germline sequence remain unchanged or are mutated into corresponding residues in a different germline sequence. Once obtained, antibodies and antigen-binding fragments containing one or more germline mutations can be readily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, improved or enhanced antagonism or agonism. Biological properties (depending on specific circumstances), reduced immunogenicity, etc. Antibodies and antigen-binding fragments obtained in this general manner are encompassed by the invention.

The invention also includes anti-SARS-CoV-2 spike protein antibodies that comprise variants of any of the HCVR, LCVR and/or CDR amino acid sequences disclosed herein with one or more conservative substitutions. For example, the invention includes anti-SARS-CoV-2 spike protein antibodies that have, for example, 10 or fewer amino acid sequences relative to any of the HCVR, LCVR and/or CDR amino acid sequences disclosed herein. HCVR, LCVR and/or CDR amino acid sequences with 8 or less, 6 or less, 4 or less, etc. conservative amino acid substitutions.

The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule, called a paratope. A single antigen can have more than one epitope. Therefore, different antibodies can bind to different regions on the antigen and can have different biological effects. Epitopes can be conformational or linear. Conformational epitopes result from the spatial juxtaposition of amino acids from different segments of a linear polypeptide chain. Linear epitopes are epitopes arising from adjacent amino acid residues in a polypeptide chain. In some cases, epitopes may include carbohydrate, phosphoryl, or sulfonyl moieties on the antigen.

When referring to a nucleic acid or a fragment thereof, the term "substantial identity" or "substantially identical" indicates that it is consistent with the insertion or deletion of the appropriate nucleotide via another nucleic acid (or its complementary strand). Optimally aligned, nucleotide sequence identity exists in at least about 95%, and more preferably at least about 96%, 97%, 98%, or 99% of the nucleotide bases, as discussed below Sequence identity is measured by any well-known algorithm such as FASTA, BLAST or Gap. In some cases, a nucleic acid molecule that is substantially identical to a reference nucleic acid molecule may encode a polypeptide having the same or substantially similar amino acid sequence as the polypeptide encoded by the reference nucleic acid molecule.

As applied to polypeptides, the term "substantial similarity" or "substantially similar" means that two peptide sequences are optimally aligned, such as by the program GAP or BESTFIT, using preset gap weights. , share at least 95% sequence identity, even better at least 98% or 99% sequence identity. Preferably, the differences in inconsistent residue positions are conservative amino acid substitutions. "Conservative amino acid substitution" is one in which an amino acid residue is replaced by another amino acid residue that has a side chain (R group) with similar chemical properties (such as charge or hydrophobicity). Substituted amino acid substituted. Generally speaking, conservative amino acid substitutions will not materially alter the functional properties of the protein. Where two or more amino acid sequences differ from each other due to conservative substitutions, the percent sequence identity or degree of similarity can be adjusted upward to correct for the conservative nature of the substitutions. The manner in which this adjustment is made is well known to those skilled in the art. See, eg, Pearson, W.R., Methods Mol Biol 24: 307-331 (1994), incorporated herein by reference. Examples of amino acid groups with chemically similar side chains include (1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; (2) aliphatic- Hydroxy side chain: serine and threonine; (3) Amide-containing side chain: asparagine and glutamic acid; (4) Aromatic side chain: phenylalanine, tyrosine and tryptophan; (5) Basic side chains: lysine, arginine and histidine; (6) Acidic side chains: aspartic acid and glutamine; and (7) Sulfur-containing side chains are cysteine and methionine. Preferable conservative amino acid substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamic acid -Aspartic acid and asparagine-glutamic acid. Alternatively, a conservative substitution is any change that has a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al., Science 256: 1443-1445 (1992), which is incorporated by reference. "Moderately conservative" is replaced by any change that has a non-negative value in the PAM250 log-likelihood matrix.

Sequence similarity (also known as sequence identity) of polypeptides is often measured using sequence analysis software. Protein analysis software matches similar sequences using a measure of similarity assigned to various substitutions, deletions, and other modifications, including conservative amino acid substitutions. For example, GCG software contains programs such as Gap and Bestfit, which can be used under preset parameters to determine whether closely related polypeptides (such as homologous polypeptides from different species of organisms) or wild-type proteins and their mutant proteins Sequence homology or sequence identity between them. See e.g. GCG version 6.1. Peptide sequences can also be compared using FASTA (program in GCG version 6.1) using preset or recommended parameters. FASTA (e.g., FASTA2 and FASTA3) provides alignments and percent sequence identity of the best regions of overlap between query and search sequences (see, e.g., Pearson, W.R., Methods Mol Biol 132: 185-219 (2000), which incorporated herein by reference). When comparing sequences of the present invention to databases containing a large number of sequences from different organisms, another preferred algorithm is the use of the computer program BLAST with preset parameters, especially BLASTP or TBLASTN. See, for example, Altschul et al., J Mol Biol 215:403-410 (1990) and Altschul et al., Nucleic Acids Res 25:3389-402 (1997), each incorporated herein by reference. specific binding

As used herein, the term "specifically binds" or the like means that an antigen-specific binding protein or antigen-specific binding domain forms with a specific antigen characterized by a dissociation constant (K _D ) of 50 nM or less. complex and does not bind other unrelated antigens under normal test conditions. "Unrelated antigen" is a protein, peptide or polypeptide that has less than 95% amino acid identity with each other. Methods for determining whether two molecules specifically bind to each other 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 antigen-specific binding domain as used in the context of the present invention includes molecules that bind a specific 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 K _D 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 surface plasmon resonance analysis.

As used herein, the term "surface plasmon resonance" refers to an optical phenomenon that allows, for ^example , the detection of biological Changes in protein concentration within the sensor matrix are used to analyze real-time interactions.

As used herein, the term " _KD " means the equilibrium dissociation constant of a particular protein-protein interaction (eg, antibody-antigen interaction). Unless otherwise indicated, K _D values disclosed herein refer to K _D values determined by surface plasmon resonance analysis at 25 ºC. Antibodies Comprising Heavy Chain Constant Region Variants

According to certain embodiments of the present invention, anti-SARS-CoV-2 spike protein antibodies are provided that include an Fc domain that includes one or more Fc domains that enhance or weaken binding of the antibody to the FcRn receptor (e.g., relative to neutral pH). ratio, at acidic pH). For example, the invention includes anti-SARS-CoV-2 spike protein antibodies comprising mutations in the _CH2 or _CH3 region of the Fc domain, wherein the mutations increase an acidic environment (e.g., wherein the pH is in the range of about 5.5 to about 6.0 The affinity between the Fc domain and FcRn in endosomes. Such mutations can result in an increase in the serum half-life of the antibody when administered to animals. Non-limiting examples of such Fc modifications include, for example, at positions 250 (e.g., E or Q), 250 and 428 (e.g., L or F), 252 (e.g., L/Y/W/W or T), 254 (e.g., S or T), and 256 (such as S/R/Q/E/D or T); or at positions 428 and/or 433 (such as H/L/R/S/P/Q or K) and/ or modifications at 434 (such as H/L/R/S/P/Q or K) and/or 434 (such as A, W, H, F or Y [N434A, N434W, N434H, N434F or N434Y]); or Modifications at positions 250 and/or 428; or modifications at positions 307 or 308 (e.g., 308F, V308F) and 434. In one embodiment, the modifications include 428L (e.g., M428L) and 434S (e.g., N434S) modifications; 428L, 259I (e.g., V259I), and 308F (e.g., V308F) modifications; 433K (e.g., H433K) and 434 (e.g., 434Y) modifications; 252 , 254 and 256 (such as 252Y, 254T and 256E) modifications; 250Q and 428L modifications (such as T250Q and M428L); and 307 and/or 308 modifications (such as 308F or 308P). In yet another embodiment, the modifications include 265A (eg, D265A) and/or 297A (eg, N297A) modifications.

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

In various embodiments, anti-SARS-CoV-2 spike protein antibodies comprise a combination of heavy chain constant region sequences derived from more than one immunoglobulin isotype. For example, a chimeric heavy chain constant region may comprise part or all of the CH2 sequence derived from a human IgG1, human IgG2, or human IgG4 _CH2 region, and part or all of a _CH2 sequence derived from human IgG1, human IgG2, or human IgG4 _CH3 sequence. Chimeric heavy chain constant regions may also contain chimeric hinge regions. For example, a chimeric hinge may comprise an "upper hinge" sequence derived from a human IgG1, human IgG2 or human IgG4 hinge region in combination with a "lower hinge" sequence derived from a human IgG1, human IgG2 or human IgG4 hinge region. Specific examples of chimeric heavy chain constant regions that may be included in any of the antibodies described herein include from N-terminus to C-terminus: [IgG4 _CH 1] - [IgG4 upper hinge] - [IgG2 lower hinge] -[IgG4 CH2]-[IgG4 CH3]. Another example of a chimeric heavy chain constant region that may be included in any of the antibodies described herein includes from N-terminus to C-terminus: [IgG1 _CH 1]-[IgG1 upper hinge]-[IgG2 lower hinge ]-[IgG4 CH2]-[IgG1 CH3]. These and other examples of chimeric heavy chain constant regions that may be included in any of the antibodies of the invention are described in WO 2014/121087 (8550-WO). Chimeric heavy chain constant regions and variants thereof with these general structural arrangements can have altered Fc receptor binding, which in turn affects Fc effector function.

In various embodiments, anti-SARS-CoV-2 spike protein antibodies comprise a heavy chain constant region including a hinge domain, wherein 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, positions are numbered by EU number. Optionally, the heavy chain constant region includes a hinge domain, a CH2 domain and a CH3 domain from the N-terminus to the C-terminus. Optionally, the heavy chain constant region includes a CH1 domain, a hinge domain, a CH2 domain and a CH3 domain from the N-terminus to the C-terminus. As appropriate, the CH1 region (if present), the remainder of the hinge region (if present), the CH2 region and the CH3 region are of the same human isotype. Optionally, the CH1 region (if present), the remainder of the hinge region (if present), the CH2 region and the CH3 region are human IgG1. Optionally, the CH1 region (if present), the remainder of the hinge region (if present), the CH2 region and the CH3 region are human IgG2. Optionally, the CH1 region (if present), the remainder of the hinge region (if present), the CH2 region and the CH3 region are human IgG4. 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 may be included in any of the antibodies of the invention are described in WO 2016/161010 (10140WO01). Epitope mapping and related technologies

The invention includes anti-SARS-CoV-2 spike protein antibodies that interact with one or more amino acids found within the SARS-CoV-2 spike protein (eg, within the spike protein RBD). The epitope to which the antibody binds can consist of 3 or more (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17) located within the RBD of the spike protein. , 18, 19, 20 or more) consisting of a single continuous sequence of amino acids. Alternatively, the epitope may consist of a plurality of non-contiguous amino acids (or amino acid sequences) located within the RBD of the spike protein.

Various techniques known to those 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, for example, conventional cross-blocking assays such as those described in Antibodies, Harlow and Lane (Cold Spring Harbor Press, Cold Spring Harb., NY); alanine scanning mutational analysis; peptide blot 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 used (Tomer, Protein Science 9:487-496 (2000)). Another method that can be used to identify amino acids within polypeptides that interact with antibodies is hydrogen/deuterium exchange detected by mass spectrometry. Generally speaking, hydrogen/deuterium exchange methods involve deuterium labeling of a protein of interest and subsequent binding of an antibody to the deuterium-labeled protein. Subsequently, the protein/antibody complexes were transferred to water to allow hydrogen-deuterium exchange to occur at all residues except the antibody-protected residues (which remained deuterated). After antibody dissociation, the target protein is subjected to protease cleavage and mass spectrometry analysis, thereby revealing deuterium-labeled residues corresponding to specific amino acids that interact with the antibody. See, for example, Ehring, Analytical Biochemistry 267(2):252-259 (1999); Engen and Smith, Anal. Chem. 73:256A-265A (2001).

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

One can readily determine whether the antibody binds to the same epitope as the reference anti-SARS-CoV-2 spike protein antibody, or to the same epitope as the reference anti-SARS-CoV-2 spike protein, by using conventional methods known in the art and exemplified herein. Antibodies compete for binding. For example, to determine whether a test antibody binds to the same epitope as a reference anti-SARS-CoV-2 spike protein antibody discussed herein, the reference antibody is bound to SARS-CoV-2 spike protein. The test antibodies are then assessed for their ability to bind to the SARS-CoV-2 spike protein. If the test antibody is able to bind to the SARS-CoV-2 spike protein after saturating with the reference anti-SARS-CoV-2 spike protein antibody, it can be concluded that the test antibody binds to the reference anti-SARS-CoV-2 spike protein antibody. Different epitopes. On the other hand, if the test antibody is unable to bind to the SARS-CoV-2 spike protein after saturating with the reference anti-SARS-CoV-2 spike protein antibody, the test antibody may bind to the reference anti-SARS-CoV-2 spike protein antibody as discussed herein. 2 The same epitope that the spike protein antibody binds to. Other routine experiments (such as peptide mutagenesis and binding assays) can then be performed to confirm whether the observed lack of binding of the test antibody is actually due to binding to the same epitope as the reference antibody, or to steric blocking (or another phenomenon) whether it causes the observed lack of binding. Such experiments can be performed using ELISA, RIA, Biacore, flow cytometry, or any other quantitative or qualitative antibody binding assay available in the art. According to certain embodiments of the invention, if, for example, a 1, 5, 10, 20 or 100-fold excess of one antibody inhibits the binding of the other antibody by at least 50%, but preferably 75%, 90% or even 99% (e.g. (as measured in a competitive binding assay), the two antibodies bind to the same (or overlapping) epitope (see, eg, Junghans et al., Cancer Res. 50:1495-1502 (1990)). Alternatively, two antibodies are considered to bind to the same epitope if substantially all amino acid mutations in the antigen that reduce or eliminate binding by one antibody reduce or eliminate binding by the other antibody. Two antibodies are said 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 antibody. Preparation of human antibodies

Methods for producing monoclonal antibodies, including fully human monoclonal antibodies, are known in the art. Any such known method can be used in the context of the present invention to produce human antibodies that specifically bind to the SARS-CoV-2 spike protein.

High-affinity chimeric antibodies against the SARS-CoV-2 spike protein with human variable regions and mouse constant regions are first isolated using, for example, VELOCIMMUNE ^™ technology or any other known method for generating fully human monoclonal antibodies. Characterize and select antibodies for desired properties including affinity, selectivity, epitope, etc. When necessary, the mouse constant region is replaced with the desired human constant region (e.g., wild-type or modified IgG1 or IgG4) to generate fully human anti-SARS-CoV-2 spike protein antibodies. Although the constant region selected can vary depending on the specific application, high-affinity antigen binding and target-specific properties are present in the variable regions. In some cases, fully human anti-SARS-CoV-2 spike protein antibodies are isolated directly from antigen-positive B cells. bioequivalent

The anti-SARS-CoV-2 spike protein antibodies and antibody fragments of the present invention encompass proteins whose amino acid sequences differ from those of the described antibodies but retain the ability to bind SARS-CoV-2 spike protein. Such variant antibodies and antibody fragments contain one or more amino acid additions, deletions, or substitutions but exhibit biological activities that are substantially equivalent to that of the described antibodies when compared to the parent sequence. Likewise, DNA sequences encoding anti-SARS-CoV-2 spike protein antibodies of the present invention include one or more nucleotide additions, deletions, or substitutions when compared to the disclosed sequences, but encode substantially bioequivalent The sequence of the anti-SARS-CoV-2 spike protein antibody or antibody fragment of the present invention.

For example, two antibodies are pharmaceutical equivalents or pharmaceutical substitutes that do not show significant differences in the rate and extent of absorption when administered at the same molar dose in single or multiple doses under similar experimental conditions. Considered bioequivalent. Some antibodies are considered equivalents or pharmaceutical substitutes and may be considered bioequivalent if they are comparable in degree of absorption but not rate of absorption because of such differences in absorption rate. Differences are intentional and reflected in the labeling, are not necessary to achieve effective subject drug concentrations in, for example, chronic use, and are not considered medically inconsequential for the particular drug under study.

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

In one embodiment, if a patient can switch between a reference product and a biologic product one or more times without having an increased risk of expected side effects, including clinically significant immune response, compared to continued therapy without such switching, Two antibodies are bioequivalent if there is a change in originality or diminished effectiveness.

In one embodiment, two antibodies are bioequivalent if they both act through one or more common mechanisms of action (provided such mechanisms are known) for one or more conditions of use.

Bioequivalence can be demonstrated by in vivo and in vitro methods. Bioequivalence measurements include, for example, (a) in vivo testing in humans or other mammals that tests time-varying concentrations of antibodies or their metabolites in blood, plasma, serum, or other biological fluids; (b) in vivo testing with humans In vitro tests that correlate with and reasonably predict in vivo bioavailability data in humans; (c) in vivo tests in humans or other mammals that measure appropriate immediate pharmacological effects of an antibody (or its target) over time testing; and (d) establishing well-controlled clinical trials of the safety, efficacy or bioavailability or bioequivalence of antibodies.

Bioequivalent variants of the anti-SARS-CoV-2 spike protein antibodies of the present invention can be constructed by, for example, making various substitutions of residues or sequences or deleting terminal or internal residues or sequences that are not essential for biological activity. . For example, cysteine residues that are not essential for biological activity can be deleted or replaced with other amino acids to prevent the formation of unnecessary or inappropriate intramolecular disulfide bridges after renaturation. In other cases, bioequivalent antibodies may include anti-SARS-CoV-2 spike protein antibody variants that contain amino acid changes that modify the glycosylation characteristics of the antibody, such as mutations that eliminate or remove glycosylation.

In some embodiments, the antibodies disclosed herein lack fucose in their constant region glycosylation. Methods of measuring fucose in antibody compositions have been described in the art, for example, U.S. Patent No. 8,409,838 (Regeneron Pharmaceuticals), which is incorporated herein by reference. In some embodiments, fucose is undetectable in a composition comprising a population of antibody molecules. In some embodiments, fucose-deficient antibodies have enhanced ADCC activity.

In some embodiments, fucose-deficient antibodies can be produced using cell lines that lack the ability to fucosylate proteins (ie, reduce or eliminate the ability to fucosylate proteins). Fucosylation of glycans requires the synthesis of GDP-fucose via either the de novo pathway or the salvage pathway, both pathways involving the sequential function of several enzymes resulting in the addition of fucose molecules to the first N- at the reducing end of the glycan. Acetylglucosamine (GlcNAc) moiety. The two key enzymes responsible for the de novo pathway to generate GDP-fucose are GDP-D-mannose-4,6-dehydratase (GMD) and GDP-keto-6-deoxymannose-3,5-epi Isomerase, 4-reductase (FX). In the absence of fucose, these two de novo pathway enzymes (GMD and FX) convert mannose and/or glucose into GDP-fucose, which is then transported to the Golgi complex In the glycan, nine fucosyl-transferases (FUT1-9) work together to fucosylate the first GlcNAc molecule of the glycan. However, in the presence of fucose, rescue pathway enzymes, fucose-kinase, and GDP-fucose pyrophosphorylase convert fucose into GDP-fucose.

Cell lines lacking the ability to fucosylate proteins have been described in the art. In some embodiments, cell lines lacking the ability to fucosylate proteins comprise mutations or genetic modifications in one or more of the endogenous FUT1-9 genes resulting in the lack of one or more functional fucosyl groups. - a mammalian cell strain that transfers the enzyme (for example, a CHO cell strain such as CHO K1, DXB-11 CHO, Veggie-CHO). In some embodiments, the mammalian cell line contains a mutation in the endogenous FUT8 gene (e.g., a FUT8 knockout cell line in which the FUT8 gene has been disrupted, resulting in a lack of functional α1,6-fucosyl in the cell line Transferases, as described in U.S. Patent Nos. 7,214,775 (Kyowa Hakko Kogyo Co., Ltd.) and U.S. Patent 7,737,725 (Kyowa Hakko Kirin Co., Ltd), which are incorporated herein by reference. In some embodiments In, mammalian cell lines contain mutations or genetic modifications in the endogenous GMD gene, resulting in cell lines (e.g., GMD genes in which the GMD gene has been disrupted) as described, for example, in U.S. Patent 7,737,725 (Kyowa Hakko Kirin Co., Ltd). Knockout cell lines), which are incorporated herein by reference. In some embodiments, mammalian cell lines contain mutations or genetic modifications in the endogenous Fx gene, resulting in a lack of functional Fx protein. In some embodiments, the mammalian cell line is an Fx knockout cell line in which the endogenous Fx gene has been disrupted (see, e.g., U.S. Patent 7,737,725 (Kyowa Hakko Kirin Co., Ltd), incorporated by reference Incorporated herein). In some embodiments, the mammalian cell lines comprise mutations in endogenous Fx mutations that confer a temperature-sensitive phenotype (as described, for example, in U.S. Patent No. 8,409,838 (Regeneron Pharmaceuticals), known as incorporated herein by reference). In some embodiments, mammalian cell lines lacking the ability to fucosylate proteins are cell lines that have been selected based on resistance to certain lectins, e.g. See, for example, U.S. Patent No. 8,409,838 (Regeneron Pharmaceuticals), which is incorporated herein by reference. Therapeutic Formulation and Administration

Anti-SARS-CoV-2 spike protein antibodies or antigen-binding fragments used in the methods and uses of the invention may be formulated for administration with one or more pharmaceutically acceptable carriers, excipients or diluents. in the composition. Pharmaceutical compositions are formulated with suitable carriers, excipients, and other agents that provide improved transfer, delivery, tolerability, and the like. Numerous suitable formulations are found in all formularies known to medicinal chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. Such formulations include, for example, powders, pastes, ointments, gels, waxes, oils, lipids, lipid-containing (cationic or anionic) vesicles (such as LIPOFECTIN ^™ , Life Technologies, Carlsbad, CA), DNA binding substances, anhydrous absorbent pastes, oil-in-water and water-in-oil emulsions, carbo wax emulsions (polyethylene glycols of various molecular weights), semi-solid gels and semi-solid mixtures containing carbo wax. See also Powell et al., "Compendium of excipients for parenteral formulations" PDA, J Pharm Sci Technol 52:238-311 (1998).

mAb10933 and mAb10987 are human IgG1 mAbs that simultaneously bind to different non-overlapping epitopes on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) glycoprotein. mAb10933 and mAb10987 (combinations of which can be found in antibody cocktails designated REGN-COV2 or REGEN-COV) were produced by recombinant DNA technology in Chinese hamster ovary (CHO) cell suspension cultures and have approximately 145.23 kDa and 144.14 kDa, respectively. Molecular weight in kDa. The antibodies described herein (eg, mAb10933 and mAb10987) can be formulated individually or co-formulated. For example, co-formulated compositions can be used to simplify streamline administration (eg, intravenous or subcutaneous), while individual formulations provide more flexibility in administration. In certain embodiments, the two antibodies (mAb10933 and mAb10987) referred to as REGEN-COV in the composition can be co-formulated, or the two antibodies can be formulated separately and combined prior to administration.

In some embodiments, mAb10933 and mAb10987 injections are sterile, preservative-free, clear to light opalescent, and colorless to light yellow solutions with a pH of 6.0. In some embodiments, each of mAb10933 and mAb10987 can be formulated as: 120 mg/mL antibody, 10 mM histidine, 8% (w/v) sucrose, and 0.1% (w/v) polysorbate 80 , pH 6.0. Each antibody is available in two concentrations: 300 mg in 2.5 mL, and 1332 mg in 11.1 mL. In some embodiments, mAb10933 and mAb10987 can each be used as a vial containing 300 mg of antibody (eg, in 2.5 mL of solution) or 1332 mg of antibody (eg, in 11.1 mL of solution). Exemplary contents of each vial are shown below: 300 mg vial • mAb10933: Contains 300 mg of mAb10933, L-histidine acid (1.9 mg), L-histidine monohydrochloride monohydrate (2.7 mg) per 2.5 mL of solution mg), polysorbate 80 (2.5 mg), sucrose (200 mg), and water for injection, USP. The pH is 6.0. • mAb10987: Contains 300 mg of mAb10987, L-histidine (1.9 mg), L-histidine monohydrochloride monohydrate (2.7 mg), polysorbate 80 (2.5 mg), sucrose per 2.5 mL of solution (200 mg) and water for injection, USP. The pH is 6.0. 1332 mg vial • mAb10933: Contains 1332 mg of mAb10933, L-histidine acid (8.3 mg), L-histidine acid monohydrochloride monohydrate (12.1 mg), Polysorbate 80 (11.1 mg) per 11.1 mL solution ), sucrose (888 mg) and water for injection, USP. The pH is 6.0. • mAb10987: Contains 1332 mg of mAb10987, L-histidine (8.3 mg), L-histidine monohydrochloride monohydrate (12.1 mg), polysorbate 80 (11.1 mg), sucrose per 11.1 mL of solution (888 mg) and water for injection, USP. The pH is 6.0.

The dose of antibody administered to a patient will vary depending on the patient's age and size, medical condition, route of administration, and the like. The preferred dose is usually calculated based on body weight or body surface area. When the antibody of the present invention is used to treat adult patients, it is usually in a dosage of about 0.01 to about 20 mg/kg body weight, more preferably about 0.02 to about 7, about 0.03 to about 5, or about 0.05 to about 3 mg/kg body weight. It may be advantageous to administer the antibodies of the invention intravenously in sub-doses. Depending on the severity of the condition, the frequency and duration of treatment can be adjusted. The effective dose and schedule for administering anti-SARS-CoV-2 spike protein antibodies can be determined empirically; for example, patient progress can be monitored through periodic assessments and the dose adjusted accordingly. Additionally, interspecies adjustment of dosage can be performed using methods well known in the art (eg, Mordenti et al., Pharmaceut. Res. 8:1351 (1991)).

Various delivery systems are known and can be used to administer the pharmaceutical compositions of the invention, for example, encapsulated in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the antibodies or other therapeutic proteins of the invention, recipients Mediates endocytosis (see, e.g., Wu et al., J Biol Chem) 262:4429-4432 (1987)). The antibodies and other therapeutically active components of the invention can also be delivered via gene therapy technology. Methods of introduction include (but are not limited to) intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compositions may be administered by any convenient route, such as by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be combined with other biologically active agents throw. Can be administered systemically or locally.

Pharmaceutical compositions can be delivered subcutaneously or intravenously using standard needles and syringes. In addition, for subcutaneous delivery, pen-type delivery devices can be easily applied to deliver the pharmaceutical compositions of the present invention. Such pen delivery devices may be reusable or disposable. Reusable pen delivery devices generally utilize replaceable cartridges containing pharmaceutical compositions. Once all of the pharmaceutical composition in the cartridge has been administered and the cartridge is empty, the empty cartridge can be discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. In disposable pen delivery devices, there are no replaceable cartridges. In practice, disposable pen delivery devices are prefilled with pharmaceutical compositions held in a reservoir within the device. After emptying the reservoir of the pharmaceutical composition, discard the entire device.

A number of reusable pen and auto-injector delivery devices are used for subcutaneous delivery of pharmaceutical compositions as discussed herein. To name just a few, 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, NOVOPEN ^™ II and NOVOPEN ^™ III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR ^™ (Novo Nordisk, Copenhagen, Denmark), BD ^™ pens (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN ^™ , OPTIPEN PRO ^™ , OPTIPEN STARLET ^™ and OPTICLIK ^™ (sanofi-aventis, Frankfurt, Germany). To name just a few, examples of disposable pen delivery devices for subcutaneous delivery of the pharmaceutical compositions of the present invention include (but are not limited to) SOLOSTAR ^™ Pen (sanofi-aventis), FLEXPEN ^™ (Novo Nordisk) and KWIKPEN ^™ (Eli Lilly), SURECLICK ^™ auto-injector (Amgen, Thousand Oaks, CA), PENLET ^™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP) and HUMIRA ^™ pen (Abbott Labs , Abbott Park IL).

In some cases, pharmaceutical compositions can be delivered in controlled release systems. 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 may be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another embodiment, the controlled release system can be placed close to the target of the composition, so that only a fraction of the systemic dose is required (see, e.g., Goodson, 1984, Medical Applications of Controlled Release, supra, vol. 2, no. 115 -138 pages). Other controlled release systems are discussed in a review by Langer, Science 249:1527-1533 (1990).

Injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injections, drip infusions, etc. These injectable preparations can be prepared by well-known methods. For example, injectable preparations can be prepared, for example, by dissolving, suspending or emulsifying the antibodies described above or salts thereof in sterile aqueous or oily media conventionally used for injection. As aqueous media for injection there are, for example, physiological saline, isotonic solutions containing glucose and other adjuvants. combination therapy

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

Additional therapeutic agents can be administered or used to the subject prior to administration of the anti-SARS-CoV-2 spike protein antibodies of the invention. For example, 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, If administered/used in the first 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, 10 minutes, 5 minutes or less than 1 minute, it can be regarded as the first One component is administered/used "before" the second component. In other embodiments, additional therapeutic agents can be administered or used to the subject after administration of the anti-SARS-CoV-2 spike protein antibodies of the invention. For example, 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, If administered/used 4 hours after, 5 hours after, 6 hours after, 12 hours after, 24 hours after, 36 hours after, 48 hours after, 60 hours after, or 72 hours after, the first component can be regarded as "in ”The second component is administered/used “afterwards”. In yet other embodiments, additional therapeutic agents may be administered or used to the subject concurrently with administration of the anti-SARS-CoV-2 spike protein antibodies of the invention. For purposes of this invention, "simultaneous" administration includes, for example, administering to a subject a SARS-CoV-2 spike protein antibody and additional Therapeutic active ingredients. If administered in separate dosage forms, each dosage form may be administered by 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, administration of components in a single dosage form, in separate dosage forms by the same route, or in separate dosage forms by different routes is considered "simultaneous administration" for the purposes of this disclosure. For purposes of this disclosure, "before", "concurrently with" the administration of an additional therapeutic agent, or "after" the administration of an additional therapeutic agent (as defined above) (for those terms) administration of an anti-SARS-CoV-2 spike protein antibody is considered to be administration of an anti-SARS-CoV-2 spike protein antibody "in combination with" another therapeutic agent. dose

The amount of active ingredient (e.g., anti-SARS-CoV-2 spike protein antibody, or other therapeutic agent administered in combination with the anti-SARS-CoV-2 spike protein antibody) that can be administered to a subject is generally a therapeutically effective amount, as described herein discussed elsewhere.

In some embodiments, a therapeutically effective amount (eg, a therapeutically effective amount of mAb10933 or mAb10987, or a combination of both antibodies) can be from about 0.05 mg to about 20 g; for example, 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, about 1.8 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, about 2.6 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, about 3.4 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, about 4.2 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 respective antibodies. In some cases, the therapeutically effective amount is 0.1 g to 3.5 g. In some cases, the therapeutically effective amount is 0.5 g to 2 g. In some cases, the therapeutically effective amount is 0.8 g to 1.6 g. In some cases, the therapeutically effective amount is 1.0 g to 1.4 g. In some cases, the therapeutically effective amount is 1 g to 7 g. In some cases, the therapeutically effective amount is 3 g to 5 g. In some cases, the therapeutically effective amount is 3.5 g to 4.5 g. In any of these embodiments discussed above, a dose may represent a dose of a single antibody or, alternatively, a total dose of a combination of antibodies. For example, two different anti-SARS-CoV-2 spike glycoprotein antibodies can be administered together, with the dose of each antibody representing half of the total dose administered. In any of these embodiments, the dose can be administered intravenously. In any of these embodiments, the dose is effective to treat or prevent (eg, pre-exposure or post-exposure prophylaxis) SARS-CoV-2 O (eg, BA.2).

In some embodiments, the combination of mAb10933 and mAb10987 is co-administered intravenously or subcutaneously in a total dose of 300 mg to 2400 mg. In some embodiments, the combination of mAb10933 and mAb10987 is co-administered intravenously or subcutaneously in a total dose of 300 mg to 4800 mg. In some embodiments, the combination of mAb10933 and mAb10987 is co-administered intravenously or subcutaneously at a total dose of 300 mg to 10 g. In some embodiments, 1200 mg to 5000 mg of mAb 10933 and 1200 mg to 5000 mg of mAb 10987 are administered together, such as 2400 mg of 10933 and 2400 mg of 10987, or 4000 mg of mAb 10933 and 4000 mg of mAb 10987. In some cases, the total dose is 100 mg to 5000 mg. In some embodiments, the total dosage is 200 mg to 400 mg, 500 mg to 700 mg, 1000 mg to 1400 mg, or 2000 mg to 2800 mg. In some embodiments, the total dosage is 250 mg to 350 mg, 550 mg to 650 mg, 1150 mg to 1250 mg, or 2300 mg to 2500 mg. In some cases, the total dose is 300 mg, 600 mg, 1200 mg, 2400 mg, or 4800 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, 3000 mg, 3100 mg, 3200 mg, 3300 mg, 3400 mg, 3500 mg, 3600 mg, 3700 mg, 3800 mg, 3900 mg, 4000 mg, 4100 mg, 4200 mg, 4300 mg, 4400 mg, 4500 mg, 4600 mg, 4700 mg, 4800 mg, 4900 mg, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g or 10 g. In some embodiments, the total dose is 4800 mg, >4800 mg, or 8000 mg. In some embodiments, the total dose is 2400 mg, and each of mAb10933 and mAb10987 is administered intravenously at a dose of 1200 mg. In some embodiments, the total dose is 4800 mg, and each of mAb10933 and mAb10987 is administered intravenously at a dose of 2400 mg. In some embodiments, the total dose is >4800 mg, and each of mAb10933 and mAb10987 is administered intravenously at a dose of >2400 mg. In some embodiments, the total dose is 8000 mg, and each of mAb10933 and mAb10987 is administered intravenously at a dose of 4000 mg. In some embodiments, the total dose is 1200 mg, and each of mAb10933 and mAb10987 is administered intravenously at a dose of 600 mg. In some embodiments, the total dose is 600 mg, and each of mAb10933 and mAb10987 is administered intravenously at a dose of 300 mg. In some embodiments, the total dose is 300 mg, and each of mAb10933 and mAb10987 is administered intravenously at a dose of 150 mg. In some embodiments, the total dose is 2400 mg, and each of mAb10933 and mAb10987 is administered subcutaneously at a dose of 1200 mg. In some embodiments, the total dose is 1200 mg, and each of mAb10933 and mAb10987 is administered subcutaneously at a dose of 600 mg. In some embodiments, the total dose is 600 mg, and each of mAb10933 and mAb10987 is administered subcutaneously at a dose of 300 mg. In some embodiments, each individual antibody system is administered at a dose of 100 mg to 200 mg, 200 mg to 400 mg, 500 mg to 700 mg, or 2300 mg to 2500 mg. In some cases, each individual antibody system is administered at a dose of 124 mg to 175 mg, 250 mg to 350 mg, 550 mg to 650 mg, or 1150 mg to 1250 mg. In any of these embodiments, the dose is effective to treat or prevent (e.g., pre-exposure or post-exposure prophylaxis) SARS-CoV-2, e.g., a variant O strain, such as BA.2.

Exemplary dosing regimens include: • A total of mAb10933 and mAb10987 combination therapy was administered, 1200 mg (600 mg per mAb) on Day 1, then 600 mg subcutaneously (SC) every four weeks (Q4W) thereafter (300 mg per mAb); • Co-administration of mAb10933 and mAb10987 combination therapy, 300 mg (150 mg per mAb) SC Q4W; and • A total of mAb10933 and mAb10987 combination therapy was administered, 300 mg (150 mg per mAb) SC Q12W. • 600 mg administered via pump or gravity (where a manually operated clamp is used and gravity pressure delivers the combination to the intravenous line at a stable and safe rate) or by subcutaneous (SC) injection as a single IV infusion mAb10933 and 600 mg of mAb10987.

In some embodiments, mAb10933 and mAb10987 are administered simultaneously as soon as possible after exposure to SARS-CoV-2. For individuals who require repeated dosing for ongoing prophylaxis, such as those with medical conditions that make them less likely to respond to or be protected by vaccination, the initial dose may be 600 mg as an IV infusion or SC injection mAb10933 and 600 mg of mAb10987, and subsequent doses can be IV infusion or SC injection of 300 mg of mAb10933 and 300 mg of mAb10987 every 4 weeks. In some embodiments, repeat dosing regimens for preventing COVID-19 allow for switching from IV infusion to SC injection or vice versa during treatment.

The amount of anti-SARS-CoV-2 spike protein antibody or other therapeutic agent contained in an individual dose may be expressed in milligrams of antibody per kilogram of patient body weight (i.e., mg/kg). For example, a dosage 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, 110.0 mg/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) to administer anti-SARS-CoV-2 spike protein antibodies to patients. investment plan

According to certain embodiments of the invention, multiple doses of an active ingredient (eg, an anti-SARS-CoV-2 spike protein antibody) may be administered to a subject over a defined time period. A method according to this aspect of the invention comprises sequentially administering to a subject a plurality of doses of an active ingredient of the invention. As used herein, "sequentially administered" means administering to a subject doses of an active ingredient at different points in time, such as on different days separated by a predetermined interval (eg, hours, days, weeks, or months). The present invention includes methods comprising sequentially administering to a patient a single initial dose of an active ingredient, followed by one or more second doses of the active ingredient, and optionally one or more third doses of the active ingredient. Element.

The terms "initial dose", "secondary dose" and "tertiary dose" refer to the administration of an active ingredient (e.g., the anti-SARS-CoV-2 spike protein antibody of the invention ) or the chronological sequence of the combination therapy of the invention (e.g., two different anti-SARS-CoV-2 spike protein antibodies). Therefore, the “initial dose” is the dose administered at the beginning of the treatment regimen (also called the “baseline dose”); the “second dose” is the dose administered after the initial dose; and the “third dose” ” is the dose administered after the second dose. The initial, second and third doses may all contain the same amount of active ingredient (e.g., anti-SARS-CoV-2 spike protein antibody), but generally may differ from each other in terms of frequency of administration. However, in certain embodiments, the initial, second and/or third doses contain active ingredients (e.g., anti-SARS-CoV-2 spike protein antibodies) in amounts that differ from each other during the course of treatment (e.g., as needed up or down). In certain embodiments, two or more (eg, 2, 3, 4, or 5) doses are administered as a "loading dose" at the beginning of the treatment regimen, followed by less frequent administrations Subsequent doses (e.g. "maintenance dose").

In certain exemplary embodiments of the invention, each second and/or third dose is 1 to 26 (e.g., 1, 1½, 2, 2½, 3, 3½, 4, 4½, 5, 5½) after the previous dose. , 6, 6½, 7, 7½, 8, 8½, 9, 9½, 10, 10½, 11, 11½, 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) weekly investments. As used herein, the phrase "the immediately preceding dose" means, in a sequence of multiple administrations, an activity that is administered to a patient before the next dose in the sequence (without intervening doses). Dosage of ingredients (e.g., anti-SARS-CoV-2 spike protein antibodies).

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

In embodiments involving multiple second doses, each second dose may be administered at the same frequency as the other second doses. For example, each second dose can be administered to the patient 1 to 2 weeks or 1 to 2 months after the previous dose. Similarly, in embodiments involving multiple third doses, each third dose may be administered at the same frequency as the other third doses. For example, each third dose can be administered to the patient 2 to 12 weeks after the previous dose. In certain embodiments of the invention, the frequency with which the second dose and/or the third dose is administered to the patient may vary over the course of the treatment regimen. The frequency of dosing can also be adjusted by the physician during the course of treatment and after clinical examination according to the needs of the individual patient.

The invention includes wherein the patient is administered 2 to 6 initial doses at 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 more frequent doses. A dosing regimen in which two or more maintenance doses are administered to patients less frequently. For example, according to this aspect of the invention, if the initial dose is administered once a month, the patient can be administered a maintenance dose once every six weeks, once every two months, once every three months, etc. . In certain embodiments, a single dose is administered to a subject as part of a course of prophylactic or therapeutic treatment. In some embodiments, one or more doses are administered to treat high-risk adult or pediatric patients diagnosed with mild to moderate coronavirus disease (COVID-19).

In some embodiments, the dosage in adult and pediatric patients (12 years of age and older, weighing at least 40 kg) is: ○ Administer 600 mg of mAb10933 (casirimab) and 600 mg of mAb10987 (Eda monoclonal antibody); or ○ Administer 1,200 mg of casirimab and 1,200 mg of idelimumab together as a single intravenous infusion via pump or gravity (see Table 4B). Exemplary preparation instructions for mAb10933 + mAb10987 (casirimab and idelimab, respectively) are as follows: 1 Remove casirumab and idelimumab vials from refrigerated storage and allow to equilibrate to room temperature for approximately 20 minutes prior to preparation. Do not expose directly to heat. Do not shake the vial. 2 Observe the casirimab and idelimab vials visually for particulate matter and discoloration before administration. If either condition is observed, the solution must be discarded and fresh solution prepared. The solution in each vial should be clear to light milky white, colorless to light yellow. 3 Obtain prefilled IV bags containing 50 mL, 100 mL, 150 mL, or 250 mL of 0.9% Sodium Chloride Injection. 4 If administering the 600 mg/600 mg dose: ○ Use two separate syringes to withdraw 5 mL of casirimab and 5 mL of idelimumab from their corresponding vials (see Table 4A) and inject all 10 mL into the prefilled infusion bag containing 0.9% sodium chloride injection medium (see Table 4A). Discard any product remaining in the vial. or If the alternative 1,200 mg/1,200 mg dose is administered, then: ○ Use two separate syringes to withdraw 10 mL of casirimab and 10 mL of idelimumab from the corresponding vials (see Table 4B) and inject all 20 mL into the prefilled infusion bag containing 0.9% sodium chloride injection medium (see Table 4B). Discard any product remaining in the vial. 5 Gently invert the infusion bag manually about 10 times. Don't oscillate. 6 This product does not contain preservatives and therefore the diluted infusion solution should be administered immediately. • If immediate administration is not possible, store diluted casirimab and idelimab infusion solutions in a freezer between 2ºC and 8ºC (36ºF and 46ºF) for no longer than 36 hours or No more than 4 hours at room temperature up to 25 ºC (77 ºF). If refrigerated, allow infusion solution to equilibrate to room temperature for approximately 30 minutes before administration.

Exemplary administration instructions are as follows: 1. Collect recommended materials for infusion: a. Polyvinyl chloride (PVC), polyethylene (PE) lined PVC or polyurethane (PU) infusion set b. Containing or adding 0.2 micron polyether sulfide (PES) Filter 2 Connects the infusion set to the IV bag. 3. Perfuse the infusion group. 4 Administer as an IV infusion via pump or gravity over at least 60 minutes through an intravenous line containing a sterile, internal or additional 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 drugs. The compatibility of mAb10933 and mAb10987 injection with IV solutions and drugs other than 0.9% sodium chloride injection is unknown. 6 After the infusion is completed, rinse with 0.9% sodium chloride injection. 7 Discard unused product. 8 Monitor patients clinically during administration and observe patients for at least 1 hour after completion of infusion. [Table 4A ]: Recommended dosage, dilution, and administration instructions for casirimab 600 mg and idelimumab 600 mg for IV infusion Casirimab and Idemumab 1,200 mg ^dosea . Add: • 5 mL Casirimab (use 1 vial 11.1 mL or 2 vials 2.5 mL ) and • 5 mL Idemumab (use 1 vial 11.1 mL or 2 vials 2.5 mL ) for a total of 10 mL to prefill 0.9% Sodium chloride infusion bag and administer ^b as directed below Prefilled 0.9% sodium chloride infusion bag size maximum infusion rate Minimum infusion time ^50mLc 180mL/hr 20 minutes 100mL 310mL/hr 21 minutes 150mL 310mL/hr 31 minutes 250mL 310mL/hr 50 minutes a Add 600 mg of casirimab and 600 mg of idelimumab to the same infusion bag and administer them together as a single intravenous infusion. b After the infusion is completed, rinse with 0.9% sodium chloride injection. c For patients who are administered casirimab with idelimumab using a 50 mL prefilled 0.9% sodium chloride infusion bag, the minimum infusion time must be at least 20 minutes to ensure safe use. [Table 4B ]: Recommended dosage, dilution, and administration instructions for casirimab 1,200 mg and idelimumab 1,200 mg for IV infusion Casirimab and Idemumab 2,400 mg ^dosea . Add: • 10 mL of Casirimab (using 1 vial of 11.1 mL or 4 vials of 2.5 mL) and • 10 mL of Idelizumab (using 1 vial of 11.1 mL or 4 vials of 2.5 mL) for a total of 20 mL added to Prefill 0.9 % sodium chloride infusion bag and administer ^b as directed below. Prefilled 0.9% sodium chloride infusion bag size maximum infusion rate Minimum infusion time ^50mLc 210mL/hr 20 minutes 100mL 310mL/hr 23 minutes 150mL 310mL/hr 33 minutes 250mL 310mL/hr 52 minutes a Add 1,200 mg casirimab and 1,200 mg idelimumab to the same infusion bag and administer them together as a single intravenous infusion. b After the infusion is completed, rinse with 0.9% sodium chloride injection. c The minimum infusion time for patients who are administered casirimab with idelimumab using a 50 mL prefilled 0.9% sodium chloride infusion bag should be at least 20 minutes to ensure safe use. set

The present invention further provides an article or kit, which includes a packaging material, a container and a pharmaceutical agent contained in the container, wherein the pharmaceutical agent includes at least one anti-SARS-CoV-2 spike glycoprotein antibody, and the packaging material includes a display indication. and labels or drug inserts with instructions for use. In one embodiment, the kit may include two anti-SARS-CoV-2 spike protein antibodies, and the two antibodies may be contained in separate containers. Example

The following examples are set 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 present invention, and are not intended to limit the scope of the inventors' invention. Every effort has been made to ensure accuracy with respect to the figures used (e.g. quantities, temperatures, etc.), but some experimental errors and deviations should be taken into account. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure. Example 1. Clinical evaluation of anti-SARS-CoV-2 spike protein antibodies in hospitalized adult patients with COVID-19 .

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

Research Objectives: The primary and secondary objectives of each stage of the research are stated below.

Primary Objectives: Phase 1 Part A • To evaluate the safety and tolerability of mAb10933 + mAb10987 compared to placebo • To evaluate the virological efficacy of mAb10933 + mAb10987 compared to placebo in reducing viral shedding of SARS-CoV-2 Part A B • To evaluate the safety and tolerability of mAb10989 compared to placebo • To evaluate the virological efficacy of mAb10989 compared to placebo in reducing viral shedding of SARS-CoV-2 Phase 2 • To evaluate mAb10933 + mAb10987 compared to placebo Virological efficacy in reducing viral shedding of SARS-CoV-2 • To assess the clinical efficacy of mAb10933 + mAb10987 in improving clinical status compared to placebo Phase 3 The primary objective of Phase 3 is to evaluate and confirm mAb10933 + mAb10987 vs. placebo The clinical efficacy of the agent in improving clinical status.

Secondary Objectives: Phase 1 Part A • Assess additional measures of virological efficacy of mAb10933 + mAb10987 compared to placebo • Assess the clinical efficacy of mAb10933 + mAb10987 compared to placebo in improving clinical outcomes • Characterize mAb10933 and mAb10987 in serum Pharmacokinetic (PK) profile in • Assessing the immunogenicity of mAb10933 and mAb10987 Part B • Assessing additional measures of virological efficacy of mAb10989 compared to placebo • Assessing the clinical efficacy of mAb10989 in improving clinical outcomes compared to placebo Efficacy • Compare quantitative reverse transcription polymerase chain reaction (RT-qPCR) results collected with different sample types (nasopharynx, nasal and saliva) • Characterize the PK profile of mAb10989 in serum • Assess the immunogenicity of mAb10989 Phase 2 • Evaluate mAb10933 + Additional measures of virological efficacy of mAb10987 compared to placebo • Additional measures to assess clinical efficacy of mAb10933 + mAb10987 compared to placebo • Assessed safety and tolerability of mAb10933 + mAb10987 compared to placebo • Characterization of serum Concentration changes of mAb10933 and mAb10987 over time • Assess the immunogenicity of mAb10933 and mAb10987 Phase 3 • Assess the clinical efficacy of mAb10933 + mAb10987 compared to placebo • Assess the safety and tolerability of mAb10933 + mAb10987 compared to placebo Properties• Characterize the changes in the concentration of mAb10933 and mAb10987 in serum over time• Assess the immunogenicity of mAb10933 and mAb10987

Study Design: This study is an adaptive, phase 1/2/3, randomized, double-blind, placebo-controlled master protocol to evaluate the efficacy, safety and efficacy of mAb10933 + mAb10987 in hospitalized adult patients with COVID-19. tolerance. The safety, tolerability and efficacy of mAb10989 were evaluated in the Phase 1 portion of the study to enable further study in other clinical configurations. Eligible patients who were hospitalized for ≤72 hours at screening were included in 1 of 4 cohorts based on disease severity at the time of randomization. Phase 2 begins after Phase 1 is cleared by the Independent Data Monitoring Committee (IDMC) of the Sentinel Security Team and is included in Phase 1 at the same time after the commencement. Once Phase 2 is active, selection for Phase 1 continues until completion, but selection for Phase 2 does not require completion of Phase 1 selection.

Study Duration : The Phase 1 portion of the study lasts up to 170 days. The Phase 2 portion of the study lasts up to 58 days. The Phase 3 portion of the study lasts up to 58 days.

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

Cohorts—Eligible patients will be assigned to 1 of 4 cohorts based on disease severity at randomization: Cohort 1A (patients with COVID-19 symptoms but do not require supplemental oxygen); Cohort 1 (patients with COVID-19 symptoms via nasal cannula, Simple mask or other similar device maintains O2 saturation >93% with low-flow oxygen); Group 2 (high-intensity oxygen therapy* but no mechanical ventilation - *high-intensity oxygen therapy is defined as using an oxygen flow rate of at least 10 L/ min non-rebreather mask; use of a high-flow device with at least 50% FiO2, or use of non-invasive ventilation to treat hypoxemia); and Group 3 (with mechanical ventilation).

Sample size—The Phase 1 portion of the study included up to 100 patients from Arm 1 only: Part A of mAb10933 + mAb10987 : approximately 20 patients in each arm, for a total of 60 patients in the 3 treatment arms; and Part B of mAb10989 : each arm Approximately 20 patients, totaling 40 patients in 2 treatment groups. The Phase 2 portion of the study included approximately 1,560 patients: Arm 1A : approximately 130 patients per arm, 390 patients total across 3 treatment arms; Arm 1A : approximately 130 patients per arm, 390 patients total across 3 treatment arms; Arm 1A: approximately 130 patients per arm, 390 patients total across 3 treatment arms ; 2 : 130 patients per group, 390 patients total across 3 treatment groups; and 3 : 130 patients per group , 390 patients total across 3 treatment groups. The sample size for Phase 3 was estimated to be approximately 1350 (150 patients in each of the 3 treatment arms in each of the 3 cohorts). The final determination of the Phase 3 sample size and patient population will change and will be determined after a comprehensive review of the Phase 2 data.

Inclusion criteria: Patients must meet the following criteria to be eligible for inclusion in the study: 1. Have provided informed consent (signed by the study patient or a legally acceptable representative); 2. Be ≥18 years old (or the legal age of majority in the country) at the time of randomization Male or female adults; 3. Have a positive SARS-CoV-2 molecular diagnostic test (by confirmed SARS-CoV-2 RT-PCR or other molecular diagnostic assay, using appropriate samples (such as NP, nasal, oropharyngeal [OP], or saliva)) and there is no alternative explanation for the current clinical condition. A history of positive results for tests taken ≤72 hours before randomization is acceptable; 4. Have symptoms consistent with COVID-19, onset ≤10 days before randomization; and 5. Hospitalized for COVID-19 illness <72 hours, in which at least 1 patient meeting more than one criterion at randomization will be classified as the most severely affected category: a. Group 1A : with COVID-19 symptoms but does not require supplemental oxygen b. Group 1 : Low-flow oxygen via nasal cannula, simple mask or other similar devices to maintain O2 saturation >93% c. Group 2 : High-intensity oxygen therapy without mechanical ventilation, where high-intensity is defined as receiving 1 of the following devices Supplemental oxygen delivered by the patient: - Non-rebreather mask (SpO2 ≤96% while receiving an oxygen flow rate of at least 10 L/min) - High-flow device with at least 50% FiO2 (e.g., AIRVO ^™ or Optiflow ^™ ) - Non-invasive respirators, including continuous positive airway pressure (CPAP), to treat hypoxemia (excluding respirators used solely for sleep disordered breathing) d. Group 3 : Mechanical ventilation.

Exclusion criteria: Patients who meet any of the following criteria are excluded from the study: 1. Stage 1 only: patients who maintain indoor air O2 saturation >94%; 2. The researcher believes that it is unlikely to survive >48 hours since screening; 3. Receive extracorporeal membrane oxygenation (ECMO); 4. Suffered a new onset of stroke or epilepsy while hospitalized; 5. Starting renal replacement therapy due to COVID-19; 6. Have circulatory shock requiring vasopressors at the time of randomization (patients who require vasopressors due to sedation-related hypotension or reasons other than circulatory shock may be eligible for this study); 7. Patients who have received convalescent plasma or IVIG within the past 5 months or plan to receive any indication during the study period; 8. Participate in clinical studies evaluating investigational products, including any double-blind studies (using remdesivir, hydroxychloroquine, or other treatments (other than COVID-19 recovery), 30 days before the screening visit and less than 5 half-lives of the investigational product) (other than phase 1 plasma or IVIG) is allowed for use in COVID-19 treatment when permitted by local standard of care or open-label studies or compassionate use agreements); 9. Any physical examination findings, medical history, and/or concomitant medications that, in the opinion of the study investigators, could confound the study results or create additional risks to the patient through their participation in the study; 10. Known allergy or allergic reaction to the components of the study drug; 11. Women who are pregnant or breastfeeding; or 12. Women of childbearing potential (WOCBP)* who are unwilling to take highly effective contraceptive measures or who are sexually active before the first dose/first treatment, during the study and for at least 6 months after the last dose Persistent sexual activity among men. Very effective birth control methods among women include: • Stable use of combination (containing estrogen and progestin) hormonal contraception (oral, intravaginal, transdermal) or progestin-only hormonal contraception (oral, injectable, implantable), which is associated with suppression before screening Ovulation-related onset of 2 or more menstrual cycles • Intrauterine device (IUD) • Intrauterine hormone releasing system (IUS) • Bilateral fallopian tube ligation • Vasectomized partner, † and/or • Sexual abstinence‡,§ Male study participants with WOCBP partners were asked to use condoms unless they had a vasectomy † or practiced abstinence. ‡,§ * WOCBP is defined as a woman who is fertile after menarche until she becomes postmenopausal, unless she is permanently infertile. Postmenopausal status is defined as the absence of menstruation for 12 months without an alternative medical cause. Follicle-stimulating hormone (FSH) levels in the postmenopausal range can be used to confirm postmenopausal status in women who are not using hormonal contraception or hormone replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the onset of postmenopausal status. The above definitions are based on Clinical Trials Facilitation Group (CTFG) guidelines. Women who have had a documented hysterectomy or tubal ligation do not need a pregnancy test or birth control. Permanent sterilization methods include hysterectomy, bilateral fallopian tube resection, and bilateral oophorectomy.  The vasectomy partner or the vasectomy study participant must have received a medical evaluation of the success of the surgery. ‡ Abstinence is considered highly effective only when defined as the avoidance of heterosexual intercourse throughout the risk period associated with the study drug. The reliability of abstinence needs to be assessed with respect to the duration of clinical trials and the preferred and common lifestyle patterns of patients. § Cyclic abstinence (calendar method, symptomatic basal body temperature method, postovulatory method), withdrawal (interruption of intercourse), spermicide-only and lactation menopausal methods (LAM) are not acceptable methods of contraception. Female condoms and male condoms should not be used together.

Study Treatment : In Phase 1 Part A, patients received a single intravenous (IV) dose of mAb10933 + mAb10987 combination therapy co-administered 2.4 g (1.2 g mAb10933 plus 1.2 g mAb10987), co-administered mAb10933 + mAb10987 combination therapy 8.0 g (4.0 g mAb10933 plus 4.0 g mAb10987) IV as a single dose, or placebo as a IV single dose. In Phase I, Part B, patients received mAb10989 monotherapy 1.2 g IV as a single dose, or placebo as a single IV dose. In Phase 2, patients received a co-administered single dose of 2.4 g (1.2 g mAb10933 plus 1.2 g mAb10987) of the mAb10933 + mAb10987 combination IV and a co-administration of 8.0 g (4.0 g mAb10933 plus 4.0 g mAb10987) of the mAb10933 + mAb10987 combination. ) IV single dose, or placebo IV single dose. The treatment group for Phase 3 is determined after reviewing the Phase 2 data.

Evaluation Metrics : Specify the primary, secondary and exploratory evaluation metrics for each period, as defined below.

Primary Outcome Measures Phase 1 (Arm 1 only) The primary endpoints for Phase 1 (Part A and Part B) are: • Proportion of patients with a treatment-emergent serious adverse event (SAE) through Day 169 • Infusion-related through Day 4 Proportion of patients with a reaction (grade ≥2) • Proportion of patients with an allergic reaction (grade ≥2) up to day 29 • Time-weighted relative to baseline viral shedding (log ₁₀ copies/ml) from day 1 to day 22 Average change, as measured by quantitative reverse transcription polymerase chain reaction (RT-qPCR) in nasopharyngeal (NP) swab samples (time-weighted average 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 of change from baseline at each time point divided by the time interval of the observation period). The primary endpoints for Phase 2 in each phase 2 arm are: Arm 1A and Arm 1 • Time-weighted average change from baseline viral shedding (log ₁₀ copies/ml) from day 1 to day 22, as measured by RT- Measured by qPCR in nasopharyngeal (NP) swabs • Proportion of patients in Groups 2 and 3 whose clinical status improved by at least 1 point from day 1 (time of randomization) to day 8 using a 7-point ordinal scale • from day 1 Time-weighted average change from baseline viral shedding (log ₁₀ copies/ml) from day 1 to day 22, as measured by RT-qPCR in NP swabs • Using a 7-point ordinal scale since day 1 (randomization time) to day 22 The proportion of patients whose clinical status improved by at least 1 point in each phase 3 group The main assessment indicators in phase 3 are: Group 1A and Group 1 • Using a 7-point ordinal scale from day 1 (randomization time) to Proportion of patients whose clinical status improved by at least 1 point on day 8 for Groups 2 and 3 • Proportion of patients who improved by at least 1 point in clinical status from day 1 (time of randomization) to day 22 using a 7-point ordinal scale Patient population (group 1A, Group 1, Group 2 and/or Group 3) and Phase 3 primary clinical efficacy evaluation indicators will be finalized after review of Phase 2 data.

Secondary Outcomes Phase 1 (Group 1 only) Secondary Outcomes for Phase 1 are: • Time-weighted average change from baseline viral shedding (log ₁₀ copies/ml) from Day 1 to Day 22, as measured by Measured by RT-qPCR in saliva samples • Time-weighted average change from baseline viral shedding (log ₁₀ copies/ml) from day 1 to day 22, as measured by RT-qPCR in nasal samples • In Time to reach negative RT-qPCR in all test samples without subsequent positive RT-qPCR in any test sample (NP swab, saliva or nasal swab) • SARS-CoV- at each visit until day 29 2 Change in viral shedding from baseline, as measured by RT-qPCR in NP swabs • Change in SARS-CoV-2 viral shedding from baseline at each visit up to day 29, as measured by RT- qPCR in saliva samples • Change from baseline in SARS-CoV-2 viral shedding at visits up to day 29, as measured by RT-qPCR in nasal swabs • Different sample types (NP, Correlation and consistency of RT-qPCR results over time between nose and saliva) Viral shedding (log10 copies/ml) from day 1 to post-baseline study days (e.g. days 5, 7, 15 and 29) ) Time-weighted mean change from baseline; proportion of patients with at least 1 point improvement in clinical status from day 1 (time of randomization) to day 8 using a 7-point ordinal scale • From day 1 (time of randomization) using a 7-point ordinal scale Proportion of patients whose clinical status improved by at least 2 points from day 1 (time of randomization) to day 8 • Proportion of patients whose clinical status improved by at least 1 point from day 1 (time of randomization) to day 29 or discharge using a 7-point ordinal scale • Proportion of patients whose clinical status improves by at least 2 points using a 7-point ordinal scale from day 1 (time of randomization) to day 29 or discharge • Time to no longer require oxygen supplementation by day 29 • Supplementation until day 29 Days of oxygen use • The proportion of patients who started high-intensity oxygen therapy until the 29th day or discharged from the hospital • The number of days of high-intensity oxygen therapy until the 29th day • The proportion of patients who started mechanical ventilation until the 29th day or discharged from the hospital • Mechanical ventilation until the 29th day Days • Days without a ventilator until day 29 • Days in hospital until day 29 • Proportion of patients who were readmitted after discharge until study end • Proportion of patients who were admitted to the intensive care unit (ICU) until day 29 • Until day 29 Days of ICU stay • All-cause mortality up to day 29 • All-cause mortality up to the end of the study • Overall survival rate • Proportion of patients with treatment-induced SAE up to day 29 • Concentrations of mAb10987, mAb10933 and mAb10989 in serum and Corresponding PK Parameters • Immunogenicity, as measured by anti-drug antibodies (ADA) against mAb10933, mAb10987 and mAb10989 Secondary assessments for Phase 2 are: Group 1A and Group 1 only • Using a 7-point ordinal scale The proportion of patients whose clinical status improved by at least 2 points from day 1 (time of randomization) to day 8 was only in Group 2 and Group 3 • Clinical status from day 1 (time of randomization) to day 22 using a 7-point ordinal scale Proportion of patients improving at least 2 points Group 1A, Group 1, Group 2 and Group 3 • Time to reach negative RT-qPCR in NP swabs, with no subsequent positive RT-qPCR • Virus at each visit until day 29 Change in shedding from baseline, as measured by RT-qPCR in NP swabs • Viral shedding (log ₁₀ replicas/ mL) from baseline • Proportion of patients whose clinical status improved by at least 1 point from day 1 (time of randomization) to day 29 or discharge using a 7-point ordinal scale • The proportion of patients whose clinical status improved by at least 2 points from day 1 (randomization time) to day 29 or discharge • The time when oxygen supplementation is no longer required as of day 29 (only groups 1, 2 and 3) • Until day 29 Number of days of supplemental oxygen use up to day 29 • Proportion of patients who started high-intensity oxygen therapy until day 29 • Number of days of high-intensity oxygen therapy up to day 29 • Proportion of patients who started mechanical ventilation up to day 29 or discharged from hospital • Number of days on mechanical ventilation • Days without ventilator up to day 29 • Days in hospital up to day 29 • Proportion of patients readmitted after discharge until end of study • Proportion of patients admitted to ICU up to day 29 • ICU up to day 29 Days of stay • All-cause mortality to day 29 • All-cause mortality to study end • Overall survival • Proportion of patients with treatment-initiated SAEs to day 29 • Proportion of patients with treatment-initiated SAEs to day 57 • Proportion of patients with infusion-related reactions (grade ≥ 2) up to day 4 • Proportion of patients with anaphylactic reactions (grade ≥ 2) up to day 29 • Concentrations of mAb10933 and mAb10987 in serum over time • Immunogenicity, Phase 3 patient populations (Cohort 1A, Cohort 1, Cohort 2 and/or Cohort 3) and Phase 3 secondary clinical efficacy measures as measured by ADA for mAb10933 and mAb10987 are finalized after review of the complete Phase 2 data. Other possible secondary endpoints for Phase 3 include: • Proportion of patients with treatment-emergent SAEs through day 57 • Proportion of patients with infusion-related reactions (grade ≥ 2) through day 4 • Anaphylaxis (anaphylaxis) through day 29 Proportion of patients with grade ≥2) Concentrations of mAb10933 and mAb10987 in serum over time Immunogenicity, as measured by ADA against mAb10933 and mAb10987

Exploratory Assessment Metrics Exploratory Assessment Metrics include: • Proportion of patients with treatment failure who have a mutation in the gene encoding the SARS-CoV-2 S protein through day 29 • Neutrophil-lymphocyte count at each visit through day 29 Changes and percentage changes in NLR • Changes and percentage changes in D-dimer at each visit up to day 29 • Changes and percentage changes in ferritin at each visit up to day 29 • Changes and percentage changes in C-reactive protein (CRP) at each visit on day 29 • Changes and percentage changes in lactate dehydrogenase (LDH) at each visit until day 29

Procedures and Assessments : Efficacy - SARS-CoV-2 RT-PCR nasopharyngeal swab (all phases), saliva swab (phase 1 only) and/or nasal swab (phase 1 only), and clinical and oxygen status; Safety —Recorded serious adverse events and adverse events of particular concern. Nasal swabs, saliva samples, and (Phase 1) nasopharyngeal samples are used to collect patient secretions to determine the presence of SARS-CoV-2 virus and 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). Statistics plan :

Phase 1—The total sample size for Phase 1 Part A is 60 patients and Part B is 40 patients. The sample size allowed preliminary estimates of the incidence of SAEs, AESIs, and Grade 3 or 4 TEAEs in the treatment group relative to placebo.

The primary efficacy measure in Phase 1 was the time-weighted average change from baseline in viral shedding (log ₁₀ copies/ml) in NP swab samples from Day 1 to Day 22. Assuming a standard deviation of 2.1 log ₁₀ copies/mL, a sample size of 20 patients per group in Phase 1 should have at least 80% power to detect a difference of 1.91 log ₁₀ copies/mL between the treatment and placebo groups, using 2-sided The significance is a two-sample t test at α=0.05.

Phase 2—Phase 2 sample size is based on the time-weighted average change from baseline in viral shedding (log ₁₀ copies/ml) in NP swab samples from Day 1 to Day 22. Assuming a dropout rate of approximately 23% (including missing data at baseline) and a standard deviation of 2.1 log ₁₀ copies/ml, across 3 treatment groups within each of the 3 cohorts, with 130 patients each (also That is, a sample size of 100 patients per group with available data) should have 80% power to detect a difference of 0.84 log ₁₀ copies/ml between each treatment group and placebo in the cohort, using a 2-sided significance of α= 0.05 of 2-sample t-test. If the standard deviation is assumed to be 3.8 log ₁₀ copies/ml, then the detectable difference at 80% power would be 1.51 log ₁₀ copies/ml.

For clinical measures of the proportion of patients who improved their clinical status by at least 1 point from baseline to day 22, for a sample size of 100 per group (assuming approximately 23% dropout rate, 130 patients per group), the difference between treatment and placebo The minimum detectable difference (MDD) (based on the chi-square test of equal proportions) will be as follows: • In Arms 1A and 1, assuming a 51% response rate in the placebo arm, the MDD would be 13.7% (i.e., 64.7% for anti-SARS-CoV-2 S protein mAb and 51% for placebo) . The hypothesized response rate in the placebo group is similar to the response rate observed with remdesivir. In Groups 2 and 3, assuming a response rate of 57.1% in the placebo group, the MDD would be 13.3% (i.e., 70.4% for anti-SARS-CoV-2 S protein mAb and 57.1% for placebo). Hypothetical response rates in the placebo arm are similar to those observed in the Seretizumab COVID-19 Phase 2/3 study (6R88-COV-2040), with the late-stage cohort similar to Arm 2 and Arm 2 in this study 3.

Phase 3—The study will continue to seamlessly enroll additional patients into the Phase 3 portion of the study until appropriate decisions regarding Phase 3 primary endpoints and final sample size are made based on analysis of complete Phase 2 data. The estimated initial sample size for the Phase 3 portion of the study is a total of 1,350 patients (across 3 treatment arms in 3 cohorts, 150 in each arm). For example, for Group 3, a sample size of 450 patients (150 patients per group) would provide 90% power using the chi-square test to detect a 15.9% treatment difference in the proportion of patients alive and off mechanical ventilation at day 22 , assuming the rate in the placebo group is 68.2%.

Results —Analysis of Phase 1/2/3 Clinical Trial ( see Figure 19 ) of Antibody Cocktail, Casirimab, and Idemumab (mAb10933 and mAb10987, respectively) in Hospitalized COVID-19 Patients Requiring Low-Flow Oxygen Prospectively designed to focus on patients who have not yet mounted their own immune response to SARS-CoV-2 (i.e., have no antibodies at baseline: seronegative), as evidence (see Example 2) suggests that these patients are more likely to be Under great risk. Additionally, among subjects treated with placebo, patients who had developed an immune response at baseline (seropositive patients) had a much lower risk of death at baseline than patients who did not develop an immune response at baseline (seronegative patients). Viral levels and even earlier achievement of viral loads below lower quantification levels (“LLQ”) without treatment. See Figure 16 . Additionally, among hospitalized COVID-19 patients receiving low-flow supplemental oxygen, seropositive patients had a lower cumulative incidence of death or mechanical ventilation compared with seronegative patients. See Figure 17 . Clinical outcomes in Group 1 were worse in patients who were seronegative at baseline or had higher viral loads at baseline. See Figure 18 . The primary clinical goal of this initial analysis was to determine whether sufficient efficacy existed in these patients to warrant continuation of the trial (i.e., futility analysis). The results passed the null analysis (p<0.3 one-sided) because seronegative patients treated with the antibody cocktail had a lower risk of dying or receiving mechanical ventilation (hazard ratio (HR): 0.78; 80% CI: 0.51-1.2). Based on a post hoc analysis, the benefit was driven by outcomes starting one week after treatment, when treatment with the antibody cocktail reduced the risk of dying or receiving mechanical ventilation by about half.

The incidence of seronegativity was compared in both the full analysis set (FAS; randomized and dosed patients) and the modified full analysis set (mFAS; patients who tested positive for SARS-CoV-2 via qualitative nasopharyngeal testing at baseline). Group 1 was analyzed, and the incidence of seronegativity was similar in the FAS and mFAS groups. See Figure 20 . Seronegative patients (n=217) had much higher viral loads than those who had developed their own autoantibodies against SARS-CoV-2 at the time of randomization (seropositivity). See Figure 16 . As hypothesized, in patients who did not develop their own immune response (who were seronegative at baseline), there was a greater antiviral effect of the antibody cocktail compared with placebo; patients treated with the antibody cocktail compared with placebo Patients experienced more rapid viral reduction; and the mixture reduced viral load more rapidly than placebo at all baseline viral load thresholds. See Figure 21 to Figure 24 . In seronegative patients, the antibody cocktail reduced the time-weighted mean daily viral load by -0.54 log10 copies/ml on day 7 and by -0.63 log10 copies/ml on day 11 (nominal p=0.002 for combination dose). On Day 5, the relative reduction compared to placebo was -1.1 log10 copies (nominal p=0.002 for combined dose). In seropositive patients (n=270), the clinical and virological benefit of the antibody cocktail was limited (clinical index HR: 0.98; time-weighted mean viral load reduction of combination dose on day 7 -0.20 log10 copies/ml). Treatment with the mixture resulted in similar viral load reductions in inpatients and outpatients, with the most pronounced differences observed among seronegative patients between those treated with the mixture and those who received placebo, consistent with the data from Example 2 consistent (Figure 25 to Figure 28 ) .

Clinical and virological analyzes included data from hospitalized patients receiving low-flow oxygen (defined as maintaining oxygen saturation >93% via nasal cannula, simple mask, or similar device), including 217 patients who were seronegative at trial entry and There were 270 seropositive cases; although seronegative patients accounted for less than half of the trial population, based on placebo rates, in the absence of antibody cocktail treatment, they accounted for approximately two-thirds of deaths. Patients were randomized to receive an antibody cocktail (8,000 mg high dose or 2,400 mg low dose) or placebo in addition to standard of care, with 67% receiving remdesivir and 74% receiving systemic corticosteroids. Similar clinical and virological efficacy was observed for high and low doses of the antibody cocktail.

Both antibody cocktail doses were well tolerated. Across the entire trial population, the incidence of serious adverse events was 21% for the high dose, 20% for the low dose, and 24% for placebo. Infusion reactions were more common with the high-dose antibody cocktail (2.7% high dose, 0.9% low dose, 1.4% placebo), and there were two interruptions due to infusion-related reactions, both of which occurred in the high-dose group. Example 2. Clinical evaluation of anti-SARS-CoV-2 spike protein antibodies in ambulatory patients with COVID-19 .

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

Research Objectives: The primary and secondary objectives of each stage of the research are stated below.

Illustrative Uses: Illustrative uses that may be authorized based on results from this example, including interim results, are as follows:

This exemplary use is for intravenous infusion of REGEN-COV where mAb10933 and mAb10987 are administered together. REGEN-COV should be administered as soon as possible after a positive SARS-CoV-2 virus test and within 7 days of symptom onset in adult and pediatric patients 12 years and older weighing at least 40 kg who are at risk for progression to severe COVID-19 and/or at high risk of hospitalization. COVID-19 illness can range from very mild (including some unreported symptoms) to severe, including illness leading to death. Although information so far suggests that most COVID-19 illness is mild, severe illness can occur and may make some of your other medical conditions worse. For example, people of all ages with severe, long-lasting (chronic) medical conditions (such as heart disease, lung disease, and diabetes) and other conditions including obesity appear to be at higher risk of hospitalization due to COVID-19. Older age also puts people at higher risk for hospitalization from COVID-19, with or without other medical conditions.

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

The following medical conditions or other factors may put adult and pediatric patients (12 to 17 years old and weighing at least 40 kg) at higher risk of progression to severe COVID-19: ○ Older age (e.g., age ≥65 years) ○ Obesity or Overweight (e.g., adults with a BMI >25 kg/ ^m2 or, if 12-17 years of age, a BMI ≥85th percentile for age and sex based on CDC growth charts, https://www.cdc.gov/ growthcharts/clinical_charts.htm) ○ Pregnancy ○ Chronic kidney disease ○ Diabetes ○ Immunosuppressive disease or immunosuppressive therapy ○ Cardiovascular disease (including congenital heart disease) or hypertension ○ Chronic lung disease (e.g., chronic obstructive pulmonary disease, asthma [moderate to severe], interstitial lung disease, cystic fibrosis, and pulmonary hypertension) ○ Sickle cell disease ○ Neurodevelopmental disorders (e.g., cerebral palsy) or other conditions that confer medical complexity (e.g., genetic or metabolic syndromes and Severe congenital anomalies) ○ Dependent on a medically relevant technology (e.g., tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19))

Other medical conditions or factors (e.g., race or ethnicity) may also place individual patients at higher risk of progression to severe COVID-19, and the authorization of REGEN-COV under the EUA is not limited to the conditions listed above. For additional information about medical conditions and factors associated with an increased risk of progression to severe COVID-19, see the CDC website: www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions .html. Health care providers should consider the benefits-risks for individual patients.

Restrictions on authorized use: • In this illustrative use, REGEN-COV should not be used in the following patients: - People who are hospitalized due to COVID-19, or - Those who require oxygen therapy due to COVID-19, or - Among those receiving long-term oxygen therapy due to underlying non-COVID-19 related comorbidities, those who require an increase in baseline oxygen flow rate due to COVID-19. However, the Alternative Authorized Use covers those who are receiving continuous oxygen therapy due to underlying non-COVID-19 related comorbidities, who may be hospitalized due to COVID-19 and/or require oxygen therapy due to COVID-19 and/or who are Use REGEN-COV in patients with COVID-19 who require increased baseline oxygen flow rates.

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

Secondary Objectives: Phase 1 Part A • Assess additional measures of virological efficacy of mAb10933 + mAb10987 compared to placebo • Assess clinical efficacy of mAb10933 + mAb10987 compared to placebo • Compare using different sample types (nasopharyngeal [NP] , nose and saliva) • Characterize the pharmacokinetic (PK) profile of mAb10933 and mAb10987 in serum • Assess the immunogenicity of mAb10933 and mAb10987 Part B • Evaluate mAb10933 + Additional indicators of virological efficacy of mAb10987 compared to placebo • Assess the clinical efficacy of mAb10989 compared to placebo • Compare RT-qPCR results collected with different sample types (NP, nasal and saliva) • Characterize mAb10989 in serum PK Profile • To assess the immunogenicity of mAb10989 Phase 2 • To assess additional measures of virological efficacy of mAb10933 + mAb10987 compared to placebo • To assess the clinical efficacy of mAb10933 + mAb10987 and mAb10989 compared to placebo. • Evaluation of MAB10933 + MAB10987 and MAB10989 Compared with placebo, the concentration of MAB10933, MAB10987 and MAB10989 in serum • Evaluation of MAB10933, MAB10987, and MAB10989 immunogenicity • Evaluation MA B10933 + MAB10987 and MAB10989 Virological efficacy in reducing viral shedding of SARS-CoV-2 compared with placebo. • Assess the safety and tolerability of mAb10933 + mAb10987 and mAb10989 compared to placebo • Characterize the concentrations of mAb10933, mAb10987 and mAb10989 in serum • Assess the immunogenicity of mAb10933, mAb10987 and mAb10989

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

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 versus placebo. On Day 1, eligible patients in Part A were randomly assigned to a single intravenous (IV) administration of mAb10933 + mAb10987 (low dose), mAb10933 + mAb10987 (high dose), mAb10989, or placebo.

The patient is then isolated for the first 48 hours after dosing, during which time the patient is closely monitored for serious adverse events (SAEs) and adverse events of special concern (AESI). On Day 3, if medically appropriate, the patient can go home after completing their assessments for the day. After completion of assessment on Day 7, all patients are sent home if medically appropriate. Safety information (SAE and AESI) will be collected throughout the study period, as will information about any medical visits related to COVID-19. Nasopharyngeal (NP swab), nasal swab, and saliva samples were collected to assess viral shedding. The study ends on Day 29, where patients undergo final in-person assessment, including NP swab, nasal swab and/or saliva sample collection (if available) and blood draw for PK, anti-drug antibodies (ADA) and exploration sexual analysis. season2 On Day 1, eligible patients will be randomized 1:1:1:1 to a single dose of mAb10933 + mAb10987 (low dose), mAb10933 + mAb10987 (high dose), mAb10989, or placebo. Patients were observed for 2 hours after infusion of study drug and sent home if no SAE or AESI was observed. Nasopharyngeal swabs were collected every other day for the first 2 weeks, and then twice weekly thereafter. Blood samples are collected regularly. Information on treatment-induced SAEs, AESIs, and COVID-19-related medical visits were recorded throughout the study period. On day 29, patients underwent final assessment, including nasopharyngeal swab collection and blood draw for PK, ADA, and exploratory analyses.

Study Duration : The study duration for each patient is 30 days.

Study population : This study included adult non-hospitalized patients with a positive diagnostic test for SARS-CoV-2.

Sample size—Phase 1 includes enrollment until up to 100 patients have been randomized. Phase 2 includes enrollment until approximately 1,300 patients have been randomized. It is estimated that Phase 3 will require 704 patients (176 patients in each arm).

Inclusion criteria: Patients must meet the following criteria to be eligible for inclusion in the study: 2. Male or female ≥18 years old (or the legal age of majority in the country) at the time of randomization; 3. Positive for SARS-CoV-2 ≤72 hours before randomization Molecular diagnostic testing (by confirmed SARS-CoV-2 RT-PCR or other molecular diagnostic assays using appropriate samples (such as NP, nasal, oropharyngeal [OP] or saliva)). A history of positive results for tests performed ≤72 hours prior to randomization is acceptable; 4. Those who meet one of the following two criteria: a. Symptomatic cohort (all periods): have a history of positive results as determined by the investigator Determined symptoms consistent with COVID-19 and onset ≤7 days prior to randomization or b. Asymptomatic Cohort ( Phase 2): All of the following: • Not present at any time <2 months prior to randomization Symptoms consistent with COVID-19 (as determined by investigator) • No positive SARS-CoV-2 test results in samples collected >7 days prior to randomization • Confirmed COVID-19 >14 days prior to randomization OR Individuals with confirmed positive SARS-COV-2 tests have no known exposure (of any duration) 5. Maintain indoor air with _O2 saturation ≥93%; 6. Are willing and able to provide data from study patients or legally acceptable representatives Signed informed consent form and 7. Willing and able to comply with study procedures, including providing samples for viral shedding testing after discharge.

Exclusion Criteria: Patients who meet any of the following criteria are excluded from the study: 1. Admitted prior to randomization or hospitalized at the time of randomization (inpatient) due to COVID-19; 2. 3 days prior to the screening visit Participated in or is participating in clinical studies evaluating COVID-19 convalescent plasma, anti-SARS-CoV-2 monoclonal antibodies, or intravenous immune globulin (IVIG) within 5 months or less than 5 months of the half-life of the investigational product (whichever is longer) ; 3. Previous, current or planned future use of COVID-19 convalescent plasma, anti-SARS CoV 2 mAb, Intravenous immune globulin (IVIG) (any indication), systemic corticosteroids (any indication), or any Emergency Use Authorization (EUA)-approved treatment; 4. Known allergy or anaphylaxis to components of the study drug ; 5. Discharged, or planned to be discharged to an isolation center; 6. Pregnant or lactating women; or 7. At least 6 months before the first dose/first treatment, during the study, and after the last dose Month, persistent sexual activity in women of childbearing potential (WOCBP)* or sexually active men who are unwilling to use highly effective contraception. Signs and symptoms of anaphylaxis, including infusion-related reactions, may include: fever, chills, nausea, headache, bronchospasm, hypotension, angioedema, throat irritation, rash (including urticaria), scrapie, myalgia, and dizziness . Very effective birth control methods in women include: • Steady use of combination (containing estrogen and progestin) hormonal contraception (oral, intravaginal, transdermal) or progestin-only hormonal contraception (oral, injectable, implantable) Intrauterine device (IUD), • Intrauterine hormone-releasing system (IUS), • Bilateral fallopian tube ligation, • Vasectomy partner , ^† and/or • Abstinence. ^‡,§ Male study participants with WOCBP partners were required to use condoms unless they had a vasectomy † or practiced abstinence. ^‡,§ * WOCBP is defined as a woman who is fertile after menarche until she becomes postmenopausal, unless she is permanently infertile. Postmenopausal status is defined as the absence of menstruation for 12 months without an alternative medical cause. Follicle-stimulating hormone (FSH) levels in the postmenopausal range can be used to confirm postmenopausal status in women who are not using hormonal contraception or hormone replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the onset of postmenopausal status. The above definitions are based on Clinical Trials Facilitation Group (CTFG) guidelines. Women who have had a documented hysterectomy or tubal ligation do not need a pregnancy test or birth control. Permanent sterilization methods include hysterectomy, bilateral fallopian tube resection, and bilateral oophorectomy. † The vasectomy partner or the vasectomy study participant must have received a medical evaluation of the success of the procedure. ‡ Abstinence is considered highly effective only when defined as the avoidance of heterosexual intercourse throughout the risk period associated with the study drug. The reliability of abstinence needs to be assessed with respect to the duration of clinical trials and the preferred and common lifestyle patterns of patients.

Study Treatment : mAb10933 + mAb10987 combination therapy, 2.4 g (1.2 g each of mAb10933 and mAb10987) IV single dose administered; mAb10933 + mAb10987 combination therapy, 8.0 g (4.0 g of each of mAb10933 and mAb10987) administered Each) IV single dose; mAb10989 monotherapy, 1.2 g IV single dose; or placebo IV single dose.

Evaluation Metrics : Specify the primary, secondary and exploratory evaluation metrics for each period, as defined below.

Primary Outcome Measures The primary endpoints for Phase 1 are: Parts A and B • Proportion of patients with a treatment-emergent serious adverse event (SAE) through day 29 • Patients with an infusion-related reaction (grade ≥ 2) through day 4 Proportion • Proportion of patients with anaphylaxis (grade ≥ 2) up to day 29 • Time-weighted average change from baseline in viral shedding (log ₁₀ copies/ml) from day 1 to day 22, as measured by quantitative regression Transcription quantitative polymerase chain reaction (RT-qPCR) measured in nasopharyngeal (NP) swab samples. The primary outcome measure for Phase 2 is the time-weighted average change from baseline in viral shedding (log ₁₀ copies/ml) from Day 1 to Day 22, as measured by RT-qPCR in NP swab samples. The primary outcome measure for Phase 3 is the proportion of patients with ≥1 COVID-19-related medical visit through day 29.

Secondary Outcome Measures Phase 1 Virology • Time-weighted average change from baseline in viral shedding (log ₁₀ copies/ml) from Day 1 to Day 22, as measured by RT-qPCR in saliva samples • Since Day 22 Time-weighted average change from baseline in viral shedding (log ₁₀ copies/ml) from day 1 to day 22, as measured by RT-qPCR in nasal swab samples • Achieved negative RT-qPCR in all samples tested time without subsequent positive RT-qPCR in any test sample (NP swab, saliva or nasal swab) • Change in SARS-CoV-2 virus shedding from baseline at each visit up to day 29, e.g. Change from baseline in SARS-CoV-2 viral shedding at visits as measured by RT-qPCR in NP swabs up to day 29, as measured in saliva samples by RT-qPCR up to day 29 Change from baseline in SARS-CoV-2 viral shedding at each visit on day 29, as measured by RT-qPCR in nasal swabs • RT-qPCR results for different sample types (NP, nasal, and saliva) Correlation and Consistency • Time-weighted average change from baseline in viral shedding (log ₁₀ copies/ml) from Day 1 to post-baseline study days (eg, Days 5, 7, 15, and 29) Clinical • Until Day 29 Proportion of patients with ≥1 COVID-19-related medical visit per day COVID-19-related medical visits will be defined as: hospitalizations with COVID-19 as the primary reason for hospitalization, or outpatient visits with COVID-19 as the primary reason for visit visits (including ER visits, UCCs, physician offices, or telemedicine visits) • Proportion of patients with ≥2 COVID-19-related medical visits through day 29 • Percentage of patients with COVID-19-related medical visits through day 29 Total • Proportion of patients admitted with COVID-19 as of day 29 • Proportion of patients with ≥1 outpatient or telemedicine visit as of day 29 PK/ADA • Serum concentrations of mAb10933, mAb10987, and mAb10989 and corresponding PK parameters • Immunogenicity, as measured by anti-drug antibodies (ADA) against mAb10933, mAb10987 and mAb10989 Phase 2 Secondary endpoints for Phase 2 are: Virology • Achieve negative RT in NP swabs - Time to qPCR, no subsequent positive RT-qPCR • Change in viral shedding from baseline at each visit up to day 29, as measured by RT-qPCR in NP samples • From day 1 to post-baseline study Time-weighted average change from baseline in viral shedding (log ₁₀ copies/ml) by day (e.g., days 5, 7, 15, and 29) Clinical • Patients with ≥1 COVID-19-related medical visit through day 29 Proportion • Proportion of patients with ≥2 COVID-19 related medical visits through day 29 • Total number of COVID-19 related medical visits through day 29 • Proportion of patients hospitalized with COVID-19 as of day 29 • Proportion of patients admitted with COVID-19 as of day 29 Proportion of patients admitted to ICU due to COVID-19 at day 29 • Proportion of patients with ≥1 outpatient or telemedicine visit due to COVID-19 as of day 29 • Proportion of patients requiring mechanical ventilation due to COVID-19 as of day 29 • Number of days hospitalized with COVID-19 • Proportion of patients with all-cause mortality as of day 29 • Proportion of patients with treatment-induced SAEs as of day 29 • Proportion of patients with infusion-related reactions (grade ≥ 2) as of day 4 • Proportion of patients with anaphylaxis (grade ≥2) until day 29 • Time of first onset of any symptoms of COVID-19 • Duration of symptoms consistent with COVID-19 PK/ADA • Serum concentrations of mAb10933, mAb10987 and mAb10989 • Immunogenicity, as measured by anti-drug antibodies (ADA) against mAb10933, mAb10987 and mAb10989 Phase 3 Secondary endpoints for Phase 3 are: Virology • Viral shedding from day 1 to day 22 (log ₁₀ Replicas/ml) time-weighted average change from baseline, as measured by RT-qPCR in NP swabs • Time to reach a negative RT-qPCR in NP swabs, with no subsequent positive RT-qPCR • Until the Change in SARS-CoV-2 viral shedding from baseline at each visit on Day 29, as measured by RT-qPCR in NP swabs • From Day 1 to post-baseline study days (e.g., Days 5, 7 , 15 and 29 days) time-weighted average change from baseline in viral shedding (log ₁₀ copies/ml) Clinical • Proportion of patients with ≥ 2 COVID-19-related medical visits through day 29 • COVID- through day 29 Total number of 19-related medical visits • Proportion of patients with ≥1 outpatient or telemedicine visit due to COVID-19 as of day 29 • Proportion of patients hospitalized with COVID-19 as of day 29 • Proportion of patients with COVID-19 as of day 29 -Proportion of patients admitted to ICU by 19 • Proportion of patients requiring mechanical ventilation due to COVID-19 as of day 29 • Number of days hospitalized with COVID-19 • Proportion of patients with all-cause mortality as of day 29 • Treatment available as of day 29 Proportion of patients with SAE • Proportion of patients with infusion-related reactions (grade ≥ 2) up to day 4 • Proportion of patients with anaphylaxis (grade ≥ 2) up to day 29 PK/ADA • mAb10933, mAb10987 and mAb10989 in serum Concentrations • Immunogenicity as measured by anti-drug antibodies against mAb10933, mAb10987 and mAb10989

Exploratory Assessment Metrics The exploratory assessment metrics for Phases 1 and 2 are: • Proportion of treatment failure patients with mutations in the gene encoding the SARS-CoV-2 S protein up to day 29 • At each visit up to day 29 Changes and percentage changes in neutrophil-lymphocyte ratio (NLR) • Changes and percentage changes in D-dimer at each visit up to day 29 • Changes in ferritin at each visit up to day 29 and percentage change • Change and percentage change in C-reactive protein (CRP) at each visit up to day 29 • Change and percentage change in lactate dehydrogenase (LDH) at each visit up to day 29 • SE-C19 Changes in item scores over time • Changes in PGIS scores over time • PGIC scores on day 29 • Proportion of patients admitted to ICU due to COVID-19 as of day 29 (period 1 only) • Needed due to COVID-19 as of day 29 Proportion of patients on mechanical ventilation

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 medical visit COVID-19 visits Depends on details; Safety - Record serious adverse events and adverse events of special concern, blood collection and vital signs in safe laboratories. Nasal swabs and saliva samples are used to collect secretions from patients to determine the presence of SARS-CoV-2 virus and measure viral shedding. Statistics plan :

Primary efficacy analysis —The primary efficacy variable for Phases 1 and 2 was the 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 primary hypothesis was estimated as the mean difference between each of the anti-S SARS-CoV-2 mAb treatments and placebo in the primary efficacy variable in the FAS. The main efficacy variable was calculated using the trapezoidal rule based on the observed data and analyzed using the analysis of covariance (ANCOVA) model, with treatment group and random stratification as fixed effects and baseline viral shedding as covariates. For phase 2, analyzes were performed separately for each cohort (symptomatic and asymptomatic) and for both cohorts combined. Least squares mean estimates of the time-weighted average change in viral shedding from baseline for each treatment group and the difference between each anti-thorn mAb treatment group and placebo are presented along with corresponding p-values, standard errors, and associated 95% confidence intervals ( In period 2, respectively for each group and for the two groups combined). The primary efficacy variable for Phase 3 was the proportion of patients with medical visits due to worsening of COVID-19 symptoms and symptoms, using a stratified Cochran-Mantel-Haenszel test at the two-sided 0.05 level. test) for comparison between groups. P values and 95% confidence intervals for treatment differences are presented below.

Safety Analysis —Safety data including serious adverse events and adverse events of particular concern, vital signs, and laboratory tests are listed and summarized by the treatment team.

Results —The Seamless Phase 1/2/3 trial described above demonstrates SARS-CoV-2 virus in non-hospitalized patients with COVID-19 when treated with the combination of mAb10933 and mAb10987 (REGN-COV-2) The burden and time to relieve symptoms are significantly reduced. REGEN-COV also significantly reduces COVID-19-related medical visits. The randomized, double-blind trial measured the effect of adding REGEN-COV to common standard of care compared with adding placebo to standard care.

The final analysis of the phase 1/2 portion included 799 patients: 275 (arm 1) and 524 (arm 2). Patients were randomly assigned (1:1:1) to placebo, 2.4 g of mAb10933+mAb10987 antibody cocktail (also known as REGEN-COV), or 8.0 g of REGEN-COV, and characterized at baseline against endogenous SARS-CoV-2 Sexual immune response (serum antibody-positive/negative). Efficacy was assessed in patients with positive baseline RT-qPCR results; safety was assessed in all patients. Prespecified hierarchical analyzes were performed on virological assessment indicators in Group 2 to confirm previously reported descriptive analyzes from Group 1. The proportion of patients with ≥1 Covid-19 related medical visit (MAV) up to day 29 was assessed in Groups 1+2.

In patients with baseline viral load >10 ⁷ copies/mL (prespecified primary outcome measure), REGEN-COV (2.4g + 8.0g combined dose group) compared with placebo, viral load through day 7 (log10 copies /mL) was significantly greater: -0.68 (95% CI, -0.94 to -0.41; P < 0.0001). Across all baseline viral loads, this change was 0.73 in seronegative patients (P<0.0001) and -0.36 in the overall population (P=0.0003). Proportion of patients with ≥1 Covid-19-related MAV: 2.8% (12/434) with REGEN-COV vs. 6.5% (15/231) with placebo (P=0.024; relative risk reduction=57%), in The relative risk reduction for MAV was greater among patients with ≥1 risk factor for hospitalization (72%) or who were seronegative (65%). Adverse events were similar among groups.

Trial Design Summary: Patients were randomly assigned (1:1:1) to receive placebo, 2.4 g REGEN-COV (1.2 g each of casirimab and idelimumab), or 8.0 g REGEN-COV ( 4.0 g each of casirumab and idelimumab) ( Figure 5 ). The 29-day Phase 2 trial includes a screening/baseline period (Day -1 to Day 1), a follow-up period (Day 2 to Day 25), and the end-of-study visit (Day 29). The Phase 1 and Phase 2 portions of the trial are identical except for additional pharmacokinetic analysis in Phase 1.

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

[ Table 5A. ] Demographic and Baseline Medical Characteristics* ( N=799 ; full analysis set) characteristic Total(N=799) Placebo (N=266) REGEN-COV 2.4 g (N=266) REGEN-COV 8.0 g (N=267) REGEN-COV combination (N=533) Demographics Median age (IQR) - years 42.0 (31.0-52.0) 42.0 (32.0-53.0) 42.0 (31.0-52.0) 42.0 (30.0-52.0) 42.0 (30.0-52.0) Male—Number (%) 376 (47.1) 134 (50.4) 122 (45.9) 120 (44.9) 242 (45.4) Hispanic or Latino Ethnicity—Number (%)† 403 (50.4) 137 (51.5) 132 (49.6) 134 (50.2) 266 (49.9) Race—Number (%) † Caucasian 681 (85.2) 227 (85.3) 224 (84.2) 230 (86.1) 454 (85.2) black or african american 74 (9.3) 24 (9.0) 27 (10.2) 23 (8.6) 50 (9.4) asian 14 (1.8) 4 (1.5) 6 (2.3) 4 (1.5) 10 (1.9) American Indian or Alaska Native 5 (0.6) 3 (1.1) 1 (0.4) 1 (0.4) 2 (0.4) unknown 7 (0.9) 3 (1.1) 1 (0.4) 3 (1.1) 4 (0.8) Not reported 18 (2.3) 5 (1.9) 7 (2.6) 6 (2.2) 13 (2.4) Median weight (IQR)—kg 81.60 (69.90-95.30) 81.80 (70.80-94.30) 81.60 (69.90-94.50) 81.20 (68.00-97.10) 81.60 (69.30-95.30) Body Mass Index‡ 29.67±8.228 29.96±10.460 29.51±6.413 29.57±7.355 29.54±6.890 Obesity—Number (%)§ 298 (37.3) 93 (35.0) 101 (38.0) 104 (39.0) 205 (38.5) Baseline viral load in nasopharyngeal swabs Original value number of patients 752 259 243 250 493 Average viral load (range)—copies/ml 18719108.2±28449769.31 20949819.7±30172071.11 17403960.8±27210806.40 17686414.3±27755446.26 17547192.8±27460771.64 Median viral load (range)—copies/ml 304500.0 (1-71000000) 437000.0 (1-71000000) 295000.0 (1-71000000) 262500.0(1-71000000) 270000.0(1-71000000) Baseline viral load in nasopharyngeal swabs (log ₁₀ scale) number of patients 752 259 243 250 493 Average viral load-log10 copies/ml 5.16±2.500 5.21±2.511 5.23±2.449 5.05±2.544 5.14±2.497 Median viral load (range)—log ₁₀ copies/ml 5.48 (0.0-7.9) 5.64 (0.0-7.9) 5.47 (0.0-7.9) 5.42 (0.0-7.9) 5.43 (0.0-7.9) Baseline viral load in nasopharyngeal swab category—Number (%) >10 ⁴ 523 (65.5) 176 (66.2) 180 (67.7) 167 (62.5) 347 (65.1) >10 ⁵ 439 (54.9) 149 (56.0) 148 (55.6) 142 (53.2) 290 (54.4) >10 ⁶ 332 (41.6) 114 (42.9) 110 (41.4) 108 (40.4) 218 (40.9) >10 ⁷ 256 (32.0) 93 (35.0) 82 (30.8) 81 (30.3) 163 (30.6) Positive baseline qualitative RT-PCR—Number (%) 665 (83.2) 231 (86.8) 215 (80.8) 219 (82.0) 434 (81.4) Baseline serum C-reactive protein level number of patients 600 203 200 197 397 Average level—mg/L 13.930±28.8461 19.449±37.5595 10.991±24.1638 11.227±21.1793 11.108±22.7035 Median level (range)—mg/L 3.750 (0.10-239.67) 4.860 (0.10-232.04) 3.240 (0.12-239.67) 3.420 (0.14-157.96) 3.320 (0.12-239.67) Baseline serum antibody status—Number (%) negative 408 (51.1) 134 (50.4) 140 (52.6) 134 (50.2) 274 (51.4) positive 304 (38.0) 106 (39.8) 96 (36.1) 102 (38.2) 198 (37.1) unknown 87 (10.9) 26 (9.8) 30 (11.3) 31 (11.6) 61 (11.4) Symptom onset to randomization number of patients 698 240 222 236 458 Median time from symptom onset to randomization (IQR) - number of days 3.0 (2-5) 3.0 (2-5) 3.0 (2-5) 3.0 (2-5) 3.0 (2-5) At least one hospitalization risk factor—Number (%)¶ 483 (60.5) 158 (59.4) 165 (62.0) 160 (59.9) 325 (61.0) SD, standard deviation. *Positive and negative values are mean ±SD. Due to rounding, percentages may not total to 100. IQR represents interquartile range, and RT-PCR reverse transcription polymerase chain reaction. †Race and ethnicity reported by patient ‡Body mass index is weight in kilograms divided by height in meters squared. §Obesity is defined as a body mass index greater than 30. ¶Risk factors for hospitalization include age over 50 years, obesity, cardiovascular disease (including hypertension), chronic lung disease (including asthma), chronic metabolic disease (including diabetes), chronic kidney disease (including receipt of dialysis), chronic liver disease, and immunocompromise ( immunosuppressed or receiving immunosuppressants).

Intervention: At baseline (Day 1), mAb10933 (casirimab) and mAb10987 (idelimab) (diluted in 250-ml standard saline solution) were administered intravenously over a 1-hour period. coadministered) or saline placebo. Evaluation indicators

The primary virological assessment and two key secondary clinical assessments were prespecified in this Phase 1+2 (collectively, Phase 1/2) analysis and graded as described in Table 5B. The primary virological assessment was defined as the time-weighted average change in viral load (log10 copies/ml) from baseline (day 1) up to day 7. Key secondary clinical outcome measures are the proportion of patients with at least one Covid-19 related medical visit (MAV) through day 29 and the proportion of patients with at least one Covid-19 medical visit (MAV) consisting solely of hospitalization or emergency room (ER) visits or urgent care visits. The proportion of patients with -19-related MAV. MAV was defined as a hospitalization or ER, urgent care, or physician office/telemedicine visit confirmed by the investigator to be related to Covid-19.

[ Table 5B. ] Phase 2 main analysis of virological and clinical evaluation indicators Evaluation index number describe 1 For the REGEN-COV 2.4 g and 8.0 g combination arm versus placebo (patients 276 to 799), among mFAS patients with baseline viral loads >10 ⁷ copies/ml, viral loads from day 1 to day 7 (log10 copies/ml mL) time-weighted average daily change from baseline 2 For the combination of REGEN-COV 2.4 g and 8.0 g versus placebo (patients 276 to 799), in mFAS patients with baseline viral load > ¹⁰ copies/ml, viral load from day 1 to day 7 (log10 copies/ml ) Time-weighted average daily change from baseline 3 For the REGEN-COV 2.4 g and 8.0 g combination arms versus placebo (patients 276 to 799), in serum antibody-negative (seronegative) mFAS, viral load (log10 copies/ml) from days 1 to 7 vs. Time-weighted average daily change from baseline 4 Time-weighted average daily viral load (log10 copies/ml) relative to baseline in mFAS from Day 1 to Day 7 for the REGEN-COV 2.4 g and 8.0 g combination arm versus placebo (patients 276 to 799) change 5 For the REGEN-COV 8.0 g arm versus placebo (patients 276 to 799), among mFAS patients with baseline viral load > ¹⁰ copies/mL, viral load (log10 copies/mL) from Day 1 to Day 7 vs. Time-weighted average daily change from baseline 6 For the REGEN-COV 2.4 g arm versus placebo (patients 276 to 799), among mFAS patients with baseline viral load > ¹⁰ copies/mL, viral load (log10 copies/mL) from Day 1 to Day 7 vs. Time-weighted average daily change from baseline 7 For the REGEN-COV 8.0 g arm versus placebo (patients 276 to 799), in mFAS patients with baseline viral load > ¹⁰ copies/ml, viral load (log10 copies/ml) from day 1 to day 7 vs. Time-weighted average daily change from baseline 8 For REGEN-COV 2.4 g versus placebo (patients 276 to 799), viral load (log10 copies/ml) relative to baseline from days 1 to 7 in mFAS patients with baseline viral load > ¹⁰ copies/ml time weighted average daily change in 9 For the REGEN-COV 2.4 g and 8.0 g combination arm versus placebo (patients, proportion of patients with MAV by day 29 in mFAS 10 For the REGEN-COV 2.4 g and 8.0 g combination arm versus placebo (patients 1 to 799), proportion of patients in the MAV subset consisting solely of hospitalizations or emergency room visits or urgent care visits through day 29 in mFAS mFAS, modified full analysis set; MAV, medical visit

Safety measures for the Phase 1/2 portion of the trial include adverse events that occurred or worsened during the observation period (Phase 1 only; Grades 3 and 4 only), serious adverse events (SAEs), and adverse events of special concern (AESI): Grade ≥2 allergic or infusion-related reaction. Statistical analysis

The statistical analysis plan for the presented analysis was completed before the database locked and unblinded the Phase 2 data set of an additional 524 patients. 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 hours from randomization (baseline) but a negative central laboratory qualitative PCR test at baseline (detection limit, 714 copies/ml) were self-administered Modify the analysis exclusion of virological and clinical evaluation indicators in the full analysis set (mFAS). Subgroup analysis by serological status and baseline viral load was prespecified in the statistical analysis plan. Safety was assessed in patients with FAS receiving study drug (active or placebo).

To confirm the virological efficacy found in analysis set 1 (patients 1 to 275), virological assessment indicators were analyzed using data from patients 276 to 799, inclusive (524 patients; analysis set 2). However, the analysis of clinical measures and safety utilized data from all available patients, including the first 275 patients (patients 1 to 799; analysis groups 1+2).

Virological efficacy assessment metrics were calculated as discussed below. Key secondary clinical measures were analyzed using Fisher's exact test. A hierarchical testing strategy was used to analyze virological and clinical evaluation indicators under two-sided α=0.05 to control type I error. Statistical analysis was performed using SAS software, version 9.4 or higher (SAS Institute). baseline characteristics

799 patients were randomized in the Phase 1/2 portion of the trial. In the combined group of 799 patients, 266, 267, and 266 patients were assigned to receive low-dose REGEN-COV, high-dose REGEN-COV, or placebo, respectively ( Figure 6 ). Of 799 patients (analysis group 1+2), 87 (10.9%) tested negative in the central laboratory SARS-CoV-2 NP RT-qPCR assay at baseline and 47 (5.9%) had no central laboratory Laboratory baseline viral load data were available; therefore, the modified full analysis (mFAS) set included 665 patients. Similarly, of the 524 patients in analysis group 2 (primary virologic efficacy analysis), the mFAS set included 437 patients.

Among the 799 randomized patients, the median age was 42.0 years, 47% were male, 9% identified as black or African American, and 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 analysis group 1 of 275 patients and analysis group 2 of 524 patients (Table 5C).

[ Table 5C. ] Phase 1/2 Demographics and Baseline Medical Characteristics* ( N=524 ; full analysis set) characteristic Total(N=524) Placebo (N=173) REGEN-COV 2.4 g (N=174) REGEN-COV 8.0 g (N=177) REGEN-COV combination (N=351) Median age (IQR)—years 41.0 (28.0-52.0) 40.0 (28.0-53.0) 42.0 (29.0-53.0) 39.0 (28.0-51.0) 41.0 (28.0-52.0) Male—Number (%) 242 (46.2) 84 (48.6) 76 (43.7) 82 (46.3) 158 (45.0) Hispanic or Latino Ethnicity—Number (%)† 250 (47.7) 91 (52.6) 80 (46.0) 79 (44.6) 159 (45.3) Race—Number (%) † Caucasian 457 (87.2) 155 (89.6) 150 (86.2) 152 (85.9) 302 (86.0) black or african american 39 (7.4) 10 (5.8) 12 (6.9) 17 (9.6) 29 (8.3) asian 11 (2.1) 2 (1.2) 6 (3.4) 3 (1.7) 9 (2.6) American Indian or Alaska Native 3 (0.6) 1 (0.6) 1 (0.6) 1 (0.6) 2 (0.6) unknown 4 (0.8) 1 (0.6) 1 (0.6) 2 (1.1) 3 (0.9) Not reported 10 (1.9) 4 (2.3) 4 (2.3) 2 (1.1) 6 (1.7) Median weight (IQR)—kg 79.80 (68.00-93.00) 81.00 (69.40-91.00) 79.30 (68.35-91.40) 79.40 (67.60-95.70) 79.40 (68.00-94.00) Body Mass Index‡ 29.38±8.800 30.07±11.828 29.03±6.291 29.04±7.386 29.04±6.855 Obesity—Number (%)§ 183 (34.9) 59 (34.1) 62 (35.6) 62 (35.0) 124 (35.3) Baseline viral load in nasopharyngeal swabs Original value number of patients 494 168 159 167 326 Average viral load—copies/ml 20153955.3±28853829.01 25281106.2±31606803.98 18101836.4±26953942.48 16949916.6±27112316.53 17511742.5±26999735.08 Median viral load (range)—copies/ml 630500.0 (1-71000000) 1660000.0 (1-71000000) 301000.0 (1-71000000) 369000.0 (1-71000000) 342500.0 (1-71000000) Baseline viral load in nasopharyngeal swabs (log ₁₀ scale) number of patients 494 168 159 167 326 Average viral load—log ₁₀ copies/ml 5.30±2.514 5.50±2.546 5.34±2.426 5.08±2.560 5.20±2.495 Median viral load (range)—log ₁₀ copies/ml 5.80 (0.0-7.9) 6.22 (0.0-7.9) 5.48 (0.0-7.9) 5.57 (0.0-7.9) 5.53 (0.0-7.9) Baseline viral load in nasopharyngeal swab category—Number (%) >10 ⁴ 353 (67.4) 120 (69.4) 120 (69.0) 113 (63.8) 233 (66.4) >10 ⁵ 301 (57.4) 108 (62.4) 96 (55.2) 97 (54.8) 193 (55.0) >10 ⁶ 237 (45.2) 87 (50.3) 76 (43.7) 74 (41.8) 150 (42.7) >10 ⁷ 185 (35.3) 71 (41.0) 61 (35.1) 53 (29.9) 114 (32.5) Positive baseline qualitative RT-PCR—Number (%) 437 (83.4) 150 (86.7) 142 (81.6) 145 (81.9) 287 (81.8) Baseline serum C-reactive protein level number of patients 333 111 112 110 222 Average level—mg/L 13.066 (25.5848) 17.722 (31.9234) 10.931 (20.8046) 10.540 (22.1667) 10.738 (21.4425) Median level (range)—mg/L 3.570 (0.10-157.96) 5.020 (0.10-153.80) 3.640 (0.12-135.36) 2.475 (0.18-157.96) 3.145 (0.12-157.96) Baseline serum antibody status—Number (%) negative 292 (55.7) 101 (58.4) 96 (55.2) 95 (53.7) 191 (54.4) positive 176 (33.6) 56 (32.4) 58 (33.3) 62 (35.0) 120 (34.2) unknown 56 (10.7) 16 (9.2) 20 (11.5) 20 (11.3) 40 (11.4) Median time from symptom onset to randomization (IQR) - number of days 3.0 (2-5) 3.0 (2-5) 3.0 (2-5) 3.0 (2-5) 3.0 (2-5) At least one hospitalization risk factor—Number (%)¶ 307 (58.6) 100 (57.8) 108 (62.1) 99 (55.9) 207 (59.0) SD, standard deviation. *Positive and negative values are mean ±SD. Due to rounding, percentages may not total to 100. IQR represents interquartile range, and RT-PCR reverse transcription polymerase chain reaction. †Race and ethnicity reported by patient ‡Body mass index is weight in kilograms divided by height in meters squared. § Obesity is defined as a body mass index greater than 30. ¶Risk factors for hospitalization include age over 50 years, obesity, cardiovascular disease (including hypertension), chronic lung disease (including asthma), chronic metabolic disease (including diabetes), chronic kidney disease (including receipt of dialysis), chronic liver disease, and immunocompromise ( immunosuppressed or receiving immunosuppressants).

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. The median baseline viral load was 5.48 log10 copies/ml (47 of 799 patients had missing baseline data); 256 (32.0%) patients had a baseline viral load >107 copies/ml. In the entire trial population, the average time from symptom onset to randomization was 3.4 days: 3.2 days for patients with negative serum antibodies; 3.6 days for patients with positive serum antibodies; 2.9 days for patients with viral loads >107 copies/ml; and For patients with a load >107 copies/ml, it was 3.8 days. Among 408 patients with ≥1 risk factor for hospitalization, 336 (82.3%) were seronegative or had a viral load >104 copies/ml. natural history

In this analysis, the natural history of Covid-19 in placebo-treated patients confirmed that the presence of endogenous antibodies to SARS-CoV-2 at baseline is an important indicator of viral and clinical outcomes. Patients in the placebo group who were seroantibody negative at baseline had a higher median viral load at baseline than those who were seroantibody positive (7.73 log10 copies/ml vs. 3.88 log10 copies/ml), and It essentially takes longer to reach LLQ or undetectable viral levels (Figures 7 and 8). Similarly, for clinical outcomes, patients who were seronegative at baseline had substantially higher Covid-19-related MAV rates (2.4%; 2/83) compared with placebo patients who were seropositive at baseline (2.4%; 2/83) 9.7%; 12/124). Because endogenous immune responses correlate with baseline viral titers, there is an expected correlation between Covid-19-related MAV risk and baseline viral load and the presence of risk factors: 0% (0/55) of baseline viral loads ≤104 replicates MAV occurred in 8.5% (15/176) of patients with a baseline viral load >104 copies/mL and 2.2% (2/89) of patients without risk factors compared with 9.2% (13/142) of patients with ≥1 MAV occurred among risk factors (Figure 9).

Virological efficacy

Prespecified comparison of graded virological efficacy assessment indicators in analysis set 2 of 524 patients with confirmed SARS-CoV-2 positivity by NP RT-qPCR at baseline (mFAS; n=437) (Table 5B and Table 5D). In all prespecified viral efficacy comparisons, treatment with REGEN-COV significantly reduced viral load through day 7 compared to placebo (Table 5D; Figure 10A , Figure 10B , and Figure 11 ). In the first comparison, REGEN-COV treatment (combination 2.4 g and ^8.0 g dose) and placebo was -0.68 log copies/ml (95% CI, -0.94 to -0.41; P<0.0001) (Table 5D). Similarly, in patients who were seronegative at baseline (n=256), the least squares mean difference in daily change in TWA from baseline for REGEN-COV treatment versus placebo was -0.73 log copies/ml (95% CI, -0.97 to -0.48; P<0.0001), compared with -0.36 log10 copies/ml (95% CI, -0.56 to -0.16; P=0.0003) in the entire modified full analysis set (n=437). These data indicate that the reduction in viral load observed with treatment with the antibody cocktail was primarily driven by effects in seronegative patients, as previously observed (Table 5D; Figure 10A , Figure 10B , and Figure 11 ). Across all virological efficacy measures compared, low-dose and high-dose antibody cocktails were similarly effective (Table 5D). Results from additional key virological assessment metrics are provided in Table 5E, Figure 12 and Figure 13 .

[ Table 5D. ] Key virological and clinical assessment indicators Evaluation indicators placebo REGEN-COV 2.4 g REGEN-COV 8.0 g REGEN-COV combination Time-weighted average change from baseline in viral load* (log ₁₀ copies/ml) from day 1 to day 7 (analysis group 2) Baseline viral load >10 ⁷ copies/ml (mFAS) number of patients 70 58 52 110 Least square mean change (SE)—log ₁₀ replicates/ml -1.46 (0.15) -2.14 (0.16) -2.13 (0.16) -2.13 (0.13) 95% CI -1.75, -1.16 -2.44, -1.83 -2.44, -1.82 -2.39, -1.87 Difference vs. placebo on day 7—log ₁₀ copies/ml Least square mean (SE) -0.68 (0.16) -0.68 (0.16) -0.68 (0.14) 95% CI † (P value) -0.99, -0.37 (<0.0001) -0.99, -0.36 (<0.0001) -0.94, -0.41 (<0.0001) Baseline viral load >10 ⁸ copies/ml (mFAS) number of patients 86 72 73 145 Least square mean change (SE)—log ₁₀ replicates/ml -1.40 (0.13) -2.13 (0.13) -1.98 (0.13) -2.06 (0.11) 95% CI -1.65, -1.14 -2.38, -1.88 -2.24, -1.72 -2.27, -1.85 Difference vs. placebo on day 7—log ₁₀ copies/ml Least square mean (SE) -0.73 (0.14) -0.58 (0.14) -0.65 (0.12) 95% CI † (P value) -1.01, -0.45 (<0.0001) -0.86, -0.30 (<0.0001) -0.89, -0.41 (<0.0001) Baseline serum antibody status: Negative (mFAS) number of patients 93 80 77 157 Least square mean change (SE)—log ₁₀ replicates/ml -1.18 (0.10) -1.92 (0.11) -1.90 (0.11) -1.91 (0.08) 95% CI -1.38, -0.99 -2.13, -1.71 -2.11, -1.69 -2.06, -1.76 Difference vs. placebo on day 7—log ₁₀ copies/ml Least square mean (SE) -0.74 (0.14) -0.71 (0.14) -0.73 (0.12) 95% CI † (P value) -1.02, -0.45 (<0.0001) -1.00, -0.43 (<0.0001) -0.97, -0.48 (<0.0001) mFAS number of patients 146 137 141 278 Least square mean change (SE)—log ₁₀ replicates/ml -1.30 (0.09) -1.69 (0.09) -1.64 (0.09) -1.66 (0.07) 95% CI -1.49, -1.12 -1.87, -1.50 -1.82, -1.46 -1.81, -1.52 Difference vs. placebo on day 7—log ₁₀ copies/ml Least square mean (SE) -0.38 (0.12) -0.34 (0.12) -0.36 (0.10) 95% CI † (P value) -0.61, -0.15 (0.0011) -0.57, -0.11 (0.0035) -0.56, -0.16 (0.0003) Proportion of patients with Covid-19 related MAV up to day 29 (analysis group 1+2) mFAS number of patients 231 215 219 434 Patients with ≥1 visit in 29 days—Number (%) 15 (6.5) 6 (2.8) 6 (2.7) 12 (2.8) Difference vs. placebo—percentage points -3.7 -3.8 -3.7 95% CI † (P value) -12.9, 5.6 (0.0754) -13.0, 5.5 (0.0737) -11.7, 4.3 (0.0240) Proportion of patients in the Covid-19-related MAV subset consisting solely of hospitalizations or ER visits or urgent care visits until day 29 (analysis group 1+2) mFAS number of patients 231 215 219 434 Patients with ≥1 visit in 29 days—Number (%) 10 (4.3) 5 (2.3) 5 (2.3) 10 (2.3) Difference vs. placebo—percentage points -2.0 -2.0 -2.0 95% CI † (P value) -11.2, 7.3 (0.2983) -11.3, 7.2 (0.2962) -10.0, 6.0 (0.1575) *Time-weighted average change in viral load is based on a covariance model analysis with treatment group, risk factor, and baseline antibody status as fixed effects and baseline viral load and viral load in each baseline treatment group as covariances. Confidence intervals are not adjusted for multiplicity. †Confidence intervals for the difference (REGEN-COV-placebo) are based on exact methods and were not adjusted for multiplicity.

[ Table 5E. ] Change from baseline in viral load (log 10 copies/ ml) _at each visit among patients with no risk factors for hospitalization or ≥1 risk factor for hospitalization Evaluation indicators placebo REGEN-COV 2.4g REGEN-COV 8.0 g REGEN-COV combination Change in viral load from baseline (log ₁₀ copies/ml) up to day 7 (analysis group 2) No risk factors for hospitalization due to COVID-19 (mFAS) number of patients 55 48 58 106 Least square mean change (SE)—log ₁₀ replicates/ml -2.50 (0.21) -2.90 (0.23) -3.02 (0.21) -2.97 (0.16) 95% CI -2.92, -2.08 -3.34, -2.45 -3.44, -2.60 -3.28, -2.65 Difference vs. placebo on day 7—log ₁₀ copies/ml Least square mean (SE) -0.39 (0.30) -0.51 (0.29) -0.47 (0.25) 95% CI (P value) -0.99, 0.20 (0.1933) -1.08, 0.05 (0.0757) -0.97, 0.03 (0.0677) ≥1 risk factor for hospitalization due to COVID-19 (mFAS) number of patients 84 83 74 157 Least square mean change (SE)—log ₁₀ replicates/ml -2.56 (0.17) -2.74 (0.17) -3.08 (0.17) -2.90 (0.13) 95% CI -2.90, -2.23 -3.08, -2.41 -3.42, -2.73 -3.14, -2.65 Difference vs. placebo on day 7—log ₁₀ copies/ml Least square mean (SE) -0.18 (0.23) -0.51 (0.24) -0.34 (0.20) 95% CI (P value)* -0.63, 0.27 (0.4310) -0.98, -0.05 (0.0302) -0.73, 0.06 (0.0951) *P values are based on a MMRM model with the terms baseline, baseline serostatus, country, treatment, visit, visit treatment, base treatment, and visit base interaction as fixed effects and subject as a random effect. CI, confidence interval; LS, least squares; SE, standard error.

Using the linear trapezoidal rule (the area under the curve of the change from baseline divided by the time interval of the observation period), the time-weighted mean of each patient up to day 7 relative to baseline (day 1) was calculated as the area under the concentration-time curve ( TWA) diurnal variation in virological efficacy estimates using a covariation analysis model with treatment group, country, and risk factor (no risk factor vs. at least one risk factor) as fixed effects and baseline viral load and interaction by baseline treatment as a covariate. clinical efficacy

There are two clinical efficacy measures prespecified for use in tiered testing: the proportion of patients with at least one Covid-19-related medical visit (MAV) and the proportion of patients with at least one Covid-19 that consists solely of hospitalization or an ER or urgent care visit. The proportion of patients with relevant MAV (Table 5B and Table 5D). Two assessment indicators were assessed up to day 29 in a pooled group of 799 patients (analysis group 1+2) with confirmed SARS-CoV-2 positivity by NP RT-qPCR at baseline (mFAS; n=665). Overall, 67% of Covid-19-related MAVs were inpatient or emergency room (ER) visits (30% and 37%, respectively), 26% were physician office visits/telemedicine, and 7% were urgent care visits. sight. A description of Covid-19 related MAVs is included in Table 5F.

［ Table 5F. ] Covid-19 Related MAV Description* Pt age gender race race Risk factors(Y/N) Duration of symptoms before randomization Baseline viral load (log10 copies/ml) treatment group 1 twenty three 42 M Non-Hispanic or Latino American Caucasian Y 7 days 7.08 placebo 2 13 77 F Hispanic or Latino American Not reported Y 6 days 4.04 placebo 3 12 40 M Hispanic or Latino American Caucasian Y 2 days 7.85 placebo 4 28 89 F Hispanic or Latino American Caucasian Y 3 days 7.85 placebo 5 30 50 F Hispanic or Latino American Caucasian Y 1 day 7.85 placebo 6 10 48 F Non-Hispanic or Latino Caucasian Y 4 days 7.09 placebo 7 19 62 F Non-Hispanic or Latino Caucasian Y To be determined 7.85 placebo 8 9 27 F Non-Hispanic or Latino asian american Y 5 days 4.41 placebo 9 twenty one 37 F Non-Hispanic or Latino Caucasian Y 6 days 6.23 placebo 10 4 31 F Non-Hispanic or Latino Caucasian N 1 day 6.59 placebo 11 26 66 M Non-Hispanic or Latino Caucasian Y 2 days 7.03 placebo 12 31 26 M Non-Hispanic or Latino Caucasian N 6 days 5.88 placebo 13 5 43 M Hispanic or Latino American Caucasian Y 4 days 6.55 placebo 14 6 53 F Hispanic or Latino American Caucasian Y 3 days 4.7 placebo 15 29 63 F Hispanic or Latino American Caucasian Y To be determined 7.85 placebo 16 16 28 F Non-Hispanic or Latino Caucasian Y 7 days 3.99 low dose 17 25 82 F Hispanic or Latino American Caucasian Y 2 days 6.73 low dose 18 7 25 M Non-Hispanic or Latino Caucasian N 7 days 6.29 low dose 19 20 19 F Non-Hispanic or Latino American Caucasian N 2 days 7.85 low dose 20 27 58 F Hispanic or Latino American Caucasian Y 6 days 4.57 low dose twenty one twenty two 44 M Non-Hispanic or Latino American Vietnamese N 5 days 4.97 low dose twenty two twenty four 20 F Non-Hispanic or Latino American Caucasian N 4 days 7.24 High dose † twenty three 14 20 M Hispanic or Latino American Caucasian Y To be determined 5.71 high dose twenty four 2 37 F Non-Hispanic or Latino American Caucasian, American Indian, or Alaska Native Y 2 days 5.45 high dose 25 8 49 M Non-Hispanic or Latino American Caucasian Y 3 days 7.85 high dose 26 17 36 F Non-Hispanic or Latino American Caucasian N 1 day 7.85 high dose 27 15 55 F Non-Hispanic or Latino American Caucasian Y 6 days 4.84 high dose

[Table 5F— continued] Pt MAV type research day Viral load at or around MAV (log 10 copies/ml) (days) Reasons for MAV Details 1 twenty three Hospitalized 2 7.80 (1) pneumonia 6 days hospital stay without supplemental oxygen, ICU care or mechanical ventilation 2 13 Hospitalized 3 4.64 (3) hypoxemia He was hospitalized for 5 days and received supplemental oxygen. No need for ICU care or mechanical ventilation 3 12 Hospitalized 9 5.97 (9) respiratory failure He was hospitalized for 6 days, treated with albuterol and supplemented with oxygen. No ICU care or mechanical ventilation is required. 4 28 Hospitalized 10 5.51 (7) COVID-19 exacerbation/acute respiratory failure He was hospitalized for 15 days, treated with steroids and antibiotics, and received supplemental oxygen. No ICU care or mechanical ventilation is required. 5 30 Hospitalized 10 5.22 (5) pneumonia No other details are available at this time. 6 10 ER visit 5 5.42 (3) Vomiting/abdominal pain No other details are available at this time. 7 19 ER visit 10 5.02 (9) Fever/shortness of breath No other details are available at this time. 8 9 ER visit 13 3.24 (13) Tachycardia Ibuprofen is prescribed and IV saline is administered 9 twenty one ER visit 15 0 (15) shortness of breath Prescription for fluticasone and albuterol 10 4 ER visit twenty one 0 (18) COVID-19 symptoms/fever/prolonged intermittent chest pain Prescription of deoxytetracycline and albuterol 11 26 Physician's Office/Telemedicine 4 5.23 (3) cough Prescription benzonatate, ibuprofen 12 31 Physician's Office/Telemedicine 5 3.36 (5) persistent cough Prescription of azithromycin and acetaminophen 13 5 Physician's Office/Telemedicine 7 3.49 (7) worsening of cough Prescription of cefoxone, azithromycin, and ambroxol 14 6 Physician's Office/Telemedicine 7 3.53 (7) worsening of cough Prescription of cefoxone, azithromycin, and ambroxol 15 29 Physician's Office/Telemedicine 10 0 (9) COVID-19 worsens Prescribing promethazine 16 16 Hospitalized 2 3.99 (1) Shortness of breath/pneumonia He was hospitalized for 2 days and treated with antibiotics, remdesivir, tocilizumab and steroids. No need for supplemental oxygen, ICU care or mechanical ventilation 17 25 Hospitalized 3 6.73 (1) pneumonia He was hospitalized for 7 days and received supplemental oxygen. No ICU care or mechanical ventilation is required. 18 7 ER visit 5 4.14 (5) pneumonia No other details are available at this time. 19 20 ER visit 5 3.83 (5) shortness of breath No other details are available at this time. 20 27 Physician's Office/Telemedicine 4 3.61 (3) Cough/shortness of breath Budesonide, albuterol, and praminetadine were prescribed. twenty one twenty two urgent care clinic 5 4.70 (5) Shortness of breath/decreased oxygen saturation Prescription for cefdinir, azithromycin and combivent twenty two twenty four ER visit 3 4.95 (3) difficulty breathing No other details are available at this time. twenty three 14 Hospitalized 1 5.71 (1) Shortness of breath/worsening of COVID-19 infection He was hospitalized for 7 days and required supplemental oxygen and ICU care. Mechanical ventilation is not required. twenty four 2 ER visit 2 5.45 (1) shortness of breath Prescription for Ketolac, Dexamethasone, Ondansetron 25 8 ER visit 2 7.90 (1) chest pain No other details are available at this time. 26 17 Physician's Office/Telemedicine 8 4.11 (7) pleurisy Prednisone prescribed 27 15 urgent care clinic 10 0 (9) Covid-19 symptoms Prescribing azithromycin and prednisone *Analysis group 1+2; modify the full analysis set. †Received only 12.7 mL infusion, discontinued due to possible infusion-related reaction. ER, emergency room; ICU, intensive care unit; MAV, medical visit.

The proportion of patients in the REGEN-COV treatment group (2.4 g and 8.0 g combined doses) with ≥1 Covid-19-related MAV was 2.8% (15 of 231) in the placebo group compared with 6.5% in the placebo group % (12 of 434), which represented a relative reduction of 57% (absolute difference relative to placebo, -3.7 percentage points; 95% CI, -7.9% to -0.3%; P=0.024) (Table 5D ). The treatment effect observed with REGEN-COV was greater among patients with baseline serum antibody negative (3.4% vs. 9.7% placebo; 65% relative reduction) (Table 5G). For the final grading measure, the proportion of patients with a Covid-19-related hospitalization or ER or emergency care visit was numerically lower in the REGENCOV group (compared with placebo), but the difference did not reach statistical significance (Table 5D ). Post hoc analysis showed that a lower proportion of antibody cocktail-treated patients (combination dose group) were hospitalized or died (0.7% [3 of 434] vs. 2.2% [5 of 231]; a relative decrease of 68 %), and the proportion of such patients who were hospitalized or had an ER visit decreased (1.8% [8 of 434] vs. 4.3% [10 of 231]; relative decrease of 58%) (Table 5H).

[ Table 5G. ] Proportion of patients with ≥1 Covid-19- related MAV by baseline serum antibody status Evaluation indicators placebo REGEN-COV 2.4 g REGEN-COV 8.0 g REGEN-COV combination Proportion of patients with MAV* up to day 29 (analysis group 1+2) Baseline serum antibody status: negative (mFAS) number of patients 124 121 115 236 Patients with ≥1 visit within 29 days—Number (%) 12 (9.7) 4 (3.3) 4 (3.5) 8 (3.4) Difference vs. placebo—percentage points -6.4 -6.2 -6.3 95% CI (P value) † -18.9, 6.0 (0.0677) -18.7, 6.6 (0.0704) -17.1, 4.6 (0.0264) Baseline serum antibody status: positive (mFAS) number of patients 83 73 80 153 Patients with ≥1 visit within 29 days—Number (%) 2 (2.4) 2 (2.7) 1 (1.3) 3 (2.0) Difference vs. placebo—percentage points 0.3 -1.2 -0.4 95% CI (P value) † -15.3, 16.0 (1.0000) -16.5, 14.1 (1.0000) -13.7, 12.9 (1.0000) Baseline serum antibody status: unknown (mFAS) number of patients twenty four twenty one twenty four 45 Patients with ≥1 visit within 29 days—Number (%) 1 (4.2) 0 1 (4.2) 1 (2.2) Difference vs. placebo—percentage points -4.2 0 -1.9 95% CI (P value) † -32.9, 24.8 (1.0000) -29.5, 29.5 (1.0000) -26.7, 22.8 (1.0000) *COVID-19 related MAVs include hospitalizations, ER visits, urgent care clinic visits, and outpatient/physician office/telehealth visits. †95% CI and P values are based on exact methods. CI, confidence interval; ER, emergency room; MAV, medical visit.

[ Table 5H. ] Proportion of patients hospitalized, visited ER , and/ or died Evaluation indicators placebo REGEN-COV 2.4 g REGEN-COV 8.0 g REGEN-COV combination Proportion of patients who were hospitalized or visited the ER until day 29 (analysis group 1+2) mFAS number of patients 231 215 219 434 Patients with events within 29 days—Number (%) 10 (4.3) 4 (1.9) 4 (1.8) 8 (1.8) Difference vs. placebo—percentage points -2.5 -2.5 -2.5 95% CI (P value)* -11.7, 6.8 (0.1766) -11.7, 6.8 (0.1749) -10.4, 5.5 (0.0778) Proportion of patients who were hospitalized or died until day 29 (analysis group 1+2) mFAS number of patients 231 215 219 434 Patients with events within 29 days—Number (%) 5 (2.2) 2 (0.9) 1 (0.5) 3 (0.7) Difference vs. placebo—percentage points -1.2 -1.7 -1.5 95% CI (P value)* -10.5, 8.0 (0.4516) -10.9, 7.6 (0.2166) -9.4, 6.5 (0.1339) Proportion of patients hospitalized until day 29 (analysis group 1+2) mFAS number of patients 231 215 219 434 Patients with events within 29 days—Number (%) 5 (2.2) 2 (0.9) 1 (0.5) 3 (0.7) Difference vs. placebo—percentage points -1.2 -1.7 -1.5 95% CI (P value)* -10.5, 8.0 (0.4516) -10.9, 7.6 (0.2166) -9.4, 6.5 (0.1339) *95% CI and P values are based on exact methods. CI, confidence interval.

Additional post hoc analyzes investigated the effect of antibody cocktail treatment on MAV in various high-risk subgroups. The proportion of patients with ≥1 hospitalization risk factor (n=408) who had Covid-19-related MAV in the REGEN-COV arm (combination dose) versus placebo was: 2.6% versus 9.2% (absolute vs. placebo difference, -6.5 percentage points; 95% CI, -17 to 4; 72% relative reduction) ( Figure 14A , Figure 14B , and Figure 14C ; Table 5I). Proportion of patients (n=217) with ≥1 risk factor and Covid-19-related MAV viral load >104 copies/ml in the REGEN-COV (combination dose) versus placebo arms with negative serum antibodies at baseline were: 2.1% vs. 13.2% (absolute difference from placebo, -11.0 percentage points; 95% CI, -21 to -3; 84% relative reduction) (Table 5J). The majority (59%) of patients who experienced MAV had a viral load ≥4 log10 copies/ml at the time of medical presentation (Table 5F; Figure 15A , Figure 15B , and Figure 15C ). As with virological assessment measures, no meaningful differences in clinical outcomes were observed between low-dose versus high-dose treatment.

[ Table 5I. ] Proportion of patients with ≥1 Covid-19- related MAV among those with no risk factors for hospitalization or ≥1 risk factor for hospitalization Evaluation indicators placebo REGEN-COV 2.4 g REGEN-COV 8.0 g REGEN-COV combination Proportion of patients with Covid-19 related MAV* up to day 29 (analysis group 1+2) No risk factors for hospitalization due to Covid-19 (mFAS) number of patients 89 81 87 168 Patients with ≥1 visit within 29 days—Number (%) 2 (2.2) 3 (3.7) 2 (2.3) 5 (3.0) Difference vs. placebo—percentage points 1.5 0.1 0.7 95% CI (P value) † -13.5, 16.4 (0.6700) -14.8, 15.1 (1.0000) -12.1, 13.5 (1.0000) ≥1 risk factor for hospitalization due to Covid-19 (mFAS) number of patients 142 134 132 266 Patients with ≥1 visit within 29 days—Number (%) 13 (9.2) 3 (2.2) 4 (3.0) 7 (2.6) Difference vs. placebo—percentage points -6.9 -6.1 -6.5 95% CI (P value) † -18.6, 5.0 (0.0185) -17.9, 5.8 (0.0447) -16.6, 3.7 (0.0065) *COVID-19 related MAVs include hospitalizations, ER visits, urgent care clinic visits, and outpatient/physician office/telehealth visits. †95% CI and P value are based on exact method. CI, confidence interval; ER, emergency room; MAV, medical visit.

[ Table 5J. ] Proportion of patients with ≥1 Covid-19- related MAV among serologically negative and high-risk patients with viral load > ¹⁰ 4 Evaluation indicators placebo REGEN-COV 2.4 g REGEN-COV 8.0 g REGEN-COV combination Proportion of patients with Covid-19 related MAV* up to day 29 (analysis group 1+2) Seronegative and viral load >10 ⁴ copies/ml and high risk number of patients 76 79 62 141 Patients with ≥1 visit in 29 days—Number (%) 10 (13.2) 1 (1.3) 2 (3.2) 3 (2.1) Difference vs. placebo—percentage points -11.9% -9.9% -11.0% 95% CI (P value) -22.0, -4.0 (0.0042) -20.0, -0.1 (0.0651) -20.8, -2.9 (0.0019) *COVID-19 related MAVs include hospitalizations, ER visits, urgent care clinic visits, and outpatient/physician office/telehealth visits. †95% CI and P value are based on exact method. CI, confidence interval; ER, emergency room; MAV, medical visit.

Medical visits for Covid-19 exacerbations were compared using Fisher's exact test at a two-sided alpha level of 0.05 between the REGEN-COV combination dose group and placebo and between each REGEN-COV treatment group and placebo. patient ratio. Similar analyzes were conducted on the proportion of patients with a Covid-19-related hospitalization or emergency room or urgent care visit, as well as the proportion of patients with each type of medical visit. safety

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 in the placebo group (i.e. , 6 of 262 patients [2.3%]) experienced serious adverse events (SAEs) (Table 5K and Table 5L). All serious adverse events were considered attributable to advanced or progressive Covid-19 disease and/or associated concomitant clinical conditions and were not assessed to be related to study drug treatment.

Adverse events of special interest (AESI) (infusion-related reactions grade ≥2 and anaphylaxis) that developed or worsened during the safety observation period were reported as follows: no patients in the 2.4 g group, 4 (1.5) in the 8.0 g group %) patients and 2 (0.8%) patients in the placebo group (Table 5K and Table 5L).

[ Table 5K. ] Overview of Serious Adverse Events and Adverse Events of Particular Concern in the Safety Population event Placebo (N=262) REGEN-COV 2.4 g IV (N=258) REGEN-COV 8.0 g IV (N=260) REGEN-COV combination (N=518) Number of patients (percentage) any serious adverse events 6 (2.3) 4 (1.6) 2 (0.8) 6 (1.2) Any adverse event of particular concern* 2 (0.8) 0 4 (1.5) 4 (0.8) Any serious adverse event of particular concern* 0 0 0 0 Infusion-related reaction grade ≥2 within 4 days 1 (0.4) 0 4 (1.5) 4 (0.8) Anaphylaxis grade ≥ 2 within 29 days 2 (0.8) 0 0 0 Patients with adverse events that developed or worsened during the observation period † Patients with grade 3 or 4 events 4 (1.5) 3 (1.2) 2 (0.8) 5 (1.0) Patients with adverse events leading to death 0 0 0 0 Patients with adverse events leading to withdrawal from the trial 0 0 1 (0.4) 1 (0.2) Patients with adverse events leading to infusion interruption* 1 (0.4) 0 1 (0.4) 1 (0.2) *Events are grade 2 or higher allergic reactions or infusion-related reactions. †Events listed here were not present at baseline or were worsening of a pre-existing condition that occurred during the observation period (defined as the time from administration of REGEN-COV or placebo to the final follow-up visit).

[ Table 5L. ] Treatment-emergent serious adverse events and adverse events of special concern reported in subjects who received REGEN-COV Better terminology for system organ classes Placebo group (N=262) REGEN-COV 2.4 g IV (N=258) REGEN-COV 8.0 g IV (N=260) REGEN-COV combination (N=518) Number of patients (percentage) Serious adverse events* gastrointestinal disorders Vomiting 0 1 (0.4) 0 1 (0.2) Intestinal obstruction 0 0 1 (0.4) 1 (0.2) Nausea 0 1 (0.4) 0 1 (0.2) Vascular disorders high blood pressure 1 (0.4) 0 0 0 Respiratory, chest and mediastinal disorders hypoxia 2 (0.8) 0 0 0 difficulty breathing 0 0 1 (0.4) 1 (0.2) Metabolic and nutritional disorders high blood sugar 0 1 (0.4) 0 1 (0.2) Infections and infestations pneumonia 2 (0.8) 1 (0.4) 0 1 (0.2) Covid-19 1 (0.4) 0 0 0 Covid-19 pneumonia 0 1 (0.4) 0 1 (0.2) Adverse events of particular concern* gastrointestinal disorders stomach ache 0 0 1 (0.4) 1 (0.2) Vomiting 1 (0.4) 0 0 0 Nausea 1 (0.4) 0 0 0 Skin and subcutaneous tissue disorders itching 0 0 1 (0.4) 1 (0.2) Urticaria 0 0 1 (0.4) 1 (0.2) rash 1 (0.4) 0 0 0 General symptoms and conditions at the site of administration Chills 0 0 1 (0.4) 1 (0.2) Fever 0 0 1 (0.4) 1 (0.2) Vascular disorders flushing 0 0 1 (0.4) 1 (0.2) neurological disorders dizziness 1 (0.4) 0 0 0 headache 1 (0.4) 0 0 0 Injury, poisoning and surgical complications infusion related reactions 0 0 1 (0.4) 1 (0.2) *Only serious adverse events and adverse events of special concern (grade 2 or higher infusion-related reactions and allergic reactions) are collected. IV, intravenous;

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

[ Table 5M. ] Average concentrations of REGN10933 and REGN10987 in serum Nominal sampling time REGN 10933 (casirimab)* REGN 10987 (idemumab)* 1.2g 4.0 g 1.2g 4.0 g before administration 0.0578 (0.594) [202] 0.0421 (0.611) [210] 0.0640 (0.603) [186] 0 (0) [195] End of infusion ^† 333 (86.8) [135] 1022 (341) [126] 336 (106) [136] 1037 (332) [125] Day ^29§ 79.7 (34.6) [210] 250 (97.4) [223] 65.2 (28.1) [212] 205 (82.7) [222] *Mean (SD) [N], where N is the number of observations ^† Injection duration is 1 hour ^§ Concentrations observed on day 29, 28 days after dosing

Serum for drug concentration analysis was collected from all patients before dosing (at screening or baseline visit), on days 1 and 29 after the end of infusion. Additional serum collection was performed from stage 1 patients only on days 3, 5, 7, and 15. Measurement of REGN10933 (casirimab) and REGN10987 (idelimumab) in humans using a validated immunoassay using streptavidin microplates from Meso Scale Discovery (MSD, Gaithersburg, MD, USA) serum concentration. The method utilizes two anti-idiotypic monoclonal antibodies, each specific for mAb10933 or mAb10987, as capture antibodies. Captured mAb10933 and mAb10987 were detected using two different non-competing anti-idiotypic monoclonal antibodies, each also specific for mAb10933 or mAb10987. The bioanalytical method specifically quantifies the levels of each anti-SARS-CoV-2 spike mAb individually without interference from other antibodies. For each analyte in undiluted serum samples, the analytical lower limit of quantification (LLOQ) was 0.156 µg/mL.

Discuss

Findings from this final Phase 1/2 analysis of the REGEN-COV antibody cocktail for the treatment of outpatients with Covid-19 confirm and extend 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 are described. These data corroborate previous findings that patients who have not yet developed their own immune response at baseline (i.e., are seroantibody-negative at baseline) have a median viral load at baseline that is higher than that of patients who are seroantibody-positive. Almost 3 log copies/ml higher and takes longer to reach low or undetectable levels. Similar to other viral infections (such as HIV, Ebola virus disease, and influenza), high viral load appears to be a predictor of disease progression in Covid-19, as demonstrated by Covid-19-associated MAV in baseline viral loads >10 ⁴ copies /ml was enriched in placebo patients. Data also suggest that risk factors for severe disease, such as older age and obesity, may help predict outpatients most likely to have subsequent Covid-19-related MAV. For example, 9.2% (13/142) of placebo patients with ≥1 risk factor had MAV compared with 2.2% (2/89) of placebo patients without any risk factor. In this trial, >80% of patients with risk factors were seronegative or had a viral load > ¹⁰ copies/ml. In the absence of rapid serological tests or quantitative PCR analysis to identify high-risk patients, identifying patients with risk factors for hospitalization may help identify outpatients most likely to benefit from early treatment with antibody cocktails.

The prespecified fractional analysis described herein prospectively and with high statistical significance confirmed the virological efficacy of REGEN-COV and revealed similar virological efficacy of the antibody cocktail at 2.4 g and 8.0 g doses. Among seronegative patients with higher viral loads at baseline, the largest reductions in viral loads occurred during the first 5 days after treatment. Treatment has no apparent additional viral benefit in patients who have already mounted an effective endogenous antibody response to infection (seroantibody positivity). The reduction in viral load after treatment with any dose of REGEN-COV was accompanied by a significant reduction in the proportion of patients requiring subsequent Covid-19-related medical visits, the majority (67%) of which were hospitalizations or ER visits. The REGEN-COV antibody cocktail resulted in a 57% relative reduction in MAV (6.5% in placebo vs. 2.8% in the combination dose group; P=0.0240). Interestingly, the reduction in the proportion of patients with MAV treated with REGEN-COV compared to placebo occurred only after the first week of treatment. One possible explanation for this finding is that despite accelerated viral clearance, medical visits that occurred during the first week were not modifiable. For example, among patients treated with the antibody cocktail, all three hospitalizations occurred within the first three days after treatment, when viral load was still ≥4 log10 copies/ml, but there were no hospitalizations after day 7 (Table 5F ; Figure 15A , Figure 15B and Figure 15C ). In contrast, among patients treated with placebo, three of the five hospitalizations occurred after day 7, when viral loads were persistently high (≥4 log10 copies/ml). This data supports early identification and rapid treatment of outpatients with Covid-19 to optimize the efficacy of REGEN-COV treatment.

A low incidence of serious adverse events, infusion-related reactions, and anaphylaxis was observed. Similar to previously reported results, based on in vitro and preclinical data, the concentration of each antibody in serum on day 29 was much higher than the predicted neutralization target concentration.

Clinical evidence from this trial suggests that treatment has the greatest benefit in high-risk patients early after diagnosis, when they are most likely to have high viral loads and may not have yet mounted their own immune responses. Additionally, no adverse study outcomes were observed in patients with serum antibody positivity at baseline. Early treatment of Covid-19 outpatients is critical, and if viral load or serum antibody status cannot be rapidly determined, risk-benefit assessment supports treatment to prevent MAV in high-risk patients.

3 pilot project

Cohort 1 Patient Population—The Cohort 1 patient population of the Phase 3 portion of the study is adult (≥18 years) male and female patients: • Positive SARS-CoV-2 antigen or molecular diagnostic test (via validated SARS CoV-2 antigen, RT-PCR, or other molecular diagnostic assay) ≤72 hours before randomization. and • If symptoms are consistent with COVID-19 as determined by the investigator, onset ≤7 days before randomization and • ≥1 risk factor for severe COVID-19

Risk factors are defined as follows: a. Age＞50 years old 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 2 diabetes f. Chronic kidney disease, including dialysis patients g. Chronic liver disease h. Pregnancy i. Immunosuppression (examples include cancer treatment, bone marrow or organ transplantation, immunodeficiency, HIV (if poorly controlled or evidence of AIDS), sickle cell anemia, thalassemia, and long-term use of immune-weakening drugs).

Primary and key secondary assessment indicators for Group 1:

For Cohort 1, the primary outcome measure was COVID-19-related medical visits (MAV) through day 29. A COVID-19 related medical visit is defined as follows: hospitalization, emergency room (ER) visit, urgent care visit, physician office visit, or telemedicine visit where the primary reason for the visit is COVID-19. Patients with multiple medical visits were considered to have 1 event.

The prespecified key secondary outcome measure was the cumulative incidence of COVID-19-related hospitalizations or emergency room visits through day 29.

Other pre-specified key secondary measures include various types of COVID-19 related MAVs and related outcomes.

Together, the virological data provide conclusive evidence that mAb10933 + mAb10987 significantly enhances SARS-CoV-2 virus clearance. Additionally, data from the pooled Phase 1/2 analyzes indicate that viral load reduction was achieved by significantly reducing COVID-19-associated MAV (defined as hospitalizations, ER visits, urgent care visits, or physician offices or telemedicine for COVID-19 visit) and translate into clinical benefit. Specifically, prespecified and multiple control analyzes pooled Phase 1/2 data (n=799) demonstrated a statistically significant reduction in MAV in the mAb10933 + mAb10987 treatment group compared with placebo (2.8% in the combined dose group versus placebo). 6.5% placebo; p=0.0240). Most MAVs occur in patients at high risk, defined as being seronegative at baseline, having a higher baseline viral load, or having at least 1 pre-existing risk factor for severe COVID-19 (e.g., age >50 years, obesity , common pathological conditions). In an exploratory analysis, treatment with mAb10933 + mAb10987 demonstrated the greatest benefit in this high-risk group, with a reduction in the proportion of patients with MAV compared with placebo for those patients with baseline viral load >104 copies/ml. 62% (3.2% combination treatment vs. 8.5% placebo), 65% (3.4% combination treatment vs. 9.7% placebo) for those patients who were seronegative at baseline, and 65% (3.4% combination treatment vs. 9.7% placebo) for those with at least 1 severe COVID-19 Risk factors were present in 72% of these patients (2.6% combination treatment and 9.2% placebo). Taking into account the clinical benefit observed in Phase 2, Phase 3 will focus on confirming the clinical benefit of mAb10933 + mAb10987 in reducing MAV in high-risk patients, thereby demonstrating the clinical benefit of reducing viral load.

The sample size for Phase 3 Cohort 1 is estimated to be approximately 5,400 patients. Arm 1 continues until at least 80 hospitalizations or ER visits are observed among patients included in the primary analysis population (patients in mFAS with at least 1 risk factor) and there are 1,000 hospitalizations during the study period in the primary analysis population or the total number of patients visited by the ER exceeds 120.

The primary efficacy endpoint for Phase 3 Arm 1 is the cumulative incidence of COVID 19-related MAV in mFAS (randomized and treated PCR-positive patients with at least 1 risk factor at baseline) through Day 29.

The key secondary outcome measure for Phase 3 Cohort 1 was the cumulative incidence of COVID-19-related hospitalizations/ER visits through day 29, based on the time to first hospitalization/ER visit.

For Phase 3, planned virological analyzes are descriptive. Using the same method as the mFAS-based phase 2 primary virological assessment index, seronegative patients and seropositive patients were analyzed separately from day 1 to the post-baseline visit time point for viral load (log10 copies/ mL) time-weighted average change from baseline. Proportionality measures based on observed virological data were compared between groups using methods similar to those used for proportionality clinical measures. Seronegative mFAS as well as mFAS were analyzed.

To analyze the time course of the treatment effect on viral load, a mixed-effects model (MMRM) for repeated measures was used, using stratification for baseline, randomization, treatment, visit, treatment by baseline interaction, and visit by visit. Changes from baseline in viral load (log10 copies/ml) at each visit were analyzed for seronegative mFAS and mFAS in terms of baseline interaction and treatment by visit interaction.

The Phase 3 portion of the study evaluated 2 doses of mAb10933 + mAb10987, 1200 mg and 2400 mg, in a 1:1 ratio (600 mg and 1200 mg of each mAb, respectively). In the Phase 1 and 2 results, the 2400 mg and 8000 mg doses of mAb10933 + mAb10987 demonstrated similar virological and clinical efficacy as assessed by MAV, 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 as the highest dose as well as the lower dose in this Phase 3 study.

Pediatric patients aged 0 to <18 years may be included as a separate cohort (Cohort 2) in the Phase 3 portion of the study to assess the safety, PK, immunogenicity and efficacy of mAb10933 + mAb10987. Two patients with COVID-19 symptoms or asymptomatic patients who are SARS-CoV-2 positive at baseline may be included in this cohort. Pediatric patients with risk factors for severe COVID-19 may be included in Group 2.

Pediatric patients in Cohort 2 may be randomized in a 1:1:1 allocation to receive a single intravenous (IV) dose of low-dose, high-dose mAb10933 + mAb10987 combination therapy, or placebo. However, mAb10933 + mAb10987 treatment groups can be stratified based on body weight, as defined in Table 6 below.

Dose selection in the pediatric population (<18 years) may utilize a weight-graded uniform dosing approach for both high and low doses. For each weight-graded dose for the higher dose in adults (2400 mg), the goal was to select a dose predicted by population PK modeling to ensure the fifth percentile of serum concentration (C28) at 28 days postdose Figures similar to or greater than the 5th percentile of C28 observed in adults at the 2400 mg dose. Additional considerations were made to ensure that the predicted Cmax and AUC0-28 for each weight-grade dose did not exceed values previously achieved in adults. Linear PK has been demonstrated for both mAb10933 and mAb10987, and therefore, the same 50% reduction used in selecting the lower adult dose in Phase 3 (2400 mg to 1200 mg) was applied to the pediatric weight bracket for the 1200 mg adult dose. of each dose (Table 6).

[Table 6 ]: mAb10933 + mAb10987 IV of each weight combination dosage, 3 period group 2 (Age 0 to <18 years) weight group 3 period group 2 mAb10933 + mAb10987 1200 mg IV Dosage (600 mg per mAb) dose equivalent ¹ 3 period group 2 mAb10933 + mAb10987 2400 mg IV Dosage (1200 mg per mAb) dose equivalent ¹ ≥40kg 1200 mg (600 mg per mAb) 2400 mg (1200 mg per mAb) ≥20 kg to <40 kg 450 mg (225 mg per mAb) 900 mg (450 mg per mAb) ≥10 kg to <20 kg 224 mg (112 mg per mAb) 450 mg (225 mg per mAb) ≥5 kg to <10 kg 120 mg (60 mg per mAb) 240 mg (120 mg per mAb) ≥2.5 kg to <5 kg 60 mg (30 mg per mAb) 120 mg (60 mg per mAb) <2.5kg 30 mg (15 mg per mAb) 60 mg (30 mg per mAb) 1 Dose values represent the total amount of mAb10933 + mAb10987 combination therapy administered as a single IV dose.

The primary objective for patients in Group 2 was safety, with MAV being a descriptive secondary objective.

The primary assessments in Group 2 were safety/tolerability and changes in serum drug concentration over time: • Proportion of patients with treatment-emergent serious adverse events (SAE) up to day 29 • Proportion of patients with infusion-related reactions (grade ≥2) by day 4 • Proportion of patients with anaphylaxis (grade ≥ 2) until day 29 • The concentration of mAb10933 and mAb10987 in serum changes over time • Immunogenicity, as measured by anti-drug antibodies (ADA) and neutralizing antibodies (NAb) against mAb10933 and mAb10987

Up to approximately 180 pediatric patients in Cohort 2 (60 per treatment group) will allow 45 patients to be randomized to each PK-ADA sampling plan. Issue 3 Adult Materials: Overview

The goal of the confirmatory Phase 3 trial ( Figures 31 and 32 ) is to prospectively demonstrate a clinically significant impact on the risk of COVID-19 hospitalization or all-cause death in high-risk outpatients and confirm safety. The trial also prospectively assessed potential benefit on symptom duration. The seamless design initially compared 8000 mg and 2400 mg with placebo and was revised to evaluate 2400 mg and 1200 mg with placebo based on the final analysis of the Phase 1/2 portion, which showed that the 8000 mg and 2400 mg doses were based on the antiviral and Clinical assessment indicators were indistinguishable (and clinical events occurred primarily in high-risk patients). Data comparing 8000 mg with placebo were transformed into descriptive analyses. Formal hierarchical analyzes first evaluated the 2400 mg dose versus concurrent placebo (in patients with ≥1 risk factor from the original and revised parts, n=~2700), and then evaluated the 1200 mg dose versus concurrent placebo (in patients with ≥1 risk factor) Among patients with 1 risk factor, n=~1500). A concomitant dose-ranging virology study in outpatients further evaluated the antiviral efficacy of REGEN-COV doses from 2400 mg to 300 mg IV (and 1200 mg to 600 mg subcutaneously) (Example 7). Key results are shown below.

[Table 7 ]: Key Results ^1-3 of the Phase 3 Outpatient Trial 1,200 mg IV placebo 2,400 mg IV placebo n=736 n=748 n=1,355 n=1,341 Patients with ≥ 1 COVID-19 related hospitalization or death through day 29 Risk reduction 70% (p=0.0024) 71% (p<0.0001) Number of patients with events 7(1.0%) 24 (3.2%) 18 (1.3%) 62 (4.6%) Time for COVID-19 symptoms to subside Median decrease (number of days) 4 (p<0.0001) 4 (p<0.0001) Median (number of days) 10 14 10 14 1. Based on the modified full analysis set (mFAS) population, which includes all randomized patients with a positive SARS-CoV-2 RT-qPCR test from a randomized nasopharyngeal swab and ≥1 risk factor for severe COVID-19. 2. Formal hierarchical analyzes first evaluated the 2,400 mg dose with concurrent placebo, and then evaluated the 1,200 mg dose with concurrent placebo. 3. Based on the phase 1/2 analysis showing that the 8,000 mg and 2,400 mg doses were indistinguishable, the phase 3 protocol was revised to compare 2,400 mg and 1,200 mg with placebo, and the 8,000 mg data were converted into descriptive analyses.

In a Phase 3 trial of 4,567 high-risk patients, mAb10933 + mAb10987 (REGEN-COV) significantly reduced COVID-19 hospitalization or all-cause death and shortened the time to symptom resolution by 4 days, confirming the clinical results seen in Phase 1/2 Benefits. Additionally, REGEN-COV administered as a single IV infusion of 1200 mg or 2400 mg significantly reduced the risk of COVID-19 in those patients who were SARS-CoV-2 PCR+ at baseline and had ≥1 risk factor for severe COVID-19 The proportion of patients who were hospitalized or died from any cause. Similar treatment effects were seen at two doses: 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). Greater reduction in COVID-19 hospitalization or all-cause death after study day 3 (89.2%, 2400 mg vs. PBO, p<0.0001; 71.7%, 1200 mg vs. PBO, p=0.0101); early events not available Modified. See Figure 35 , Figure 36 , and Figure 37. The effect was more pronounced in patients with high viral load and/or seronegative patients at baseline, but a meaningful risk reduction was found in seropositive patients. At Day 7, subgroup The viral load was also significantly reduced, with consistency between the 2400 mg and 1200 mg doses ( Figure 43 , Figure 44 , Figure 52 , Figure 53, Figure 54, Figure 55 , Figure 56 and Figure 58 ). Administration at two doses Administration of REGEN-COV resulted in faster symptom resolution: 2400 mg versus PBO, median 10 days versus 14 days; p<0.0001; 1200 mg versus PBO, median 10 days versus 14 days; p<0.0001 ( Figure 38 , Figure 39 ). A summary of these data is presented in Figure 33. Additionally, serious adverse events, including fatal events, were more frequent in the placebo (PBO) group compared with the REGEN-COV dose group (4.0% PBO vs. 1.4% combined REGEN-COV group) ( Figure 40 , Figure 41 , Figure 42 ). Demographic data for this study are shown in Figure 34. Phase 3 Adult Data: Complete Results and Discussion

In the Phase 1/2 portion of this adaptive Phase 1 to 3 randomized placebo-controlled master protocol, REGEN-COV demonstrated efficacy in outpatients, demonstrating rapid reduction in viral load and need for Covid-19-related medical attention. In fact, on February 19, 2021, the Independent Data Monitoring Committee (IDMC) recommended discontinuing enrollment of patients in the placebo arm of the Phase 3 portion of the master protocol due to the clear efficacy of REGEN-COV.

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 randomly assigned to intravenous placebo or a single treatment of various doses of REGEN-COV and followed for 29 days. Prespecified hierarchical analyzes compared the REGEN-COV 2400 mg dose with concurrent placebo and subsequently the 1200 mg dose with concurrent placebo on measures of risk of hospitalization or death and time to symptom resolution. Safety was assessed in all treated patients.

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

Treatment with REGEN-COV was well tolerated and resulted in significant reductions in Covid-19-related hospitalization or all-cause death, rapid resolution of symptoms, and reduction in viral load.

Trial Design—This is an adaptive, multicenter, randomized, double-blind, placebo-controlled Phase 1/2/3 master protocol in outpatients with Covid-19 (NCT04425629). The Phase 3 part included 3 cohorts: Cohort 1 (≥18 years old), Cohort 2 (<18 years old), and Cohort 3 (pregnant at randomization). Initially, Phase 3 patients were randomized 1:1:1 to receive placebo, REGEN-COV 2400 mg (1200 mg of each of casirimab and idelimumab) IV, or REGEN-COV 8000 mg (4000 mg of each) IV. mg of each antibody) IV ( Figure 81 ). Based on the phase 1/2 results showing that the 8000 mg and 2400 mg doses had similar antiviral and clinical efficacy, and that most clinical events occurred in high-risk patients, the trial was subsequently revised on November 14, 2020 to modify the population and dose. As a result of the revision, patients were subsequently enrolled with ≥1 risk factor for severe Covid-19 and randomized 1:1:1 to receive placebo, REGEN-COV 1200 mg (600 mg for each antibody) IV, or REGEN-COV 2400 mg (1200 mg of each antibody) IV. On February 19, 2021, according to IDMC recommendations, patients will no longer be randomized to receive placebo. The Phase 3 analysis presented here included Cohort 1 patients (≥18 years of age) randomized to REGEN-COV 2400 mg or 1200 mg, with a concurrent placebo arm serving as comparator.

Eligible patients (Group 1) were ≥18 years of age and non-hospitalized, with confirmed local SARS-CoV-2 positive diagnostic test results ≤72 hours prior to randomization and any Covid-19 symptom onset ≤7 days. Randomization in the initial Phase 3 portion will be stratified by country and presence of severe Covid-19 risk factors. In the revised Phase 3 portion, only patients with ≥1 risk factor for severe Covid-19 are eligible. Anti-SARS-CoV-2 antibodies were assessed in all patients at baseline: anti-thorn [S1] IgA, anti-thorn [S1] IgG, and anti-nucleocapsid IgG. Because analytical results were not available at the time of randomization, patients were subsequently grouped for virological and subgroup analysis purposes as serum antibody negative (if all available tests were negative), serum antibody positive (if any available tests were positive), or other ( Uncertain/unknown outcome).

At baseline (Day 1), REGEN-COV (diluted in standard saline solution for co-administration) or saline placebo was administered intravenously. Hospitalizations were assessed by investigators as related to Covid-19. The Electronic Diary COVID-19 Symptom Evolution (SE-C19) instrument assesses 23 Covid-19 symptoms daily. Quantitative virological analysis of nasopharyngeal (NP) swab samples and serum antibody testing were performed in a central laboratory and have been described previously.

Perform hierarchical testing on pre-specified primary and two key secondary assessment indicators ( Figure 89 ). The primary outcome measure was the proportion of patients with ≥1 Covid-19-related hospitalization or all-cause death by day 29. Two key secondary clinical outcomes were (1) the proportion of patients with ≥1 Covid-19-related hospitalization or all-cause death from day 4 to day 29, and (2) time to resolution of Covid-19 symptoms. The time to resolution of Covid-19 symptoms is defined as the time from randomization to the first day during which subjects rated "no symptoms" (score of 0) for all symptoms except cough, fatigue, and headache, which can It is "mild/moderate symptoms" (a score of 1) or "no symptoms" (a score of 0). Safety assessment indicators for the Phase 3 portion of the trial include serious adverse events (SAEs) and adverse events of special interest (AESI) that occurred or worsened during the observation period: grade ≥2 allergic reactions and infusion-related reactions and in health Adverse events resulting from treatment requiring medical attention at a nursing facility.

The statistical analysis plan for the presented analyzes was completed prior to database lock and unblinding of Phase 3 Cohort 1; the primary analysis did not include patients from Phase 1/2 of the previously reported trial. The full analysis set (FAS) included all randomized symptomatic patients. Efficacy analyzes were performed based on modified FAS (mFAS) defined as all randomized patients with a positive SARS-CoV-2 central laboratory-confirmed RT-qPCR test at baseline and ≥1 risk factor for severe Covid-19 . Safety was assessed in treated patients in 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 hierarchical Cochran-Mantel-Haenszel (CMH) test. , with country as the grading factor. P values for hierarchical CMH tests and 95% confidence intervals (CI) for relative risk reduction using the Farrington-Manning method are presented. Time to resolution of Covid-19 symptoms was assessed in patients with a baseline total severity score >3 and analyzed using the hierarchical log-rank test, with country as the grading factor. The median time and associated 95% CI were derived from the Kaplan-Meier method. Hazard ratios and 95% CIs were estimated by Cox regression models. The hierarchical test strategy was used to analyze the main and key clinical evaluation indicators under two-sided α=0.05 to control type I error ( Figure 89 ). Statistical analysis was performed using SAS software, version 9.4 or higher (SAS Institute). Results (test population)

Phase 3 patients were enrolled between September 24, 2020, and January 17, 2021. Initially, in the initial Phase 3 portion, a total of 3,088 patients with or without risk factors for severe Covid-19 were randomized to receive a single dose of placebo, REGEN-COV 8000 mg, or REGEN-COV 2400 mg. Subsequently, in the revised Phase 3 portion, an additional 2519 patients with ≥1 risk factor were randomized to receive a single dose of placebo, REGEN-COV 2400 mg, or REGEN-COV 1200 mg ( Figure 76 ). The median follow-up duration of patients was 45 days, with 96.6% of patients followed for >28 days.

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

The median NP viral load was 6.98 log ₁₀ copies/ml (IQR 5.45-7.85), and the majority of patients (69%) were SARS-CoV-2 serum antibody negative at baseline ( Figure 78 ); these high viral loads and the lack of endogenous immune response at baseline indicates that the included individuals were early in their infectious course. NP viral load and serum antibody negative status were similar among 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)

The risk of hospitalization or all-cause death related to Covid-19 is associated with baseline viral load: hospitalization/death occurred in a greater proportion of patients with a high viral load (baseline viral load) compared with patients with a lower viral load at baseline. Load > ¹⁰ copies/mL: 6.3% [55/876] and 4.2% [20/471] in the concurrent placebo group for 2400 mg and 1200 mg, respectively; baseline viral load ^≤10 copies/mL: For 2400 mg and 1200 mg, it was 1.3% [6/457] and 1.5% [4/273] in the concurrent placebo group, respectively) ( Figure 92 ).

Patients in the placebo group who were seroantibody negative at baseline had a higher median viral load at baseline than those who were seroantibody positive (7.45 log ₁₀ copies/ml vs. 4.96 log ₁₀ copies/ml) and their cost longer to keep virus levels below the lower limit of quantification (LLQ) ( Figure 82 ).

Baseline serum antibody status in placebo patients did not predict subsequent Covid-19-related hospitalization or all-cause death, as these rates were similar in seronegative and antibody-positive patients (antibody-negative: for 2400 mg and 1200 mg, in concurrent 5.3% [49/930] and 3.5% [18/519] of patients in the placebo group; antibody positive: 4.0% [12/297] in the concurrent placebo group for 2400 and 1200 mg, respectively and 3.7% [6/164]). However, placebo patients who were seropositive and subsequently required hospitalization or died had high viral loads at baseline and day 7, similar to seronegative patients who required hospitalization or died, suggesting that some seropositive patients may have ineffective congenital Antibody reaction ( Figure 93 ). Efficacy (primary evaluation metric)

REGEN-COV 2400 mg and 1200 mg similarly reduced Covid-19-related hospitalization or all-cause death by 71.3% (1.3% vs. 4.6% placebo; 95% CI: 51.7%, 82.9%; p<0.0001) and 70.4%, respectively. % (1.0% vs. 3.2% placebo; 95% CI: 31.6%, 87.1%; p<0.0024) ( Figure 79 , Figure 77A , Figure 77B , Figure 94 ). Similar reductions in Covid-19-related hospitalization or all-cause death were observed across the entire subgroup, including patients who were seropositive at baseline ( Figure 79 , Figure 83A , Figure 83B , and Figure 83C ). Efficacy (key secondary assessment metric)

A 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 ( Figure 77A , Figure 77B , Figure 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%]), with few events occurring at 2400 mg or 1200 mg mg REGEN-COV treatment group (5/1351 [0.4%] and 5/735 [0.7%] respectively) ( Figure 79 , Figure 84A , Figure 84B ).

Median time to resolution of Covid-19 symptoms was 4 days shorter than placebo in both REGEN-COV dose groups (10 days vs 14 days for 2400 mg and 1200 mg, respectively; p<0.0001) ( Figure 79 and Figure 77C ). More rapid resolution of Covid-19 symptoms was evident with either dose of REGEN-COV on Day 3. Both REGEN-COV doses were associated with similar improvements in symptom resolution across subgroups ( Figure 85 ).

All REGEN-COV doses (1200 mg, 2400 mg, and 8000 mg) resulted in similar and rapid reductions in viral load compared to placebo ( Figure 86A , Figure 86B , Figure 86C , Figure 87 , Figure 88A , Figure 88B , and Figure 88C ) . Efficacy (other secondary evaluation metrics)

REGEN-COV treatment was associated with a lower proportion of patients with Covid-19-related hospitalization ( Figure 95 ). Among patients hospitalized with Covid-19, patients in the REGEN-COV group had shorter hospital stays and lower ICU admission rates ( Figure 96 ).

REGEN-COV treatment was associated with a lower proportion of patients having a Covid-19-related hospitalization, emergency room visit, or all-cause death through day 29 ( Figure 97 ) and a lower proportion requiring any medical visit due to exacerbation of Covid-19 (hospitalization, emergency room visit, urgent care visit, or physician office/telemedicine visit) or all-cause death ( Figure 95 , Figure 98, and Figure 99 ). safety

More patients in the placebo group (4.0%) experienced serious adverse events (SAEs) compared with the REGEN COV dose group: 1.1% at 1200 mg, 1.3% at 2400 mg, and 1.7% at 8000 mg ( Figure 80 ). More patients experienced a treatment-emergent adverse event (TEAE) leading to death in the placebo group (5 patients, 0.3%) compared with the REGEN-COV dose group: 1 at 1200 mg (0.1%) and 1 at 2400 mg (<0.1%), and 0 cases in 8000 mg ( Figure 80 and Figure 100 ). Most adverse events were consistent with complications of Covid-19 ( Figure 101 and Figure 102 ) and most were considered unrelated to the study drug. Rare patients experienced infusion-related reactions (0 on placebo; 2, 1, and 3 on 1200 mg, 2400 mg, and 8000 mg) and anaphylaxis (1 on placebo and 1 on 2400 mg) ( Figure 91). Similar safety profiles were observed between REGEN-COV doses, with no discernible imbalance in safety events. No safety signals were observed in the safety laboratory parameters collected up to day 29. Pharmacokinetics

The mean concentrations of casirumab and idelimumab in serum on day 29 increased in a dose-proportional manner and were consistent with linear pharmacokinetics ( Figure 103 ). The mean day 29 concentrations of casirimab and idelimumab in serum were 46.4±SD22.5 and 38.3±SD19.6 mg/L, respectively, for the 1200 mg dose and 73.2±SD27, respectively, for the 2400 mg dose. 2 and 60.0 ± SD 22.9 mg/L; the estimated mean half-lives were 28.8 days for casirimab and 25.5 days for idelimumab ( Figure 103 ). Discuss

The aforementioned Phase 1/2 data show that in outpatients with Covid-19, REGEN-COV steadily reduces viral load, reduces the need for medical care, and despite the small number of events, is highly suggestive of a reduced risk of hospitalization. These clinical outcome data now clearly demonstrate that early treatment with REGEN-COV significantly reduces the risk of hospitalization or all-cause death in outpatients with risk factors for severe Covid-19. REGEN-COV at both the 1200 mg IV and 2400 mg IV doses resulted in an approximately 70% reduction in Covid-19 hospitalizations or all-cause death (versus placebo) within 28 days of treatment. Among hospitalized patients, REGEN-COV treatment also resulted in shorter duration of hospitalization and a lower proportion of patients requiring intensive care. Additionally, REGEN-COV at both doses led to faster resolution of Covid-19 symptoms, a median of four days. Therefore, a single dose of REGEN-COV in Covid-19 outpatients has the potential to improve patient outcomes and substantially reduce the health care burden experienced during this pandemic by reducing morbidity and mortality, including hospitalization and intensive care. potential. In addition, REGEN-COV can substantially accelerate recovery from Covid-19, which represents an additional benefit for patients as there is growing evidence that some patients, including those with mild symptoms, will have a variable prolonged recovery.

Without wishing to be bound by theory, we previously hypothesized that although host factors play a role in the course of the disease, SARS-CoV-2 morbidity and mortality are caused by high viral loads and that early treatment with a cocktail of anti-thorn monoclonal antibodies can Significantly improve this risk. In the placebo group, we found that patients who were hospitalized or died from any cause had significantly higher viral loads and slower viral clearance at baseline, independent of baseline serological status. Patients in the placebo group who had developed their own endogenous antibody response to SARS-CoV-2 (seroantibody positivity) had similar rates of hospitalization or death compared with seroantibody-negative patients, suggesting that some seroantibody-positive patients have ineffective immune response. Furthermore, seroantibody-positive placebo patients with Covid-19-related hospitalization or death also had high baseline viral load levels similar to seroantibody-negative patients who also had such events, supporting the identification of high viral load as severe Covid- 19 key driving factors. In addition, this study also confirms that there is a clinical benefit of REGEN-COV regardless of baseline serum antibody status, making serological testing at the time of Covid-19 diagnosis unimportant for clinical treatment decisions. This is important given the prevalence of vaccine use, which may not be effective in preventing serious infection in some patients (as appeared to be the case for some patients with ineffective natural immunity in this trial) or baseline serum antibody positivity status due to emerging variants of concern (VOC).

Both the 1200 mg and 2400 mg doses of REGEN-COV had similar antiviral and clinical efficacy, indicating that we were well above the minimum effective dose. Both doses rapidly reduced viral load and resulted in faster viral clearance compared with placebo. In addition to providing clinical benefit to individual patients receiving REGEN-COV, rapid antiviral effects may be associated with public health benefits through reduced risk of viral transmission and suppression of SARS-CoV-2 VOCs.

A low incidence of serious adverse events and allergic and infusion-related reactions was observed. Based on in vitro and preclinical data, the concentration of each antibody in serum on day 29 was well above the predicted neutralization target concentration.

The emergence of resistant variants of SARS-CoV-2 during treatment with antiviral agents or by circulating SARS-CoV-2 in communities around the world will continue to challenge the success of Covid-19 treatments and vaccines. Although in vitro studies using recombinant viruses or in vivo animal studies have demonstrated that combinations of non-competing antibodies (such as REGEN-COV) can inhibit the emergence of resistant variants, the relevance of these studies to natural human infections remains problematic. We therefore recently studied and reported the presence of the entire spike protein in samples from 1,000 outpatients included in the outpatient REGEN-COV trial described in this Example or the separate hospital Covid-19 REGEN-COV trial (described in Example 1). of genetic diversity. Analysis of 4,882 samples from these 1,000 patients treated with REGEN-COV or placebo confirmed 15 RBD variants in placebo compared with those treated with REGEN-COV at doses of 1200 mg and 2400 mg. REGEN-COV prevents selection of resistant variants, as demonstrated by a similar number of receptor-binding domains found in patients treated with placebo compared with 12 in patients treated with the 1200 mg dose and 12 in the 2400 mg dose (RBD) variants. Three of these RBD variants were found only in the REGEN-COV treatment group, but were identified at baseline or shortly after treatment (<5 days) and did not increase in frequency over time, suggesting that the emergence of these variants is not attributable to treat stress.

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

Additional details

The COVID-19 Symptom Evolution (SE-C19) instrument is an electronic diary completed daily from Day 1 to Day 29. SE-C19 was initially developed based on the CDC symptom list and available public literature specific to COVID-19 patients. It includes 23 symptoms (fever, 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 fuzzy, dizzy, pressure or chest tightness, chest pain, stomach pain, rash, sneezing, coughing up phlegm or phlegm, runny nose). Patients indicate which of 23 symptoms they experienced during the last 24 hours, and then rate each selected symptom at their worst moment during that period on a scale of mild, moderate, or severe. In parallel with the main clinical trial, patient and clinician interviews were conducted to confirm the content validity of the newly developed SE-C19, and psychological validation was conducted using blinded Phase 1/2 data to explore the reliability and validity of the measurements and refine symptoms. Evaluation indicators. Results indicated that 19 of the original 23 items were most valid, reliable, and relevant to COVID-19 outpatients (i.e., excluding sneezing, rash, vomiting, and confusion) and refined response selection into three categories (0 -none, 1-mild/moderate, 2-severe). The detailed, rigorous scientific methods performed and the results of this additional research will be independently disclosed.

Missing data for virological assessment indicators were treated as follows: Analytical positive polymerase chain reaction (PCR) results below the lower limit of quantification (LLOQ) of 714 copies/ml (2.85 log10 copies/ml) were estimated to be half the LLOQ (357 copies/ml) ) and a negative PCR result is estimated to be 0 log ₁₀ replicates/ml (1 replicate/ml). Patients lacking baseline symptom assessment were not included in the analysis of symptom resolution measures. Patients who did not experience resolution of symptoms will be censored at the last observation time point. Patients who died or had COVID-19-related hospitalization before day 29 were censored on day 29.

Before protocol amendment 6, collected from all patients randomized to 2.4 g IV, 8.0 g IV, or placebo before dosing (at screening or baseline visit) and at end of infusion on Days 1 and 29 Serum for drug concentration analysis. After protocol amendment 6, doses were collected from patients randomized to 1.2 g IV, 2.4 g IV, or placebo in the PK substudy before dosing (at screening or baseline visit), Day 29, and Day 120. Serum analyzed for drug concentration. Measurement of REGN10933 (casirimab) and REGN10987 (idelimumab) in humans using a validated immunoassay using streptavidin microplates from Meso Scale Discovery (MSD, Gaithersburg, MD, USA) serum concentration. Methods Two anti-idiotypic monoclonal antibodies, each specific for REGN10933 or REGN10987, were utilized as capture antibodies. Captured REGN10933 and REGN10987 were detected using two different non-competing anti-idiotypic monoclonal antibodies, each also specific for REGN10933 or REGN10987. The bioanalytical method specifically quantifies the levels of each anti-SARS-CoV-2 spike monoclonal antibody individually without interference from other antibodies. For each analyte in undiluted serum samples, the analytical LLOQ was 0.156 µg/ml. Example 3. Clinical evaluation of anti-SARS-CoV-2 spike glycoprotein antibodies in preventing SARS-CoV-2 infection and COVID-19 in high-risk subjects.

The clinical study described below is a randomized, double-blind, placebo-controlled Phase 3 study to evaluate first responders at risk of exposure to SARS-CoV-2 in geographic areas with ongoing COVID-19 outbreaks. Safety and efficacy of anti-Acanthus SARS-CoV-2 monoclonal antibodies in health care workers and other adult individuals.

Study objectives: To analyze the assessment indicators, there are two defined groups based on the SARS-CoV-2 infection status of the subjects at baseline, as measured by central laboratory SARS-CoV-2 quantitative reverse transcription polymerase chain reaction (RT-qPCR). ) measured: negative (group A) or positive (group B).

Strict definitions (i.e., strict terminology) of COVID-19 signs and symptoms were used for the primary assessment indicators, which included: fever (≥38°C) plus ≥1 respiratory symptom (sore throat, cough, respiratory quality) or ≥2 1 respiratory symptom, 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). Includes strictly defined signs/symptoms plus additional non-specific symptoms (fever, sore throat, cough, shortness of breath, chills, nausea, vomiting, diarrhea, headache, red or watery eyes, body aches, loss of taste/smell, A broader definition (i.e., a broad term) of fatigue, loss of appetite, confusion, dizziness, pressure/chest tightness, chest pain, stomach pain, rash, sneezing, runny nose, or expectoration/phlegm) was used for secondary assessment measures. Unless otherwise noted, targets were for subjects who were seronegative at baseline.

Cohort A : SARS-CoV-2 RT-qPCR Negative at Baseline Cohort A Primary Efficacy Objective • To evaluate mAb10933 + mAb10987 compared to placebo in preventing symptomatic SARS-CoV-2 infection confirmed by RT-qPCR (strict terminology) Efficacy • To assess the efficacy of mAb10933 + mAb10987 compared to placebo in preventing symptomatic (strict or broad term) and asymptomatic SARS-CoV-2 infection confirmed by RT qPCR Group A Primary Safety Objective • Assessment Safety and Tolerability of mAb10933 + mAb10987 Compared to Placebo Following Subcutaneous (SC) Administration Group A Secondary Objectives • To evaluate mAb10933 + mAb10987 compared to placebo in the prevention of symptomatic SARS confirmed by RT-qPCR - Efficacy in CoV-2 infection (broad term) • To evaluate the efficacy of mAb10933 + mAb10987 compared to placebo in preventing asymptomatic SARS-CoV-2 infection confirmed by RT-qPCR • To evaluate the efficacy of mAb10933 + mAb10987 compared to placebo Comparative Effect on Symptoms and Duration of Symptoms in Subjects with Symptomatic SARS-CoV-2 Infection Confirmed by RT-qPCR • To evaluate mAb10933 + mAb10987 compared to placebo on SARS-CoV-2 RT-qPCR test results Impact • Assess the impact of mAb10933 + mAb10987 compared to placebo on SARS CoV-2 infection: ○ On health care utilization ○ On absenteeism from daily duties • Characterize drug concentration-time profiles of mAb10933 and mAb10987 in serum and selected drugs Kinetic (PK) parameters. • Assess the immunogenicity of mAb10933 and mAb10987 • Assess the safety and tolerability of mAb10933 + mAb10987 following SC administration in seropositive subjects • Estimate seronegative mAb10933 + mAb10987-treated subjects compared with placebo-treated subjects Incidence and severity of symptomatic SARS-CoV-2 infection over time (including the period after study drug treatment) among seropositive subjects

Cohort B : SARS-CoV-2 RT-qPCR Positive at Baseline Cohort B Secondary Objective • To assess the efficacy of mAb10933 + mAb10987 compared to placebo in preventing the progression of: ○ Symptomatic SARS-CoV-2 infection (strict terminology) ○ Symptomatic SARS-CoV-2 infection (broad term) • To assess the effect of mAb10933 + mAb10987 compared to placebo on symptoms and duration of symptoms in subjects with symptomatic SARS-CoV-2 infection confirmed by RT-qPCR • To evaluate the effect of mAb10933 + mAb10987 compared to placebo on SARS-CoV-2 RT-qPCR test results • To evaluate the effect of mAb10933 + mAb10987 compared to placebo on SARS CoV-2 infection: ○ About health care utilization ○ About daily life Responsibilities • Characterize concentration-time profiles of mAb10933 and mAb10987 in serum and selected PK parameters • Assess the immunogenicity of mAb10933 and mAb10987 • Assess mAb10933 + mAb10987 following SC administration in both seronegative and seropositive subjects Safety and Tolerability • Estimates of symptomatic SARS-CoV-2 infection over time (including the period following study drug treatment) in seronegative and seropositive subjects treated with mAb10933 + mAb10987 compared with placebo-treated subjects The incidence and severity of transition

STUDY DESIGN: This is a 3-phase randomized, double-blind, randomized, double-blind, phase 3 study among first responders, health care workers, and other adult individuals at risk for exposure to SARS-CoV-2 in a geographic area with an ongoing COVID-19 outbreak. Placebo controlled study. Approximately 6000 subjects were included. Subjects were randomized in a 1:1:1 ratio to 1 of 3 treatment groups. Randomization was performed on-site and determined by local molecular diagnostic analysis of SARS-CoV-2 from respiratory samples (negative, positive, or inconclusive), on-site LFIA serological testing of SARS-CoV-2 (seropositive, seronegative, or Not judged) and age ≥50 years (yes or no).

Group configuration was based on the central laboratory baseline SARS-CoV-2 RT-qPCR used for data analysis: Group A (negative) and Group B (positive). Approximately 5000 subjects were included in Group A and Group B was capped at 1000 subjects. For the purpose of research and analysis, Group A and Group B are independent. Because this is an event-driven study, the trial sponsor may decide to close arm B once arm A is fully included and/or the necessary number of events has been added to arm A for the primary efficacy analysis.

Included in this study during Phase 2: 1. Regardless of assignment to Group A or Group B, a sentinel group of approximately 30 subjects: Subjects will be monitored for safety on-site for a minimum of 4 hours after the first dose of study drug and thereafter for the first 4 days (96 hours) daily via visits to study sites or telephone calls. Because mAb10933 + mAb10987 has cleared the sentinel safety group at higher doses administered IV, the sentinel group in this study will focus on safety assessment of injection site reactions and anaphylaxis. Approximately 30 subjects from the combined SC-administered mAb10933 + mAB10987 prevention program (either from this study or combined with the concomitant post-exposure prophylaxis study in household exposures (Example 4), which included the Sentinel Safety Group) through Day 4 Sky-blinded safety data will be reviewed before proceeding to include additional study subjects. 2. After the blinded safety data review concludes that the study can proceed, the study will be reinstated for inclusion.

Study Duration : For each subject, the study consisted of 3 periods: up to a 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.

Study Population : The study population includes asymptomatic, healthy adult first responders, health care workers, and other individuals at risk for exposure to SARS-CoV-2. The inclusion of “other individuals” at risk for SARS CoV-2 infection should only occur in geographic areas where there is widespread and high incidence of COVID-19. The decision to include such subject groups in the study will be based on a review of epidemiological data.

Cohorts and sample sizes—Cohort A: approximately 5,000 subjects with negative baseline rapid SARS-CoV-2 RT-PCR; Cohort B: up to 1,000 subjects with positive baseline rapid SARS-CoV-2 RT-PCR.

Inclusion Criteria: Subjects must meet the following criteria to be eligible for inclusion in the study: 1. 18 years old and above when signing the informed consent form; 2. Groups at high risk of exposure to SARS-CoV-2 include (but are not limited to) the following: a. Active first responders and/or health care workers include (but are not limited to) physicians, nurses, nurse aides, respiratory therapists and law enforcement members, firefighters, emergency medical technician or paramedic; or b. Other individuals believed to be at risk for SARS-CoV-2 infection in geographic areas with active COVID-19 outbreaks (including (but not limited to) industrial workers; meat processors; nursing home residents and workers; congregating in places of worship those; college students, teachers and workers). The decision to include such subject groups in the study will be based on review of epidemiological data by the trial sponsor and other collaborating partners; 3. Judged by the researcher to be in good health based on the medical history and physical examination at screening/baseline; 4. Be willing and able to comply with research visits and research-related procedures; 5. Provide signed informed consent.

Exclusion criteria: Subjects who meet any of the following criteria are excluded from the study: 1. Subject reports a history of a previous 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 of or consistent with COVID-19; 3. In the opinion of the researcher, a history of respiratory disease with signs/symptoms of COVID-19 within one month before screening; 4. If a clinically significant history of disease or any problem arises, as assessed by the investigator, the investigator may confuse the study results or create additional risks to the subjects through his or her participation in the study; 5. Hospitalization for any reason within 30 days of the screening visit (i.e., >24 hours); 6. Cancers other than non-melanoma skin cancer or cervical/anal in situ that require treatment currently or in the past year; 7. Have a significant history of multiple and/or severe allergies (e.g., latex gloves), or allergic reactions to prescription or over-the-counter drugs or foods. This is to avoid potential confusion of safety information and is not due to a specific safety risk; 8. Before the screening visit, treated with another investigational drug within the last 30 days or 5 half-lives of the investigational drug (whichever is longer); 9. Receive investigational or approved SARS-CoV-2 vaccines; 10. Accept investigational or approved passive antibodies for the prevention of SARS-CoV-2 infection (e.g., convalescent plasma or serum, monoclonal antibodies, hyperimmune globulin); 11. Use of hydroxychloroquine/chloroquine, remdesivir, intravenous immune globulin (IVIG) or other anti-SARS viral agents within 2 months before screening; 12. Members of the clinical site research team and/or close relatives; 13. Pregnant or lactating women; 14. Women of childbearing potential (WOCBP) who are unwilling to use highly effective contraception before the first dose/initiation of treatment, during the study, and for at least 8 months after the last dose (WOCBP)*. Very effective birth control methods include: a. Stable use of combination (containing estrogen and progestin) hormonal contraception (oral, intravaginal, transdermal) or progestin-only hormonal contraception (oral, injectable, implantable), which is related to inhibition in screening Associated with the onset of ovulation 2 or more previous menstrual cycles; b. Intrauterine device (IUD); intrauterine hormone releasing system (IUS); c. Bilateral fallopian tube ligation; *WOCBP is defined as a woman who is fertile after menarche until she becomes postmenopausal, unless she is permanently infertile. Permanent sterilization methods include hysterectomy, bilateral fallopian tube resection, and bilateral oophorectomy. Postmenopausal status is defined as the absence of menstruation for 12 months without an alternative medical cause. Follicle-stimulating hormone (FSH) levels in the postmenopausal range can be used to confirm postmenopausal status in women who are not using hormonal contraception or hormone replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the onset of postmenopausal status. The above definitions are based on Clinical Trials Facilitation Group (CTFG) guidelines. Women who have had a documented hysterectomy or tubal ligation do not need a pregnancy test or birth control. 15. Sexually active men who are unwilling to use the following forms of medically acceptable birth control during the study drug follow-up period and for 6 months after the last dose of study drug: vasectomy, where the procedure is medically judged to be successful or ongoing use of insurance set. Sperm donation is prohibited during the study and for up to 6 months after the last dose of study drug.

Study treatment : Patients received mAb10933 + mAb10987 600 mg (300 mg + 300 mg) every 4 weeks (Q4W)/subcutaneously (SC) on days 1, 29, 57, and 85; mAb10933 + SC on day 1 mAb10987 1200 mg (600 mg + 600 mg) starting dose, followed by 600 mg (300 mg + 300 mg) Q4W/SC on days 29, 57, and 85, or on days 1, 29, 57, and 85 Q4W/SC received matching placebo.

Evaluation Metrics : Specify the primary and secondary evaluation metrics for each group, as defined below.

Primary Outcome Measure Group A: Negative SARS-CoV-2 RT-qPCR at Baseline Primary Efficacy Outcome Measure: • Incidence of RT-qPCR-confirmed symptomatic SARS-CoV-2 infection (strict terminology) during EAP • During EAP Incidence of SARS-CoV-2 infection (symptomatic or asymptomatic) confirmed by RT-qPCR Main safety assessment indicators: incidence and severity of treatment-emergent adverse events (TEAE)

Secondary Outcome Measures Group A: SARS-CoV-2 RT-qPCR Negative at Baseline Group A Secondary Efficacy Outcome Measures: • Incidence of symptomatic SARS-CoV-2 infection (broad term) confirmed by RT-qPCR during EAP • Incidence of positive SARS-CoV-2 RT-qPCR during EAP and absence of signs and symptoms (strict term) • Incidence of positive SARS-CoV-2 RT-qPCR during EAP and absence of signs and symptoms (broad term) Incidence • Symptomatic SARS-CoV-2 infection from the first day of first sign or symptom until the last day of the last sign or symptom associated with the first positive SARS-CoV-2 RT-qPCR during EAP (strict term) • Number of days from the first day of the first sign or symptom until the last day of the last sign or symptom associated with the first positive SARS-CoV-2 RT-qPCR during the EAP, symptomatic SARS- Days to CoV-2 infection (broad term) • Number of days since the first positive SARS CoV-2 RT-qPCR nasal swab sample (which began during the EAP period) until 22 days after the positive test, viral shedding (log10 copies/ml) Time-weighted average • Time-weighted average of viral shedding (log10 copies/ml) from the first positive SARS CoV-2 RT-qPCR saliva sample (which began during the EAP period) until 22 days after the positive test • During the EAP period Maximum SARS-CoV-2 RT-qPCR log10 viral copies/ml in nasal swab samples among individuals who started with ≥1 positive RT-qPCR result • Among individuals who started with ≥1 positive RT-qPCR result during EAP Maximum SARS-CoV-2 RT-qPCR log10 virus copies/ml in saliva sample among individuals • From first positive SARS-CoV-2 RT-qPCR in nasal swab sample until first confirmed negative starting during EAP Test, area under the curve (AUC) for viral shedding (log10 copies/ml) • From first positive SARS-CoV-2 RT-qPCR in saliva sample until first confirmatory negative test, viral shedding (log10 copies/ml) initiated during EAP /ml) • Number of medical visits to the emergency room or urgent care center associated with RT qPCR-confirmed SARS-CoV-2 infection that occurred during EAP • Number of medical visits to the emergency room or urgent care center that required RT-qPCR confirmation of SARS-CoV-2 infection during EAP Proportion of emergency room or urgent care center medical visits related to SARS-CoV-2 infection that occurred during EAP • Proportion of hospitalizations related to RT-qPCR-confirmed SARS-CoV-2 infection that occurred during EAP • Proportion of hospitalizations due to RT-qPCR Number of days spent in hospital and ICU for subjects hospitalized with confirmed SARS CoV-2 infection that occurred during EAP • Missed daily responsibilities (including work (employed) due to SARS-CoV-2 infection confirmed by RT-qPCR that occurred during EAP Adults) or school (enrolled students) or family obligations/responsibilities (child care or elderly care)) Days Group A Pharmacokinetics and Immunogenicity Secondary Assessment Endpoints: • Concentrations of mAb10933 and mAb10987 in serum over time and serum Selected PK parameters in seronegative and seropositive subjects (based on central laboratory testing) • In seronegative and seropositive subjects (based on central laboratory testing), as determined by antidrug antibodies (ADA) against mAb10933 and mAb10987 Immunogenicity Group A safety secondary endpoints measured over time: • Incidence and severity of TEAEs in baseline seropositive subjects (based on central laboratory testing) • Seronegative and seropositive subjects in the EAP and follow-up periods Incidence and severity of symptomatic SARS-CoV-2 infection (based on central laboratory testing) Group B: Positive SARS-CoV-2 RT-qPCR at baseline Group B Secondary efficacy endpoints: • Subsequent positive RT-qPCR Proportion of subjects who developed signs and symptoms (strict terminology) of symptomatic SARS-CoV-2 infection within 14 and 28 days of qPCR • Proportion of subjects who subsequently developed symptomatic SARS-CoV-2 infection within 14 and 28 days of positive RT-qPCR Proportion of subjects with signs and symptoms (broad term) • Days of symptomatic SARS CoV-2 infection (strict term) • Days of symptomatic SARS CoV-2 infection (broad term) • Viral shedding in nasal swab samples until day 23 (log10 Copies/mL) time-weighted average change from baseline. • Time-weighted average change from baseline in viral shedding (log10 copies/ml) in saliva samples up to day 23 • Under the curve of viral shedding (log10 copies/ml) in nasal swab samples until first confirmed negative test Area (AUC) • Area under the curve (AUC) for viral shedding (log10 copies/ml) in saliva samples up to first confirmed negative test • Maximum SARS-CoV-2 RT-qPCR log10 virus in nasal swab samples copies/ml • Maximum SARS-CoV-2 RT-qPCR log10 virus copies/ml in saliva sample • Number of medical visits to the emergency room or urgent care center associated with RT-qPCR confirmed SARS-CoV-2 infection • In Proportion of persons admitted to the emergency room or urgent care center who required medical attention due to RT-qPCR-confirmed SARS-CoV-2 infection • Proportion of persons hospitalized due to RT-qPCR-confirmed SARS-CoV-2 infection • Number of days of stay in hospital and ICU for subjects hospitalized with confirmed SARS CoV-2 infection • Missed daily responsibilities (including work (employed adults) or school (enrolled students) or family obligations due to RT-qPCR confirmed SARS-CoV-2 infection /Responsibility (child care or elderly care)) Group B Secondary assessment indicators of pharmacokinetics and immunogenicity: • Concentrations of mAb10933 and mAb10987 in serum over time and seronegative and seropositive subjects (based on central laboratory Selected PK parameters in the test • Immunogenicity Panel B Safety secondary assessment as measured over time by ADA against mAb10933 and mAb10987 in seronegative and seropositive subjects (based on central laboratory testing) Indicators: • Incidence and severity of TEAEs in seronegative and seropositive subjects (based on central laboratory testing) • Symptomatic SARS-CoV in seronegative and seropositive subjects (based on central laboratory testing) during the EAP and follow-up periods -2Incidence and severity of infection

Procedures and Assessments : Efficacy procedures and assessments include the following: • Nasal swab and saliva SARS-CoV-2 RT-qPCR testing (central laboratory) • COVID-19 symptoms (broad and strict terms): On each scheduled or unscheduled basis During the visit/contact, the investigator or sub-PI investigator or designee (i.e., nurse practitioner in the country where local law permits) asks the subject about the subject's status since the subject's last visit/contact (e.g., if the subject has had regular weekly visits/contacts) visit, within the previous week) and inquire about all signs and symptoms related to these adverse events, including their respective start dates, end dates and severity. Researchers should avoid querying subjects by running a checklist of signs and symptoms and instead allow subjects to spontaneously report everything they present. All signs and symptoms associated with the AE were recorded in the subject's medical record (source document) along with the corresponding start date, end date, and severity. Because signs and symptoms can appear and subside on different days and can occur before or after the collection of nasal swabs and saliva samples for SARS-CoV-2 RT-qPCR testing, it is important that this detailed information is extracted from the source document . All adverse events must be recorded in the AE CRF regardless of the results (positive or negative) of SARS-CoV-2 RT-qPCR testing of samples collected from study subjects during weekly or unscheduled visits. Report on a separate CRF (individual signs or symptoms on start and end dates, and associated severity) that are related to and confirmed to be temporally related to the adverse event reported in the AE CRF collected from the subject's nasal swab and/or saliva sample Signs and symptoms associated with a positive SARS-CoV-2 RT qPCR test. ○ Signs and symptoms of COVID-19 in strict terms are defined as: n fever (≥38°C) plus ≥1 respiratory symptoms (sore throat, cough, shortness of breath); or n ≥2 respiratory symptoms (sore throat, cough, shortness of breath); or n 1 respiratory symptom (sore throat, cough, shortness of breath) plus ≥ 2 non-respiratory symptoms (chills, nausea, vomiting, diarrhea, headache, conjunctivitis, myalgia, arthralgia, loss of taste or smell) , fatigue or general discomfort). ○ COVID-19 symptoms and symptoms in broad terms: defined as any of the 23 symptoms listed below in the protocol or fever (≥38°C). • Medical visits: Medical visits to the emergency department (ED), urgent care center (UCC), or hospitalization related to SARS-CoV-2 infection starting from the time point of positive SARS-CoV-2 RT-qPCR and until the end of EAP. Data collected include the nature of the visit (ED, UCC, inpatient), date of visit, length of stay, and primary reason for the visit • Absenteeism Responsibility: Data include absenteeism, defined as due to RT-qPCR confirmed SARS-CoV-2 The number of days missed from daily responsibilities, including work (employed adults) or school (enrolled students) or family obligations/responsibilities (child care or elder care). • Analysis of endogenous anti-SARS-CoV-2 antibodies (central laboratory)

Safety procedures and assessments include vital signs, targeted physical examinations, clinical laboratory testing, ADA assessments and clinical assessments. Subjects will be asked to report all adverse events (AEs) experienced from the time of informed consent until their last study visit.

Pharmacokinetics: Serum samples will be collected at designated time points for analysis of mAb10933 and mAb10987 concentrations.

Statistics plan: Primary efficacy analysis (Cohort A) - Primary database lock occurred when 157 all positive SARS-CoV-2 RT-qPCR symptomatic infections were observed in Cohort A.

A hierarchical log-rank test using age (<50, ≥50 years) as a binning factor was used to compare doses of mAb10933 + mAB10987 and placebo. The Kaplan-Meier method was used to estimate the cumulative odds of laboratory-confirmed symptomatic SARS-CoV-2 infection and the associated 95% CI for each treatment group will be reported. Cox proportional hazards models were used to estimate hazard ratios and their 95% CIs. The model included treatment group and age as previously specified grading factors.

Subjects who completed the EAP and had no events during the EAP were reviewed on the last date of their EAP completion. Review objects that have not yet completed the EAP and do not have an incident at the data deadline. Data for subjects without post-baseline information will be reviewed on the date of randomization plus 1 day. Data from subjects lost to trace in the EAP prior to positive SARS-CoV-2 RT-qPCR were censored at the time of their last available SARS-CoV-2 RT-qPCR assessment. Additional details of the analysis as well as sensitivity analyzes are provided in the Statistical Analysis Plan (SAP).

A similar analysis was performed to compare mAb10933 + mAb10987 and placebo for the incidence of positive SARS-CoV-2 RT-qPCR, regardless of symptoms.

As a sensitivity analysis, subjects who developed asymptomatic or symptomatic SARS-CoV-2 infection within 72 hours of the first dose of study drug were excluded. Additional sensitivity and supporting analyzes are described in SAP.

Secondary efficacy analysis (Panel A)—Secondary efficacy measures were analyzed as described below. For a comprehensive assessment of power, nominal p values may be reported even if analysis of some secondary measures results in non-randomized comparisons. The following secondary assessment measures were analyzed using the analytical methods specified for the primary efficacy analysis. • Incidence of symptomatic SARS-CoV-2 infection (broad term) confirmed by RT-qPCR during EAP • Incidence of positive SARS-CoV-2 RT-qPCR and absence of signs and symptoms (strict terminology) during EAP • Incidence of positive SARS-CoV-2 RT-qPCR and absence of signs and symptoms (broad term) during EAP

Analysis of other secondary measures—Use descriptive statistics (mean, median, standard deviation, and quartiles) to summarize continuous or count measures (e.g., time-weighted average of viral shedding, number of symptom days, medical visits number). Analytical methods used nonparametric Van-Elteren test by age (<50, ≥50 years) or ANOVA by treatment and age (<50, ≥50 years) in the model.

Binary assessment indicators such as the proportion of hospitalized subjects associated with RT-qPCR confirmed SARS-CoV-2 infection will be summarized using frequencies, percentages, absolute differences, or odd ratios, and will be divided by age (<50, ≥50 years). Analyzes were performed using the Cochrane-Mantel-Hensel (CMH) test or Fisher's exact test with hierarchical factor adjustment.

Secondary efficacy analysis (Panel B)—The Cochrane-Mantel-Hensel (CMH) test adjusted for the hierarchical factor of age (<50, ≥50 years) will be used to analyze whether there was any development during the efficacy assessment period. Symptoms Proportion of subjects with signs and symptoms (strict terminology) of SARS-CoV-2 infection. Subjects who remained asymptomatic at the time of final analysis but did not confirm a negative SARS-CoV-2 RT-qPCR were estimated to have become symptomatic.

Results —This study demonstrates the prevention of symptomatic and asymptomatic SARS-CoV-2 infection in adults at high risk of exposure, as assessed by SARS-CoV-2 RT-qPCR test results from weekly nasal swabs and saliva samples, and by Collect daily clinical signs/symptoms commonly reported associated with COVID-19 to assess prevention of symptomatic SARS-CoV-2 infection. Example 4. Clinical evaluation of anti -SARS-CoV-2 spike protein antibodies for prevention of SARS-CoV-2 infection in household contacts of individuals infected with SARS-CoV-2

The clinical study described below was a phase 3, randomized, double-blind, placebo-controlled study that evaluated the effectiveness of anti-Acanthus SARS-CoV-2 monoclonal antibodies in preventing SARS-CoV-2 infection in individuals infected with SARS-CoV-2 at home. 2. Efficacy and safety in terms of infection.

Research objectives: To analyze the assessment indicators, there are 4 defined groups based on subject age and SARS-CoV-2 infection status at baseline, as measured by central laboratory SARS-CoV-2 quantitative reverse transcription polymerase chain reaction (RT-qPCR). ) measured: negative (group A [adults and adolescent subjects ≥12 years old] and group A1 [pediatric subjects <12 years old]) or positive (group B [adults and adolescent subjects ≥12 years old] and group B1 [< Pediatric subjects aged 12 years]). Strict definitions of COVID-19 signs and symptoms are used for secondary assessment indicators, which include: fever (≥38°C) plus ≥1 respiratory symptom (sore throat, cough, shortness of breath) or ≥2 respiratory symptoms, or 1 Respiratory symptoms 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 including signs/symptoms within the strict definition and additional symptoms was used for additional secondary measures (24 terms: fever, sore throat, cough, shortness of breath/dyspnea [rhinitis in pediatric subjects], chills, nausea , vomiting, diarrhea, headache, red or watery eyes, body pain (such as muscle or joint pain), loss of taste/smell, fatigue [fatigue or general malaise or lethargy in pediatric subjects], loss of appetite or poor eating/feeding , confusion, dizziness, pressure/chest tightness, chest pain, abdominal pain, stomach pain, rash, sneezing, runny nose, expectoration/phlegm). Unless noted, targets were for subjects who were seronegative at baseline (by central laboratory testing). Cohort A: SARS-CoV-2 RT-qPCR Negative at Baseline Cohort A Primary Efficacy Objective • To evaluate mAb10933 + mAb10987 compared to placebo in preventing asymptomatic or symptomatic SARS-CoV-2 infection confirmed by RT-qPCR Efficacy Group A and Group A1 Primary Safety Objectives • To assess the safety and tolerability of mAb10933 + mAb10987 compared to placebo following subcutaneous (SC) administration Group A and Group A1 Secondary Objectives • To evaluate the safety and tolerability of mAb10933 + mAb10987 compared to placebo Efficacy of mAb10933 + mAb10987 compared with placebo in preventing symptomatic SARS-CoV-2 infection (broad term) confirmed by RT-qPCR • Efficacy of mAb10933 + mAb10987 compared with placebo in preventing asymptomatic SARS confirmed by RT-qPCR - Efficacy in CoV-2 infection • To evaluate the efficacy of mAb10933 + mAb10987 compared to placebo in preventing symptomatic SARS-CoV-2 infection (strict terminology) confirmed by RT-qPCR • To evaluate the efficacy of mAb10933 + mAb10987 compared to placebo Comparative Effect on Symptoms and Duration of Symptoms in Subjects with Symptomatic SARS-CoV-2 Infection Confirmed by RT-qPCR • To evaluate mAb10933 + mAb10987 compared to placebo on SARS-CoV-2 RT-qPCR test results Impact • To assess the impact of mAb10933 + mAb10987 compared to placebo − on health care utilization − on absenteeism from daily responsibilities • Characterize drug concentration-time profiles and selected pharmacokinetic (PK) parameters of mAb10933 and mAb10987 in serum. • Assess the immunogenicity of mAb10933 and mAb10987 • Assess the safety and tolerability of mAb10933 + mAb10987 following subcutaneous (SC) administration in seropositive subjects • Estimate the safety and tolerability of mAb10933 + mAb10987 compared with placebo-treated subjects Incidence and severity of symptomatic SARS-CoV-2 infection over time (including the period following study drug treatment) in seronegative and seropositive subjects Additional Group A1 Secondary Objectives • Evaluate mAb10933 + mAb10987 compared to placebo Efficacy in preventing asymptomatic or symptomatic SARS-CoV-2 infection confirmed by RT-qPCR Group B: SARS-CoV-2 RT-qPCR positivity at baseline Group B and Group B1 Secondary Objectives - Group B &amp; The objectives of B1 were for all subjects regardless of their serological status (positive or negative) at baseline (by central laboratory testing). • To assess the efficacy of mAb10933 + mAb10987 compared with placebo in preventing the progression of: − symptomatic SARS-CoV-2 infection (strict term) − symptomatic SARS-CoV-2 infection (broad term) • To assess the efficacy of mAb10933 + mAb10987 versus placebo Effect on symptoms and duration of symptoms in subjects with symptomatic SARS CoV-2 infection confirmed by RT-qPCR compared with placebo • Evaluation of mAb10933 + mAb10987 compared with placebo on SARS-CoV-2 RT-qPCR testing Impact of results • To assess the impact of mAb10933 + mAb10987 compared to placebo on SARS CoV-2 infection: − On health care utilization − On absenteeism from daily duties • Characterize drug concentration-time profiles of mAb10933 and mAb10987 in serum and selected PK Parameters • Assess the immunogenicity of mAb10933 and mAb10987 • Assess the safety and tolerability of mAb10933 + mAb10987 following SC administration • Estimate seronegative and sera in mAb10933 + mAb10987-treated subjects compared with placebo-treated subjects Incidence and severity of symptomatic SARS-CoV-2 infection among positive subjects over time, including the period following study drug treatment

Study Design: This is a phase 3 randomized, double-blind, placebo-controlled study in adults, adolescents, and children with household exposure to individuals with SARS-CoV-2 infection. All subjects in the study were household contacts who were closely exposed to a known SARS-CoV-2 infection (the index case) but were asymptomatic at the time of screening (did not have active respiratory or non-respiratory symptoms consistent with COVID-19). First family member. The index case was diagnosed with SARS-CoV-2 infection using diagnostic testing (e.g., RT-PCR, antigen testing, or other testing formats). Randomization was performed by individual study subjects, not by household. Approximately 2200 adults and adolescents (≥12 years old) plus 100 pediatric patients (<12 years old) were included.

Screening/Baseline (Day 1)—Randomization is performed on an individual subject basis, however in cases where multiple members of the same family are enrolled and receive study drug, all randomized subjects are given a family identification number. This ensures that correlations between subjects within the same household can be taken into account in statistical analyses. Randomization was performed by site and by use of appropriate sample (eg, nasopharyngeal (NP), oropharyngeal (OP), nasal or saliva, and age group (≥12 to <18, ≥18 to <50, or ≥ 50)) Test results (positive, negative, or unavailable) of a local diagnostic assay for SARS-CoV-2 (e.g., RT-PCR assay for SARS-CoV-2 or SARS-CoV-2 antigen test) are assigned to treatment groups to grade (yes or no). For pediatric subjects (<12 years), weight groups (≥20 kg, ≥10 kg to <20 kg, and <10 kg) were used as additional grading factors. Local diagnostic assays for SARS-CoV-2 must be deemed acceptable for clinical use by local standards.

Statistical analyzes were performed separately within each cohort and were based on central laboratory determination of viral positivity and serological status. Subjects were randomized in a 1:1 allocation to 1 of 2 treatment groups (placebo or mAB10933 + mAb10987 [1200 mg (600 mg of each mAb subcutaneously (SC))]). This study follows a safety review of data from other studies: In a previous Phase 1 study of mAb10933 + mAb10987 in COVID-19 patients, a safety sentinel group of 30 COVID-19 patients were given mAb10933 + mAb10987 2400 mg IV, mAb10933 +mAb10987 8000 mg IV or placebo.

Sentinel Group (Days 1 to 4)—Enrollment in this study during Phase 2: Sentinel Group of approximately 30 adult subjects, regardless of assignment to Group A or Group B.

Subjects will be monitored for safety on-site for a minimum of 4 hours after the first dose of study drug and then daily for the first 4 days (96 hours) via study site visits or telephone calls. Because mAb10933 + mAb10987 cleared the adult sentinel safety group at higher doses administered IV, the sentinel group in this study focused on the safety assessment of injection site reactions and anaphylaxis and will be conducted as additional subjects are enrolled. Review information before. The blinded safety data review is led by a designated member of the Regeneron clinical team (generally a medical monitor or clinical trial manager). The study was reinstated for inclusion after a blinded review of safety data concluded that the study could proceed.

Pediatric Sentinel Subjects and Staggered Enrollment/Dosing—Approximately 100 pediatric subjects were enrolled across all weight stratified dose ranges. However, since the enrollment of pediatric subjects (<12 years old) ends after the enrollment of adult and adolescent subjects, the number of pediatric subjects can be adjusted. Inclusion of pediatric subjects in this study during Phase 2:

The sentinel group consisted of 12 pediatric subjects (subject number assigned by IWRS; regardless of assignment to group A1 or group B1) in 3 body weight groups (≥20 kg; 10 kg to 20 kg; <10 kg). Each weight group has 4 subjects randomly assigned in a 1:1 ratio. After all 4 subjects in a weight group complete the sentinel review, enrollment of subjects in that weight group continues. Pediatric subjects will be monitored for safety on-site for at least 2 hours after administration of study drug, and then daily via study site visit or telephone call for the first 4 days (96 hours). Because REGN10933+REGN10987 has cleared the adult safety sentinel arm at higher doses administered IV in previous studies and the adult safety sentinel arm in this study, the pediatric sentinel arm in this study focused on injection site reactions. and safety assessment of allergic reactions. Data will be reviewed prior to inclusion of additional pediatric subjects. The blinded safety data review is led by a designated member of the Regeneron clinical team (generally a medical monitor or clinical trial manager). Following the conclusion that a blinded safety data review is available for a weight group, resume enrollment of pediatric subjects in that weight group until approximately 25 subjects per weight group (<10 kg, 10 kg to 20 kg, ≥20 kg) been included.

Evaluate PK data for approximately the top 20 subjects in each weight group to confirm that doses for the weight group are providing the expected exposure. Once dose is confirmed, more than 25 subjects in this weight group will continue to be enrolled. If dosing needs to be adjusted for a particular group, the new dose for that weight group is applied and the exposure of the next 20 subjects from that weight group who received the new dose is examined.

After subjects provide informed consent, their study eligibility is assessed. The screening visit and the randomization visit should occur on the same day. If necessary, a remote visit occurs on the day before but within 24 hours of study drug administration to flag ICF and collect medical history and concomitant medication use to streamline individual screening and randomization due to COVID-19 considerations . Administration of study drug must have occurred within 96 hours of collection of the index case's positive SARS-CoV-2 diagnostic test sample. On day 1 prior to randomization, local molecular diagnostic analysis of SARS-CoV-2 from appropriate samples was performed. The results of these analyzes were used as grading factors for randomization to treatment group (placebo or mAb10933 + mAb10987). The requirement for local diagnostic assays for SARS-CoV-2 is waived when the expected results cannot be used for randomization in a timely manner. Nasopharyngeal (NP) swab samples (swabbed through both nostrils) for central laboratory testing of SARS-CoV-2 RT-qPCR and blood samples for central laboratory serology are also collected and delivered to the center on the same day of collection laboratory. On Day 1, after completion of baseline assessments and sample collection, all subjects received a single dose of study drug.

Efficacy Assessment Period (Day 1 to Day 29)—Efficacy, safety, sample collection, and other study assessments are conducted at designated time points throughout the Efficacy Assessment Period (EAP). If the subject is able to travel and can travel while maintaining social distancing guidelines, a follow-up visit is performed; alternatively, a telemedicine visit, phone call, mobile unit, or home health nurse may have been utilized. Throughout the study, biological samples were obtained by adequately trained and commissioned research personnel at study sites where appropriate personal protective equipment (PPE) was available.

Subjects are instructed to expose site staff to any new or changing symptoms or symptoms, including fever, that may be associated with COVID-19. The investigators recommend that subjects (either themselves or through their parents/guardians) take their temperature daily during EAP, at approximately the same time, and each time the subject feels hot, chilly, or sick. Subjects and/or their parents/guardians may already receive automated reminders (e.g., text messages sent to mobile phones; implemented as soon as technically feasible and subject confirms opt-in) between weekly visits to prompt them as needed Contact research site staff.

At each weekly visit, NP swab samples were collected for SARS-CoV-2 RT-qPCR testing at the central laboratory. The investigator or designated personnel will contact each subject weekly (onsite visit or telemedicine) to assess the subject's general health status and record all general AEs and any symptoms related to SARS-CoV-2 infection since the last contact and Symptoms.

Any subject who develops fever, acute respiratory illness, or other symptoms that they feel may be associated with COVID-19 should alert research personnel immediately. If the investigator or designee suspects SARS-CoV-2 infection, NP swab samples should be collected and sent to a central laboratory for testing. If the subject corresponds to a scheduled visit, the subject may also be asked to provide a blood sample.

Subjects with laboratory-confirmed SARS-CoV-2 infection during EAP should have been notified as soon as possible and should have been medically isolated to prevent contact with others to reduce the risk of further transmission. Because subjects may be isolated, study visits, assessments, and sample collection are conducted through a variety of methods.

For all subjects with confirmed SARS-CoV-2 infection, they continued testing (weekly sample collection) until 2 consecutive confirmed negative SARS-CoV-2 RT-qPCR test results were achieved ≥24 hours apart. This test lasts until EAP and enters the tracking period.

At the discretion of the treating physician, subjects presenting with acute illness should be medically managed in accordance with local standards of care. If a subject is hospitalized with suspected SARS-CoV-2 infection, on-site personnel should make every effort to collect nasal swabs and/or saliva samples for central laboratory SARS-CoV-2 RT-qPCR testing as quickly as possible.

Follow-up period (day 30 to day 225)—Those who remain SARS-CoV-2 RT-qPCR negative throughout the EAP complete the EAP and enter the follow-up period, which will be followed for 7 months.

Subjects who become SARS-CoV-2 RT-qPCR positive during the EAP period continue to take NP swab samples weekly for SARS-CoV-2 RT-qPCR testing until they achieve 2 confirmed negative SARS-CoV-2 tests at least 24 hours apart. RT-qPCR test results were tracked for 7 months even after they completed the EAP and entered the study tracking period. In these cases, the visits used for sample collection should have been characterized as unscheduled visits. At each scheduled visit, the investigator or designated personnel contacted each subject (onsite visit or telemedicine) to assess and record the subject's general health status, general AEs, and SARS-CoV-2 infection since the last contact The signs and symptoms are as described for EAP.

Study Duration : For each subject, there were 3 study periods: 1-day screening/baseline period, 1-month EAP, and 7-month follow-up period after EAP.

Study population : The study population included asymptomatic healthy adults (≥18 years), adolescents (≥12 years to <18 years), and children (<12 years) who were related to the first family member diagnosed with SARS-CoV-2 infection ( Index case) had household contacts.

Cohorts and Sample Size—Cohort A: Approximately 1980 adult and adolescent subjects with negative SARS-CoV-2 RT-qPCR at baseline were included. Group B: Approximately 220 adult and adolescent subjects with positive SARS-CoV-2 RT-qPCR at baseline were included. Group A1: Approximately 90 pediatric subjects (<12 years old) with negative SARS-CoV-2 RT-qPCR at baseline were included. Group B1: Enroll approximately 10 pediatric subjects (<12 years old) with positive SARS-CoV-2 RT-qPCR at baseline.

Inclusion Criteria: Subjects must meet the following criteria to be eligible for inclusion in the study: 1. Adult subjects aged 18 years and above (regardless of weight) or adolescent subjects aged ≥12 to <18 years old at the time of signing the informed consent form, or pediatric subjects <12 years old at the time of signing the consent form (parents/guardians sign the informed consent form Book); 2. Sustained contact with an asymptomatic household exposed to an individual with a positive SARS-CoV-2 RT-PCR analysis (index case). To be included in the study, subjects must be randomized within 96 hours of collection of a positive SARS-COV-2 diagnostic test sample from the index case; 3. Subjects are expected to live in the same household as the index case until day 29 of the study; 4. Subjects who are judged to be in good health by the investigator based on the medical history and physical examination at screening/baseline, including subjects who are healthy or have chronic, stable medical conditions; 5. Willing and able to comply with research visits and research-related procedures/assessments; 6. Provide informed consent signed by the research subject or a legally acceptable representative.

Exclusion criteria: Subjects who meet any of the following criteria are excluded from the study: 1. At any time before screening, the subject reported a history of a previous positive SARS-CoV-2 RT-PCR test or positive SARS-CoV-2 serology test; 2. The subject has lived with an individual who has previously had SARS CoV-2 infection or currently lives with an individual who has SARS-CoV-2 infection, except for the index case, the first individual known to be infected in the family; 3. Active respiratory or non-respiratory symptoms consistent with COVID-19; 4. The researcher believes that there is a history of respiratory disease with signs/symptoms of SARS CoV-2 infection within 6 months before screening; 5. Nursing home residents; 6. In the opinion of the study investigators, any physical examination findings and/or any medical history, concomitant medications, or recent live vaccines that could confound the study results or create additional risks to the subject through their participation in the study; 7. Currently hospitalized or hospitalized for any reason within 30 days of the screening visit (i.e., >24 hours); 8. Have a significant history of multiple and/or severe allergies (e.g., latex gloves), or allergic reactions to prescription or over-the-counter medications or foods. This is to avoid any putative increased risk that could confound the safety analysis and is not attributable to these individuals' reactions to the investigational product; 9. Treatment with another investigational agent within the last 30 days or 5 half-lives of the investigational agent (whichever is longer) prior to the screening visit; 10. Accept investigational or approved SARS-CoV-2 vaccines; 11. Accept investigational or approved passive antibodies for the prevention of SARS-CoV-2 infection (e.g., convalescent plasma or serum, monoclonal antibodies, hyperimmune globulin); 12. Use of hydroxychloroquine/chloroquine or anti-SARS viral agents (e.g., remdesivir) for prevention/treatment of SARS-CoV-2 within 60 days of screening (the use of hydroxychloroquine/chloroquine for prevention/treatment of SARS-CoV-2 is allowed other purposes); 13. Members of the clinical site research team and/or close relatives;

Study Treatment : Adult and adolescent subjects (≥12 years) received mAb10987 and mAb10933 1200 mg (600 mg each mAb)/SC/single dose on Day 1 or matching solution SC/single dose on Day 1. Pediatric subjects (<12 years) received SC/single dose by weight group on Day 1 (intramuscular formulation may be used in pediatric subjects <10 kg):

[Table 8 ]: Pediatric subject weight classification group weight class group mAb10987+mAb10933 Day 1 as SC single dose total per mAb ≥40 kg 1200 mg 600 mg ≥20 to <40 kg 792 mg 396 mg ≥10 to <20 kg 408 mg 204 mg ≥5 to <10 kg 144 mg 72 mg ≥2.5 to <5 kg 96 mg 48 mg <2.5kg 48 mg 24 mg

Evaluation Metrics : Specify the primary and secondary evaluation metrics for each group, as defined below. Symptomatic SARS-CoV2 infection was identified during the EAP by a positive central laboratory SARS-CoV-2 RT-qPCR result, with signs/symptoms occurring within ±14 days of the positive RT-qPCR. The above points out the definitions of “strict-term” and “broad-term” signs/symptoms of SARS-CoV-2 infection. Unless otherwise noted, assessments are for subjects who were seronegative at baseline (based on central laboratory testing).

Primary Efficacy Measurement Group A and Group A1: SARS-CoV-2 RT-qPCR Negative at Baseline Group A Primary Efficacy Measurement • RT-qPCR confirmed SARS-CoV-2 infection (asymptomatic) during the Efficacy Assessment Period (EAP) or symptomatic). Main safety assessment indicators for Group A and Group A1 • Proportion of subjects with treatment-emergent adverse events (TEAE) and TEAE severity

Secondary Outcome Measures Group A and Group A1: SARS-CoV-2 RT-qPCR Negative at Baseline Group A and Group A1 Secondary Efficacy Outcome Measures • Symptomatic SARS-CoV-2 infection with RT-qPCR confirmation during EAP ( Proportion of subjects with positive SARS-CoV-2 RT-qPCR during EAP and absence of signs and symptoms (strict term) • Proportion of subjects with positive SARS-CoV-2 RT-qPCR during EAP and absence of symptoms (strict term) Proportion of subjects with signs and symptoms (broad term) • From the first day of the first sign or symptom until the last day of the last sign or symptom associated with the first positive SARS-CoV-2 RT-PCR during the EAP, Number of days of symptomatic SARS-CoV-2 infection (strict term) • From the first day of first sign or symptom until the last sign or symptom associated with the first positive SARS-CoV-2 RT-PCR during EAP Last day of symptomatic SARS-CoV-2 infection (broad term) • Number of days since the first positive SARS-CoV-2 RT-qPCR in nasopharyngeal (NP) swab sample (which started during the EAP period) until Time-weighted average of viral shedding (log ₁₀ copies/ml) over a range of visits including 22 days following a positive test during EAP • NP swab samples among individuals with ≥1 RT-qPCR positive episode during EAP Maximum SARS-CoV-2 RT-qPCR log ₁₀ viral copies/ml • Viral shedding from first positive SARS-CoV-2 RT-qPCR in NP swab sample until first confirmed negative test initiated during EAP ( area under the curve (AUC) of log10 copies/ml) • Number of medical visits to the emergency room or urgent care center associated with RT-qPCR confirmed SARS-CoV-2 infection that occurred during EAP • Requires RT-qPCR confirmation Proportion of emergency room or urgent care center medical visits related to SARS-CoV-2 infection that occurred during EAP • Proportion of hospitalizations related to RT-qPCR-confirmed SARS-CoV-2 infection that occurred during EAP • Number of days of stay in hospitals and intensive care units (ICU) for subjects hospitalized due to SARS-CoV-2 infection confirmed by RT-qPCR that occurred during EAP • Number of days spent in hospitals and intensive care units (ICUs) due to SARS-CoV-2 infection confirmed by RT-qPCR that occurred during EAP Number of additional days missed from daily responsibilities including work (employed adults) or school (students), daycare, or family obligations/responsibilities (childcare or elder care) Additional Group A1 Secondary Efficacy Measures • Having a positive SARS- Proportion of subjects with CoV-2 RT-qPCR confirmed infection (based on central laboratory testing) Group A and Group A1 Secondary Safety Assessment Metrics • Proportion of baseline seropositive subjects (based on central laboratory testing) with TEAEs and ratio of TEAEs Severity • Incidence and severity of symptomatic SARS-CoV-2 infection in seronegative and seropositive subjects (based on central laboratory testing) during EAP and follow-up periods Group A and Group A1 pharmacokinetics and immunogenicity assessment Indicators • Concentration of mAb10933 + mAb10987 in serum over time and selected PK parameters in seronegative and seropositive subjects (based on central laboratory testing) • In seronegative and seropositive subjects (based on central laboratory testing), Immunogenicity as measured by anti-drug antibodies (ADA) and neutralizing antibodies (Nab) against mAb10933 + mAb10987 over time Group B and Group B1: SARS-CoV-2 RT-qPCR positive group B at baseline Key efficacy measures • Proportion of subjects subsequently developing symptomatic SARS-CoV-2 signs and symptoms (strict terminology) during EAP within 14 and 28 days of positive RT-qPCR • Subsequently, 14 and 28 days of positive RT-qPCR Proportion of subjects with symptomatic SARS-CoV-2 signs and symptoms (broad term) during EAP • Days of symptomatic SARS CoV-2 infection (strict term) • Days of symptomatic SARS CoV-2 infection (broad term) • Until Time-weighted average change from baseline in viral shedding (log ₁₀ copies/ml) in NP swab samples at day 23 • Virus shedding (log ₁₀ copies/ml) in NP swab samples until first confirmed negative test Area under the curve (AUC) • Maximum SARS-CoV-2 RT-qPCR log ₁₀ viral copies/ml in NP swab samples • In emergency room or urgent care center associated with RT-qPCR confirmed SARS-CoV-2 infection Number of medical visits • Proportion of persons in emergency rooms or urgent care centers who required medical visits related to RT-qPCR-confirmed SARS-CoV-2 infection • Number of persons hospitalized related to RT-qPCR-confirmed SARS-CoV-2 infection Proportion • Days of stay in hospital and ICU among subjects hospitalized with RT-qPCR confirmed SARS CoV-2 infection • Missed daily responsibilities (including work (employed adults) or school () due to RT-qPCR confirmed SARS-CoV-2 infection students) or family obligations/responsibilities (child care or elder care)) Group B and Group B1 Secondary Safety Assessment Endpoints • Treatment-emergent adverse events in seronegative and seropositive subjects (based on central laboratory testing) ( TEAE) and severity of TEAE • Incidence of symptomatic SARS-CoV-2 infection among seronegative and seropositive subjects (based on central laboratory testing) during the EAP and follow-up periods as evidence for surveillance of ADE Group B and Group B1 Pharmacokinetic and Immunogenicity Assessment Indicators • Concentration of mAb10933 + mAb10987 in serum over time and selected PK parameters in seronegative and seropositive subjects (based on central laboratory testing). Immunogenicity of anti-drug antibodies (ADA) and neutralizing antibodies (Nab) as measured over time against mAb10933 + mAb10987 in seronegative and seropositive subjects (based on central laboratory testing).

Procedures and Assessments : Efficacy Procedure: Nasopharyngeal Swab SARS-CoV-2 RT-qPCR Test (Central Laboratory): Nasopharyngeal swab samples are collected from subjects to determine the presence of SARS-CoV-2 virus and to determine viral RNA shedding relative quantification. COVID-19 symptoms (broad and strict terms): During each scheduled or unscheduled visit/contact, the investigator asks the subject and/or the subject's parent or guardian about the subject's symptoms since the subject's last visit/contact (e.g., if he/she Weekly regular visits (in the previous week), ask about all signs and symptoms related to these adverse events, including their respective start dates, end dates and severity. Medical Visits: Ask SARS-CoV-2 RT-qPCR positive subjects and/or their parents/guardians (as appropriate) about any medical visits related to SARS-CoV-2 infection in the ED, UCC, or hospital. Based on the time the subject first became SARS-CoV-2 RT-qPCR positive or the time they developed symptoms suspected of being COVID-19 (subsequently confirmed by a positive RT-qPCR result) until the subject has 2 negative tests or COVID-19 Relevant symptoms resolve (whichever lasts longer) or a medical visit to the ED, UCC, or hospitalization occurs until the end of the study visit. Absenteeism assessment: Ask subjects who are or become SARS-CoV-2 RT-PCR positive and/or their parents/guardians during the EAP about any SARS-CoV-2 infection-related absences. Information includes absenteeism, defined as days missed from daily responsibilities including work (employed adults) or school (enrolled students), day care, or family obligations/responsibilities (child care or elder care) due to COVID-19. Safety Procedures: Objective Physical Examination and Vital Signs: Objective Physical Examination and Vital Signs include measurement of temperature, blood pressure (measured after the subject has rested quietly for at least 5 minutes and can be obtained from a seated or supine position), pulse rate, and respiratory rate, and examination of the oropharynx, skin, heart, lungs, and any other systems, depending on any discomfort or problems the subject is experiencing. Laboratory testing: Collection and analysis of samples for blood chemistry, hematology and urinalysis. A urine pregnancy test is performed on site for all women of childbearing potential, and any positive urine pregnancy test is confirmed with a central laboratory serum pregnancy test. Other procedures: Drug concentration and immunogenicity measurements: Dense and sparse sample collections for drug concentration measurements were performed in subgroups of subjects. Samples for anti-drug antibody (ADA) assessment were collected at various times throughout the study. Serological analysis of endogenous anti-SARS-CoV-2 antibodies: To assess the impact of baseline humoral immune/antibody responses to SARS-CoV-2 on the efficacy of mAb10933 + mAb10987 in preventing SARS-CoV-2 infection, serum was measured at baseline Anti-SARS-CoV-2, including (but not limited to) baseline detection of antibodies against S protein and/or N protein and/or neutralization assays. Samples were collected from adult and pediatric subjects (<18 years). Exploratory pharmacodynamic/biomarker and serum/plasma samples for studies: Samples for evaluation of pharmacodynamics and exploratory studies were collected from adult and adolescent subjects. Pharmacogenomic analysis (optional): Adult and adolescent subjects may have participated in optional genomic substudies (separate informed consent required). Blood samples for RNA and DNA were collected for this substudy.

Statistical Plan: Primary Power Analysis (Panel A) - Analysis of the primary power assessment measure in the FAS-A population. To account for correlations between subjects within families and control for correlated type 1 error inflation, generalized linear models were used to estimate odds ratios between treatment groups by using the generalized estimating equations (GEE) method. This model estimates single within-family correlation coefficients.

If any of the results of the subject is positive, the subject is considered to be RT-qPCR positive. Otherwise, it is considered negative. If a subject's infection status cannot be determined due to all missing RT-qPCR results, the following rules apply to the primary analysis. If all post-baseline RT-qPCR results are missing, the subject is considered to have a positive RT-qPCR. A subject is considered to have a positive RT-qPCR if he or she has at least 1 COVID-19 sign and symptom (in strict terms) within ±14 days of the scheduled visit with a missing RT-qPCR result. Safety analysis—Safety and tolerability Overview of the list of treatment-emergent adverse events (TEAEs).

Results — Exploratory analysis of 409 evaluable subjects prior to trial inclusion who were randomized to receive passive vaccines with mAb10933 and mAb10987 (collectively referred to here as REGEN-COV ^™ ) (1200 mg via subcutaneous injection) or placebo Vaccination. The 409 evaluable participants enrolled early in the trial did not have COVID-19 at baseline and were "seronegative," meaning they had no existing antibodies against SARS-CoV-2 in their blood. Individuals are eligible for the trial if a family member has COVID-19. Participants were tested weekly via nasopharyngeal swabs. The results confirmed the ability of REGEN-COV to prevent asymptomatic and symptomatic COVID-19 infection as the primary assessment outcome.

Preliminary results : • Passive vaccination with REGEN-COV ^™ resulted in 100% protection against RT-PCR-positive symptomatic infection (8/223 placebo vs. 0/186 REGEN-COV ^™ ; odds ratio 0.00 (confidence interval 0.00, 0.69)) , and reduced overall infection rates (symptomatic and asymptomatic) by 48% (23/223 placebo vs. 10/186 REGEN-COV ^™ ; odds ratio 0.49 (confidence interval 0.20, 1.12)) (Table 9 below).

[Table 9 ]: Preliminary results Evaluation indicators Placebon /N (%) REGEN-COV (1200 mg SC) n/N (%) probability ratio 95% confidence interval PCR+all infections (all swab types) 23/223 (10.3%) 10/186 (5.4%) 0.49 0.20, 1.12 PCR+all infections (NP swab only) 21/212 (9.9%) 9/179 (5.0%) ND ND ‘Broad term’ symptomatic infection 8/223 (3.6%) 0/186 (0%) 0.00 0.00, 0.69 "CDC Terminology" Symptomatic Infection 7/223 (3.1%) 0/186 (0%) ND ND ‘strict term’ symptomatic infection 5/223 (2.2%) 0/186 (0%) ND ND High viral PCR+ (>10 ⁶ copies/ml) 12/212 (5.7%) 0/179 (0%) 0.00 0.00, 0.41 High viral PCR+ (>10 ⁴ copies/ml) 13/212 (6.1%) 0/179 (0%) 0.00 0.00, 0.37 High viral PCR+ (>10 ³ copies/ml) 19/212 (9.0%) 8/179 (4.5%) 0.48 0.18, 1.17 ND: Not determined • Lower numbers of infections with REGEN-COV™ therapy were all asymptomatic, with reduced peak viral levels and shorter duration of viral shedding. ○ Infections occurring in the placebo group had an average of more than 100 times higher peak viral loads. ○ 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 ( Figure 30 ). ○ No infections in the REGEN-COV ^™ group had high viral loads (>10^4 copies/ml), compared with 62% of those in the placebo group who were infected (13/21 placebo vs. 0/9 REGEN-COV ^™ ). ○ REGEN-COV ^™ is associated with overall infection reduction and complete elimination of high viral load infections (>10 ⁴ ) among evaluable subjects n Levels of RT-qPCR for infection reduction between placebo and REGEN-COV ^™ groups (table below 10).

[Table 10 ]: Level of RT-qPCT RT-qPCR level during infection (only from NP swab available subjects) Placebon /N (%) REGEN-COV (1200 mg SC) n/N (%) qPCR (all) 21/212 (9.9%) 9/179 (5.0%) qPCR＞10 ³ 19/212 (9.0%) 8/179 (4.5%) qPCR＞10 ⁴ 13/212 (6.1%) 0/179 (0%) qPCR＞10 ⁵ 12/212 (5.7%) 0/179 (0%) • REGEN-COV ^™ is associated with lower disease load: ○ Fewer total weeks of viral shedding (44 weeks placebo vs. 9 weeks REGEN-COV ^™ ) ○ Fewer total weeks of high viral shedding (>10^4 copies/ml ) (22 weeks placebo vs. 0 weeks REGEN-COV ^™ ) ○ Fewer total symptom weeks (21 weeks placebo vs. 0 weeks REGEN-COV ^™ ). • REGEN-COV ^™ was well tolerated, with similar proportions of participants experiencing at least one serious adverse event: placebo, 4/286, and REGEN-COV ^™ , 3/267. None were considered related to study treatment. Injection site reactions were similar: placebo, 1.4%; REGEN-COV ^™ , 2.6%.

Of the first 409 participants, approximately 49% were Hispanic and 13% were African American. On average, participants were 43 years old, approximately 46% were male and 54% were female.

Results: Phase 3 Prevention Trial (2069A) —This trial demonstrates an 81.4% reduction in the risk of symptomatic SARS-CoV-2 infection with subcutaneous administration of REGEN-COV ^™ (casirimab and idelimumab) ( Figure 72 ) . REGEN-COV works quickly, with 72% protection against symptomatic infection in the first week, rising to 93% in subsequent weeks. Among individuals who still experienced symptomatic infection, those who received REGEN-COV cleared the virus more quickly and had significantly shorter symptom duration (93.1% fewer total weeks with symptoms with REGEN-COV, corresponding to each symptomatic The average duration of symptoms among symptomatic infected participants was reduced by 2 weeks). The relative risk reduction of any infection (symptomatic or asymptomatic) with REGEN-COV was 66.4%, and the total number of weeks with any infection with REGEN-COV was reduced by 82.3%, corresponding to a reduction in the average duration of any infection per infected participant of approximately 1 week. The relative risk reduction of high viral load infection with REGEN-COV is 85.8%. The total number of weeks of high viral load infection with REGEN-COV was reduced by 89.6%, corresponding to an average reduction of approximately 6 days per infected participant in the duration of high viral load infection.

The trial met its primary and key secondary endpoints, demonstrating that REGEN-COV reduced the risk of symptomatic infection by 81% in uninfected individuals at the time of its entry into the trial. Specifically, the Phase 3, double-blind, placebo-controlled trial evaluated the effects of REGEN-COV in individuals without any symptoms of COVID-19 who had tested positive for SARS-CoV-2 within the previous 4 days. Living in the same family. It included 1,505 people who were not infected with SARS-CoV-2 at baseline and received 1 dose of REGEN-COV (1,200 mg) or placebo, administered as a subcutaneous injection.

Data suggest that REGEN-COV, which retains its efficacy against emerging COVID-19 variants, could complement a broad vaccination strategy, especially for those at high risk of infection. Regardless of standard precautions to reduce transmission, almost 10% of infected individuals develop symptomatic infection if they do not receive REGEN-COV. Convenient subcutaneous administration of REGEN-COV may help control outbreaks in high-risk settings, including individual households and congregate living settings, among unvaccinated individuals. Additionally, due to high-risk exposure, there remains a large number of people who have not yet been vaccinated and will need immediate protection, where traditional vaccines cannot be used at such a late stage. The data presented in this study demonstrate that REGEN-COV can be extremely effective in this setting. Additionally, there will be many individuals who may not respond to vaccines, such as immunocompromised individuals, including those with and undergoing solid organ transplantation, and certain cancers and immune diseases. REGEN-COV's rapid protection and its potential for chronic prevention may also provide important solutions in this context.

[Table 11 ]: Overview: Key ^results from the Phase 3 prevention trial of symptomatic SARS-CoV-2 infection1 REGEN-COV (single 1,200 mg dose) placebo n=753 n=752 Risk of symptomatic SARS-CoV-2 infection Until day 29 (main evaluation indicator) Risk reduction 81% (p<0.0001) Number of patients with events 11 (2%) 59 (9%) Within 1 week Risk reduction 72% (p=0.0002) Number of patients with events 9 (1.2%) 32 (4.3%) 1 week later Risk reduction 93% (p<0.0001) Number of patients with events 2 (0.3%) 27 (3.6%) Symptoms and viral load Total number of weeks symptoms have been present Risk reduction 93% (p<0.0001) total number of weeks 13 188 Number of weeks since symptom onset among symptomatic individuals (mean) 1 3 Total number of weeks with high viral load (>10 ⁴ copies/ ml) Risk reduction 90% (p<0.0001) total number of weeks 14 136 Number of weeks with high viral load (average) in qPCR-positive subjects 0.4 1.3 1. Based on the seronegative modified full analysis set population, which includes all randomized subjects with a negative SARS-CoV-2 RT-qPCR test and a negative SARS-CoV-2 antibody test at randomization

[Table 12 ]: Detailed primary and key secondary efficacy evaluation indicators* Placebo (n=752) REGEN-COV 1200 mg SC (n=753) Proportion of participants with symptomatic RT-qPCR confirmed SARS-CoV-2 infection (broad term) ^† n/N (%) 59/752 (7.8) 11/753 (1.5) relative risk reduction - 81.4% Odds ratio (95% CI) - 0.17 (0.09, 0.33) P-value¶ - <0.0001 Proportion of participants with viral load >10 ⁴ copies/mlǂ n/N (%) 85/749 (11.3) 12/745 (1.6) relative risk reduction - 85.8% Odds ratio (95% CI) - 0.13 (0.07, 0.24) P-value¶ - <0.0001 Weeks of symptomatic RT-qPCR confirmed SARS-CoV-2 infection (broad term) total number of weeks 187.7 12.9 Total duration per 1000 participants (weeks) 249.6 17.1 reduce ǁ - 93.1% P value§ - <0.0001 Duration of symptomatic infection per symptomatic participant, mean (SD), number of weeks 3.2 (2.68) 1.2 (0.99) Number of weeks of high viral load (>10 ⁴ copies/ml) total number of weeks 136.0 14.0 Total duration per 1000 participants (weeks) 181.6 18.8 reduce ǁ - 89.6% P ^value§ - <0.0001 Duration of high viral load per infected participant, mean (SD), number of weeks 1.3 (0.87) 0.4 (0.60) Number of weeks since any RT-qPCR confirmed SARS-CoV-2 infection (symptomatic or asymptomatic) total number of weeks 231.0 41.0 Total duration per 1000 participants (weeks) 307.2 54.4 reduce ^ǁ - 82.3% P ^value§ - <0.0001 Duration of any infection per infected participant, mean (SD), weeks 2.2 (1.07) 1.1 (0.42) Proportion of participants with any RT-qPCR confirmed SARS-CoV-2 infection (symptomatic or asymptomatic) n/N (%) 107/752 (14.2) 36/753 (4.8) relative risk reduction - 66.4% Odds ratio (95% CI) - 0.31 (0.21, 0.46) P value - <0.0001 *Key secondary endpoints and presented in order of tiered testing sequence ^† Primary endpoint ^ǂ n=749 (placebo) and n=745 (REGEN-COV 1200 mg SC) for viral load assessment. ^§Based on the graded Wilcoxon rank sum test (Van Eltren's test), by region (US vs. outside the US) and age group (12 to <50 years vs. ≥50 years). . ^ǁBased on normalized weeks per 1,000 participants. SC, subcutaneous; SD, standard deviation.

Adverse events (AEs) occurred in 20% (n=265) of REGEN-COV participants and 29% (n=379) of placebo participants, and 1% (n=10) of REGEN-COV participants and 1% (n =15) Serious AEs occurred in placebo participants. There were 0 REGEN-COV participants and 4 placebo participants who experienced COVID-19 hospitalization or emergency room visits. No individuals in either group withdrew from the trial due to AEs, and none of the deaths in the trial (2 REGEN-COV, 2 placebo) were attributed to COVID-19 or the study drug.

[ Table 13. ] Treatment-emergent adverse events occurring in ≥2% of participants throughout the study period Best term , n (%) Placebo (n=1306) REGEN-COV 1200 mg SC (n=1311) COVID-19 112 (8.6) 15 (1.1) Asymptomatic COVID-19 108 (8.3) 54 (4.1) headache 46 (3.5) 24 (1.8) injection site reaction 19 (1.5) 55 (4.2) SC, subcutaneous.

To be eligible for the REGEN-COV Regeneron/NIAID program, all participants enter the program without any COVID-19 symptoms (asymptomatic) and live in the same household as an individual who tested positive for SARS-CoV-2 within the previous 4 days in life. All participants were tested for SARS-CoV-2 at baseline using RT-qPCR testing from nasopharyngeal swabs. Participants with negative test results are enrolled in the Phase 3 preventive trial (2069A) and participants with positive test results are enrolled in the Phase 3 therapeutic trial (2069B), discussed below.

All participants were then randomized (1:1) to receive 1 dose of REGEN-COV (1,200 mg) or placebo administered via 4 SC injections. Of the participants included in the trial, 31% were Latino/Hispanic and 9% were black/African American. A total of 31% of participants had at least one known factor that put them at high risk for severe consequences of COVID-19, as defined in the REGEN-COV fact sheet. Additionally, 33% were obese and 38% were aged 350 years (median age: 43 years; range: 12-92 years).

Extended Results: Phase 3 Treatment Trial in Asymptomatic Patients with Recent Infection (2069B) — This trial demonstrated significant reduction in progression of symptomatic COVID-19. Results from this second Phase 3 trial evaluated 1,200 mg REGEN-COV ^™ (casirimab and idelimumab) administered via subcutaneous (SC) administration in asymptomatic patients with recent infection. REGEN-COV reduced the overall risk of progression to symptomatic COVID-19 by 31% (primary endpoint) and by 75% after day three. Trials have also proven that REGEN-COV ^™ shortens the duration of symptoms and significantly reduces virus levels. The trial is being conducted in conjunction with the National Institute of Allergy and Infectious Diseases (NIAID), a division of the National Institutes of Health (NIH). The trial enrolled 207 individuals without any COVID-19 symptoms who tested positive for SARS-CoV-2 at baseline and were randomized to receive 1 dose of REGEN-COV ^™ (1,200 mg) or placebo.

Because COVID-19 transmission often occurs in people who are not yet symptomatic, the results of this study demonstrate that REGEN-COV ^™ can be administered more conveniently subcutaneously in these patients.

This second Phase 3 trial met all primary and key secondary endpoints. In addition to reducing the risk of symptomatic infection, REGEN-COV ^™ reduces the total number of weeks patients experience symptoms by almost half (45%) and reduces viral load by more than 90%. Researchers also found that compared to 6 participants in the placebo group, the participants who received REGEN-COV ^™ required no COVID-19-related hospitalizations or emergency room visits. Treatment with REGEN-COV ^™ 1200 mg subcutaneous (SC) during the efficacy evaluation period resulted in a 31.5% relative risk reduction in progression from asymptomatic to symptomatic infection (29/100 [29.0%] vs. 44/104 [42.3] for placebo %]; p=0.0380), with a more pronounced effect (76.4% relative risk reduction) 3 days or more after REGEN-COV ^™ administration ( Figure 73 ). Among 73 household contacts who developed symptomatic infection, REGEN-COV ^™ reduced the number of symptomatic weeks by 45.3% (per 1,000 participants) relative to placebo; this corresponds to the average number of symptomatic weeks per symptomatic participant The number decreases by approximately 1 week. The number of weeks with high viral load was reduced by 39.7%, which corresponds to approximately 2 fewer days per participant. A higher proportion of participants in the placebo group had ≥1 treatment-emergent adverse event compared to participants in the REGEN-COV ^™ group, which was consistent with a higher number of COVID-19 among those participants who received placebo The relevant events are consistent.

Data build on results discussed in Examples 2 and 7 among non-hospitalized COVID-19 patients. Phase 3 results of the trial in high-risk symptomatic outpatients showed that REGEN-COV (administered intravenously [IV] at 2,400 mg and 1,200 mg) reduced hospitalization or death by 70% (Example 2). A Phase 2 virology trial in low-risk outpatients demonstrated that all doses of REGEN-COV ^™ studied had similar efficacy in rapidly reducing viral load (IV: 2,400 mg, 1,200 mg, 600 mg, and 300 mg; SC: 1,200 mg and 600 mg) (Example 7).

These Phase 3 data provide even more evidence that REGEN-COV, this time given via a convenient injection to asymptomatic patients, can alter the course of COVID-19 infection in non-hospitalized patients and prevent asymptomatic patients from becoming symptomatic , and quickly reduce its viral load.

[Table 14 ]: Overview of primary and key secondary efficacy evaluation indicators Placebo (N=104) REGEN-COV 1200 mg SC (N=100) Participants who subsequently developed signs and symptoms (broad term) within 14 days of a positive RT-qPCR at baseline or during EAP* n(%) 44 (42.3) 29 (29.0) Relative risk reduction (total) - 31.4% Odds ratio (95% CI) - 0.54 (0.30 to 0.97) P value † - 0.0380 Relative risk reduction after day 3 (days 4-29 only) ^O - 75% P value † - 0.0014 n(%) 5 (7%) 22 (27%) Number of weeks of symptomatic SARS-CoV-2 infection (broad term) within 14 days of positive RT-qPCR at baseline or during EAPǂ total number of weeks 170.3 89.6 Total weeks per 1,000 participants 1637.4 895.7 reduce - 45.3% P value§ - 0.0273 Number of weeks per symptomatic participant, mean (SD) 3.9 (4.5) 3.1 (4.1) Number of weeks per participant, mean (SD) 1.6 (3.5) 0.9 (2.6) Number of weeks with high viral load (>4 log ₁₀ copies/ml) in NP swab samples during EAPǂ total number of weeks 82 48 Total weeks per 1,000 participants 811.9 489.8 reduce - 39.7% P value§ - 0.0010 Number of weeks per participant, mean (SD) 0.8 (0.8) 0.5 (0.7) COVID-19 related hospitalization or emergency room ^visitX Risk reduction - 100% Nominal p-value - 0.029 Number of patients with events (%) 0 (0%) 6 (6%) *Main evaluation indicators. †Based on logistic regression models adjusted by region (US vs. outside the US) and age group (12 to <50 years vs. ≥50 years). ǂThe key secondary evaluation indicators are presented in the order of the graded test sequence. §Based on the hierarchical Wilcoxon rank-sum test (Van Eltren's test), with stratification by region (US vs. outside the US) and age group (12 to <50 years vs. ≥50 years). CI, confidence interval; EAP, efficacy assessment period; NP, nasopharyngeal; RT-qPCR, quantitative reverse transcription polymerase chain reaction; SC, subcutaneous; SD, standard deviation. ^O does not include results from days 1-3, when events were similar between treatment groups. ^X is not part of the statistical stratum, so the p-value is nominal.

Adverse events (AEs) occurred in 33% (n=52) of REGEN-COV patients and 48% (n=75) of placebo patients, and in 0% (n=0) of REGEN-COV patients and 3% (n=4) Serious AEs occurred in placebo patients. No patients in either group withdrew from the trial due to AEs, and there were no deaths.

[Table 15 ]: Summary of treatment-emergent adverse events throughout the study period n(%) Placebo (N=156) REGEN-COV 1200 mg SC (N=155) TEAE 109 67 TEAE not related to COVID-19 42 26 TEAE with level ≥3 5 1 Serious TEAE 4 0 AESI* 0 0 TEAEs leading to study drug discontinuation 0 0 TEAE causing death 0 0 Participants with ≥1 TEAE 75 (48.1) 52 (33.5) Participants with ≥1 TEAE not related to COVID-19 25 (16.0) 17 (11.0) Participants with ≥1 TEAE grade ≥3 4 (2.6) 1 (0.6) Participants with ≥1 serious TEAE 4 (2.6) 0 Participants with ≥1 AESI* 0 0 Participants with ≥1 TEAE leading to study drug discontinuation 0 0 Participants with ≥1 TEAE leading to death 0 0 *Injection site reaction or allergic reaction of grade ≥3. AESI, any adverse event of special concern; SC, subcutaneous; TEAE, treatment-emergent adverse event.

To be eligible for this clinical trial, all participants entered the program without any symptoms of COVID-19 (asymptomatic) and lived in the same household as an individual who had tested positive for SARS-CoV-2 within the previous 4 days. All participants were tested for SARS-CoV-2 at baseline using RT-qPCR testing from nasopharyngeal swabs. Participants with negative test results are enrolled in the Phase 3 preventive trial (2069A) as discussed above, and participants with positive test results are enrolled in the Phase 3 therapeutic trial (2069B).

All participants were then randomized (1:1) to receive 1 dose of REGEN-COV ^™ (1,200 mg) or placebo administered via 4 SC injections. Of the participants included in the trial, 35% were Latino/Hispanic and 5% were black/African American. A total of 32% had at least 1 known factor that put them at high risk for severe consequences of COVID-19, as defined in the REGEN-COV fact sheet. Additionally, 32% were obese and 34% were aged ≥50 years (median age: 41 years; range: 12-87 years).

The results of these two phase 3 trials (2069A and 2069B) are also shown in Figure 59 , Figure 60 , Figure 61, Figure 62 , Figure 63 , Figure 64 , Figure 65 , Figure 66 , Figure 67 , Figure 68 , Figure 69 , Figure 70 , and shown in Figure 71 .

Other data come from Cohort A of this study, which includes uninfected individuals at the start of the study. Subjects were followed for 32 weeks after a single dose of REGEN-COV ^™ (600 mg casirimab and 600 mg idelimumab, combined at a 1200 mg dose administered via four subcutaneous injections). PCR testing was performed at baseline and weekly during the initial efficacy evaluation period (four weeks). If the PCR test is positive, patients are tested weekly until they receive two negative PCR tests, including until the follow-up period. During this initial period, patients were also assessed weekly by researchers for signs and symptoms of COVID-19, and symptomatic participants were instructed to call if symptoms began between visits. These symptomatic participants then underwent assessment and PCR testing. During the follow-up period (week 5 until study end, 32 weeks or 2 to 8 months), PCR testing will not be performed unless participants report COVID-19 signs/symptoms. Symptomatic participants were instructed to call if they experienced symptoms between visits, and they underwent assessment and PCR testing. If participants are unable to undergo PCR testing, local laboratory molecular testing will be utilized. The information provided below is a list of symptomatic infections confirmed by positive PCR tests (eg, as assessed by a central laboratory) reported by investigators. Infections during the first four weeks were most likely due to household exposure; infections after the first month and to the end of the study were most likely to be community-acquired. Each week, the number and percentage of infected objects observed is provided. New analysis shows REGEN-COV ^™ reduces the risk of COVID-19 infection (i.e., laboratory-confirmed symptomatic SARS-CoV-2 infection) by 81.6% during the prespecified follow-up period (months 2-8) , thereby maintaining an 81.4% risk reduction during the first month after investment.

Prespecified assessment measures for the 7-month follow-up period included: 1) proportion of baseline seronegative participants with first PCR-confirmed symptomatic SARS-CoV-2 infection during the follow-up period; 2) seroconversion to SARS-CoV-2 Proportion of participants who converted from baseline-seronegative to seropositive, as assessed by anti-nucleocapsid IgG analysis; and 3) had first PCR-confirmed SARS-CoV-2 infection (symptomatic or asymptomatic) during the follow-up period Baseline - Proportion of seronegative participants. Additional assessment metrics include 1) SARS-CoV-2-related medical visits—defined as the number of hospitalizations, emergency room visits, or urgent care center visits; and 2) symptomatic SARS-CoV-2 after COVID-19 vaccination Number of CoV-2 infections.

These results build on the initial structure of the trial meeting its primary endpoint, which is the reduction of COVID-19 (i.e., laboratory-confirmed symptomatic SARS-CoV-2) within 1 month of receiving REGEN-COV ^™ . infection) was reduced by 81.4% (p<0.001). The new results describe the next seven months of the prespecified analysis. Across the entire 8-month study, mAb10933/mAb10987 reduced the risk of symptomatic SARS-CoV-2 infection by 81.2% relative to placebo (nominal P < 0.0001), across all SARS-CoV-2 infections (symptomatic and asymptomatic). symptoms) by 68.2% relative to placebo (nominal P < 0.0001). The overall relative risk reduction of symptomatic infection during the follow-up period (months 2-8) was 80.9% (nominal P < 0.0001), consistent with the 81.4% relative risk reduction during month 1. During months 2-5, the risk of symptomatic and all infections was reduced by 100% and 89.5%, respectively (nominal P < 0.0001). There was recovery from symptomatic and all SARS-CoV-2 infections during months 6-8 in the mAb10933/mAb10987 group (19.9% and 30.7% risk reduction, respectively; nominal P = not significant). Figure 109 shows all these results. These results were collected from individuals who were SARS-CoV-2 PCR negative and had no evidence of SARS-CoV-2 immunity (seronegative) as baseline. In additional analyzes that included all SARS-CoV-2 PCR-negative participants at baseline without regard to baseline serostatus, REGEN-COV ^™ versus placebo in symptomatic PCR-confirmed SARS-Cov- 2 The risk of infection is reduced by 79.9%, and the risk of all SARS-CoV-2 infections (symptomatic and asymptomatic) is reduced by 64.4%. Seroconversion, considered indicative of any SARS-CoV-2 infection (symptomatic and asymptomatic), occurred in 4.5% and 21.5% of participants in the REGEN-COV and placebo groups, respectively (relative risk reduction 79.0 vs. placebo %; nominal P<0.0001). Seroconversion indicative of SARS-CoV-2 infection was demonstrated in patients who were seronegative at baseline but subsequently seropositive by anti-nucleocapsid IgG testing one or more times during the study.

Relative to placebo, fewer mAb10933/mAb10987 participants had a medical visit during the 8-month period (16/842 [1.9%] vs. 1/841 [0.1%], respectively). Additionally, during the 8-month evaluation period, 0 individuals in the REGEN-COV ^™ group were hospitalized with COVID-19 compared with 6 individuals in the placebo group (1 in the first month; 5 in months 2-8 name). During the 8-month evaluation period, there were no deaths due to COVID-19 in any treatment group and no new safety signals were identified for REGEN-COV. Taken together, these data provide evidence that a single subcutaneous administration of REGEN-COV provides protection both during the initial efficacy assessment and throughout the 8-month study period. The cumulative incidence of symptomatic infections and all infections (asymptomatic or symptomatic) over the entire duration of the 8-month study is shown in Figure 104 and Figure 105 , respectively. The incidence of symptomatic or all SARS-COV-2 infections was consistently lower in the group receiving REGEN-COV ^™ relative to placebo. The relative risk reduction (RRR) for maintaining symptoms and all SARS-CoV-2 infections during months 2-5 of the study is shown in Figure 106 and Figure 107 , respectively.

The fully enrolled trial in early 2021 will allow participants to receive the vaccine on a voluntary basis. Balancing vaccination rates, 34.5% (n=290) of the REGEN-COV ^™ group and 35.2% (n=296) of the placebo group had received at least 1 COVID-19 vaccine dose at the end of the 8-month evaluation period. Demographics and baseline characteristics of participants in the REGEN-COV ^™ and placebo groups were balanced. Study time period of SARS-CoV-2 infection time period mAb10933/mAb10987 (REGEN-COV) 1200 mg SC (N=841) Total (%) Placebo (N=842) Total (%) Relative risk reduction % Odds ratio (95% CI) Nominal P value Symptomatic SARS-CoV-2 infection 28-day EAP (1st month) 13 (1.5) 70 (8.3) 81.4 0.17 (0.09-0.31) <0.0001 Tracking (Months 2-8) 8 (1.0) 42 (5.0) 80.9 0.18 (0.09-0.39) <0.0001 Entire study (day 1 to month 8) 21 (2.5) 112 (13.3) 81.2 0.17 (0.10-0.27) <0.0001 All SARS-CoV-2 infections (symptomatic or asymptomatic) 28-day EAP (1st month) 42 (5.0) 122 (14.5) 65.5 0.31 (0.22-0.45) <0.0001 Tracking (Months 2-8) 13 (1.5) 51 (6.1) 74.5 0.24 (0.13-0.45) <0.0001 Entire study (day 1 to month 8) 55 (6.5) 173 (20.5) 68.2 0.27 (0.20-0.37) <0.0001 • Data include patients with central laboratory confirmed symptomatic COVID-19 (SARS CoV-2 PCR+) from the beginning of Week 5 to the end of the study ( symptomatic infection is defined as a broad term within 14 days of laboratory confirmation test signs and symptoms) • Months 2-8 are weeks 5 to 32 • CI, confidence interval; EAP, efficacy assessment period; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 First time over time Positive RT-qPCR Number of weeks (nominal) Placebo (n=842) REGEN-COV ^™ (n=841) Subjects with at least one positive RT-qPCR 169 (20.1%) 54 (6.4%) Week 1 81 (9.6%) 26 (3.1%) Week 2 17 (2%) 7 (0.8%) Week 3 15 (1.8%) 5 (0.6%) Week 4 9 (1.1%) 4 (0.5%) Week 5 2 (0.2%) 0 Week 6 3 (0.4%) 0 Week 7 3 (0.4%) 1 (0.1%) Week 8 6 (0.7%) 0 Week 9 1 (0.1%) 0 Week 10 4 (0.5%) 0 Week 11 1 (0.1%) 0 Week 12 1 (0.1%) 1 (0.1%) Week 13 1 (0.1%) 0 Week 14 1 (0.1%) 0 Week 15 4 (0.5%) 1 (0.1%) Week 16 1 (0.1%) 0 Week 17 1 (0.1%) 0 Week 18 5 (0.6%) 1 (0.1%) Week 19 2 (0.2%) 2 (0.2%) Week 20 1 (0.1%) 0 Week 21 0 1 (0.1%) Week 22 1 (0.1%) 1 (0.1%) Week 23 3 (0.4%) 1 (0.1%) Week 24 2 (0.2%) 1 (0.1%) Week 25 2 (0.2%) 1 (0.1%) Week 26 2 (0.2%) 1 (0.1%) Week 27 17 (2%) 7 (0.8%) Week 28 15 (1.8%) 5 (0.6%) Week 29 9 (1.1%) 4 (0.5%) Week 30 2 (0.2%) 0 Week 31 3 (0.4%) 0 Week 32 3 (0.4%) 1 (0.1%) Subjects with first symptomatic infection (positive RT-qPCR and symptoms within 14 days) Number of weeks (nominal) Placebo (n=842) REGEN-COV ^™ (n=841) Subject with first symptomatic infection 108 (12.8%) 20 (2.4%) Week 1 50 (5.9%) 11 (1.3%) Week 2 5 (0.6%) 1 (0.1%) Week 3 11 (1.3%) 0 Week 4 4 (0.5%) 1 (0.1%) Week 5 3 (0.4%) 0 Week 6 2 (0.2%) 0 Week 7 3 (0.4%) 0 Week 8 5 (0.6%) 0 Week 9 1 (0.1%) 0 Week 10 4 (0.5%) 0 Week 11 1 (0.1%) 0 Week 12 1 (0.1%) 0 Week 13 1 (0.1%) 0 Week 14 0 0 Week 15 1 (0.1%) 0 Week 16 3 (0.4%) 0 Week 17 0 0 Week 18 1 (0.1%) 0 Week 19 1 (0.1%) 2 (0.2%) Week 20 1 (0.1%) 0 Week 21 0 0 Week 22 0 0 Week 23 0 0 Week 24 2 (0.2%) 2 (0.2%) Week 25 0 0 Week 26 1 (0.1%) 0 Week 27 0 1 (0.1%) Week 28 1 (0.1%) 1 (0.1%) Week 29 2 (0.2%) 1 (0.1%) Week 30 2 (0.2%) 1 (0.1%) Week 31 1 (0.1%) 1 (0.1%) Week 32 1 (0.1%) 0 The first adverse event of COVID-19 or COVID-19 pneumonia over time Number of weeks (nominal) Placebo (n=842) REGEN-COV ^™ (n=841) Subjects with at least one adverse event resulting from COVID-19 treatment 116 (13.8%) 21 (2.5%) Week 1 38 (4.5%) 8 (1%) Week 2 18 (2.1%) 2 (0.2%) Week 3 6 (0.7%) 1 (0.1%) Week 4 5 (0.6%) 1 (0.1%) Week 5 3 (0.4%) 0 Week 6 4 (0.5%) 0 Week 7 5 (0.6%) 0 Week 8 3 (0.4%) 0 Week 9 2 (0.2%) 0 Week 10 5 (0.6%) 0 Week 11 2 (0.2%) 0 Week 12 1 (0.1%) 0 Week 13 4 (0.5%) 0 Week 14 1 (0.1%) 0 Week 15 2 (0.2%) 0 Week 16 1 (0.1%) 0 Week 17 1 (0.1%) 0 Week 18 1 (0.1%) 0 Week 19 1 (0.1%) 0 Week 20 1 (0.1%) 0 Week 21 1 (0.1%) 0 Week 22 0 1 (0.1%) Week 23 1 (0.1%) 1 (0.1%) Week 24 1 (0.1%) 0 Week 25 0 2 (0.2%) Week 26 1 (0.1%) 0 Week 27 2 (0.2%) 1 (0.1%) Week 28 3 (0.4%) 2 (0.2%) Week 29 3 (0.4%) 2 (0.2%) Week 30 116 (13.8%) 21 (2.5%) Week 31 38 (4.5%) 8 (1%) Week 32 18 (2.1%) 2 (0.2%) First adverse event over time for COVID-19 or COVID-19 pneumonia or asymptomatic COVID-19 Number of weeks (nominal) Placebo (n=842) REGEN-COV ^™ (n=841) Subjects with at least one COVID-19 or asymptomatic treatment-induced adverse event 177 (21%) 58 (6.9%) Week 1 43 (5.1%) 15 (1.8%) Week 2 46 (5.5%) 12 (1.4%) Week 3 18 (2.1%) 6 (0.7%) Week 4 9 (1.1%) 7 (0.8%) Week 5 7 (0.8%) 2 (0.2%) Week 6 2 (0.2%) 0 Week 7 6 (0.7%) 0 Week 8 5 (0.6%) 1 (0.1%) Week 9 2 (0.2%) 0 Week 10 4 (0.5%) 0 Week 11 3 (0.4%) 0 Week 12 1 (0.1%) 1 (0.1%) Week 13 4 (0.5%) 0 Week 14 1 (0.1%) 0 Week 15 2 (0.2%) 0 Week 16 1 (0.1%) 0 Week 17 1 (0.1%) 1 (0.1%) Week 18 1 (0.1%) 0 Week 19 2 (0.2%) 0 Week 20 4 (0.5%) 1 (0.1%) Week 21 1 (0.1%) 0 Week 22 0 1 (0.1%) Week 23 1 (0.1%) 1 (0.1%) Week 24 1 (0.1%) 0 Week 25 0 2 (0.2%) Week 26 1 (0.1%) 0 Week 27 2 (0.2%) 1 (0.1%) Week 28 4 (0.5%) 2 (0.2%) Week 29 1 (0.1%) 2 (0.2%) Week 30 3 (0.4%) 3 (0.4%) Week 31 1 (0.1%) 0 Week 32 177 (21%) 58 (6.9%)

Rates of overall adverse events (AEs) were similar or reduced among participants who received REGEN-COV ^™ during the 8-month study period, as shown in the table below. Treatment-emergent AEs (TEAEs) occurred in fewer participants who received REGEN-COV ^™ , primarily due to a higher proportion of participants with COVID-19 in the placebo group. Severe TEAS occurred at similarly low rates in both treatment groups. No participants experienced adverse events of particular concern. There were five deaths, none attributed to study drug or attributed to COVID-19. Participants, n (%) REGEN-COV ^™ 1200 mg SC (n=1439) Placebo (n=1428) Have ≥1 TEAE 405 (28.1) 512 (35.9) Have ≥1 non-COVID-19 TEAE 342 (23.8) 326 (22.8) Have ≥1 serious TEAE 24 (1.7) 23 (1.6) Have ≥1 serious non-COVID-19 TEAE 24 (1.7) 16 (1.1) Having any TEAE that results in death 3 (0.2) 2 (0.1)

As discussed above, protection against symptomatic SARS-CoV-2 infection with REGEN-COV ^™ was maintained for approximately 5 months. For the time point closest to month 5 with available data (Day 140), the mean (SD) concentration of combined REGEN-COV ^™ observed in serum was 3.60 (2.19) mg/L (N=9); There was good agreement between the observed concentrations and the population PK predicted median (5th, 95th percentile) concentration of 3.50 (0.47, 12.9) mg/L. Based on the population-pharmacokinetic model, the predicted concentration of combination REGEN-COV ^™ in serum at the end of the 5-month period (day 150) is 2.73 mg/L, which corresponds to the reference SARS- Estimated 50% neutralizing titer of CoV-2 variant (D614G) 1:963

These data demonstrate the efficacy of REGEN-COV ^™ in preventing COVID-19 in susceptible strains of SARS-CoV-2. As demonstrated, a single dose of REGEN-COV ^™ (1200 mg) is highly effective in preventing SARS-CoV-2 infection for up to 5 months (100% relative risk reduction for symptomatic infection and 89.5% relative risk reduction for all infections). Example 5. Efficacy of anti-SARS-CoV-2 spike glycoprotein antibodies in rhesus monkeys and golden hamsters infected with SARS-CoV-2

Because animal models of COVID-19 are still under active development, no single model is more relevant to the human disease. In fact, based on the different manifestations of COVID-19 in humans, multiple animal models may be needed to simulate various environments of human SARS-CoV-2 infection. In the following studies, two different models capturing the different pathologies of SARS-CoV-2 infection were used. The rhesus monkey model is widely used to assess the efficacy of therapeutics and vaccines and shows a brief and mild course of the disease. In contrast, the golden hamster model showed a more severe form of the disease, with severe lung lesions. Assessing the efficacy of anti-SARS-CoV-2 spike glycoprotein antibodies in two of these models allows comparison of antibody efficacy in different disease settings to more fully understand the role of antibody therapies in limiting viral load and pathology in infected individuals. mechanism.

In the study discussed in this example, the anti-SARS-CoV-2 spike protein antibodies administered to the animals were two potent neutralizing antibodies targeting non-overlapping residues on the SARS-CoV-2 spike protein. (mAb10987 + mAb10933), using the following assays and procedures:

(I) Quantitative RT-PCR analysis of SARS-CoV-2 RNA . Use qRT-PCR analysis to determine the amount of RNA copies per milliliter of body fluid or per gram of tissue. The qRT-PCR analysis uses primers and probes specifically designed to amplify and bind to conserved regions of the nucleocapsid gene of coronaviruses. The signal is compared to a known standard curve and calculated to obtain the number of replicates per milliliter. For qRT-PCR analysis, viral RNA was first isolated from nasal wash fluid using the Qiagen MinElute Viral Spin Kit (Cat. No. 57704). For tissue, it was extracted with RNA-STAT 60 (Tel-test "B")/chloroform, pelleted and resuspended in RNase-free water. To generate controls for amplification reactions, RNA was isolated from applicable SARS-CoV-2 stocks using the same procedure. qPCR analysis was performed with an Applied Biosystems 7500 sequence detector and amplified using the following program: 48°C for 30 min, 95°C for 10 min, followed by 40 cycles of: 95°C for 15 sec, and at 55°C 1 minute. Calculate the number of replicates per ml of RNA by extrapolating from the standard curve and multiplying by the reciprocal of the 0.2 mL extraction volume. This gives a practical range of 50 to 5 × ¹⁰⁸ RNA copies per ml for nasal wash or gram of tissue. Primer/probe sequence: 2019-nCoV_N1-F: 5'-GAC CCC AAA ATC AGC GAA AT-3' (SEQ ID NO: 63) 2019-nCoV_N1-R: 5'-TCT GGT TAC TGC CAG TTG AAT CTG- 3' (SEQ ID NO: 64) 2019-nCoV_N1-P: 5'-FAM-ACC CCG CAT TAC GTT TGG TGG ACC-BHQ1-3' (SEQ ID NO: 65).

(I) Quantitative RT-PCR analysis of SARS-CoV-2 secondary genomic RNA . SARS-CoV-2 E gene subgenomic mRNA (sgRNA or sgmRNA) is assessed by RT-PCR using primers and probes known in the art. Briefly, to generate a standard curve, SARS-CoV-2 E gene sgRNA was cloned into pcDNA3.1 expression plasmid; the insert was transcribed using the AmpliCap-Max T7 High Yield MessageMaker Kit (Cellscript) to obtain standard RNA. . Prior to RT-PCR, samples or standards collected from challenged animals were reverse transcribed using Superscript III VILO (Invitrogen) according to the manufacturer's instructions. A Taqman custom gene expression assay (ThermoFisher Scientific) was designed using the sequence of sgRNA20 targeting the E gene. Reactions were performed on QuantStudio 6 and 7 Flex real-time PCR systems (Applied Biosystems) according to the manufacturer's specifications. Use the standard curve to calculate the number of sgRNA replicas per milliliter or per swab; the sensitivity of quantitative analysis is 50 replicas per milliliter or per swab. For nasal washes, this gives a practical range of 50 to 5 × 10^7 RNA copies per milliliter, and for tissue, the viral load per gram. Subgene RNA primer: SG-F: CGATCTTGTAGATCTGTTCCTCAAACGAAC (SEQ ID NO: 66) SG-R: ATATTGCAGCAGTACGCACACACA (SEQ ID NO: 67) PROBE: FAM-ACACTAGCCATCCTTACTGCGCTTCG-BHQ (SEQ ID NO: 68)

(III) Cells and viruses. Vero E6 cells (VERO C1008, catalog number NR-596, BEI resources) were grown in Dulbecco's modified essential medium containing 10% heat-inactivated fetal bovine serum (FBS; Gibco) at 37°C and 5% _CO (Dulbecco's modified essential media; DMEM; Gibco). SARS-CoV-2 isolate USA-WA1/2020 (BEI source NR-52281, GenBank accession number MN985325.1) was used to generate animal exposure stocks. Fourth generation cell culture (P4) of SARS-CoV-2 was obtained and propagated. The fourth passage cell culture (P4) stock virus obtained from BEI was passaged once to generate a master stock by infecting Vero E6 cells at a magnification of infection (MOI) of approximately 0.001 in DMEM containing 2% FBS; Viral supernatants were collected 3 days post-infection. P5 stock was used to generate exposure stocks by infecting Vero E6 cells at an MOI of 0.02 in DMEM containing 2% FBS; viral supernatants were collected three days post-infection. The stock solution has been confirmed to be SARS-CoV-2 by deep sequencing and confirmed to be free of exogenous agents. The virus titer was determined to be 2.1 × 10 ⁶ PFU/mL.

(IV) RNA extraction for viral load determination via RT-qPCR . Deactivate the sample using TRIzol LS separation reagent (Invitrogen): Mix 250 µL of test sample with 750 µL TRIzol LS. Prepare inactivation controls from each batch of samples. Prior to extraction, 1 × 10 ³ pfu of MS2 phage (E. coli phage MS2, ATCC) was added to each sample to assess extraction efficiency. RNA extraction was performed using EpMotion M5073c liquid handler (Eppendorf) and NucleoMag pathogen kit (Macherey-Nagel). Extraction controls were prepared from each batch of samples. After processing, confirm the presence of the eluate and store the extracted RNA at 80°C ± 10°C.

(V) Viral load determination via RT-qPCR . 5 µL RNA samples were used in duplex RT-qPCR reactions to detect both SARS-CoV-2 and MS2 phage. Two assays were used to assess the presence of SARS-CoV-2 in samples. The 2019-nCoV_N1 assay developed by CDC targets the region of the N gene. The SARS-CoV-2_N1 probe (ACCCCGCATTACGTTTGGTGACC; SEQ ID NO: 69) was labeled with 6-FAM fluorescent dye. The forward primer sequence used is: GACCCCAAAATCAGCGAAAT (SEQ ID NO: 63), and the reverse primer sequence used is: TCTGGTTACTGCCAGTTGAATCTG (SEQ ID NO: 64). Secondary qPCR analysis for measuring subgenomic RNA was also performed to target the region of the E (mantle) gene.

The probe was also labeled with 6-FAM fluorescent dye (ACACTAGCCATCCTTACTGCGCTTCG; SEQ ID NO: 68). The forward primer sequence is: CGATCTCTTGTAGATCTGTTCTC (SEQ ID NO: 70), and the reverse primer sequence is: ATATTGCAGCAGTACGCACACA (SEQ ID NO: 71). Label the MS2 probe with VIC fluorescent dye. Both assays were performed on a QuantStudio 3 instrument (Applied Biosystems) using TaqPath ^™ 1-Step RT-qPCR Master Mix, CG (Thermo Fisher). QuantStudio design and analysis software (Applied Biosystems) was used to run and analyze results. The cycle parameters were set as follows: holding phase at 25°C for 2 min (min), at 50°C for 15 min, and at 95°C for 2 min. PCR phase: 45 cycles (N1 analysis) or 40 cycles (E analysis) at 95°C for 3 sec and at 60°C for 30 sec. The average Ct value of MS2 phage was calculated for all processed samples and SARS-CoV-2 quantification was performed only in samples in which the MS2 Ct value was lower than the average MS2 + 5%.

(VI) Histopathology. A necropsy was performed and selected tissue samples were collected (tracheobronchial lymph nodes, nasal cavity, trachea, heart, liver, spleen, kidneys, and all 4 right lung lobes). Tissues were fixed by immersion in 10% neutral buffered formalin for a minimum of fourteen days, then trimmed, routinely processed, and embedded in paraffin. Paraffin-embedded tissue sections were cut into 5 µm thick, and histological coverslips were deparaffinized, stained with hematoxylin and eosin (H&E), coverslipped, and labeled. Slides were evaluated indiscriminately by a board-certified veterinary pathologist.

(VII) Viral RNA sequencing. 10 µl RNA and 25 ng human universal reference RNA (Agilent) were purified by PureBeads (Roche Sequencing). cDNA synthesis was performed using the SuperScript ^™ IV first-strand synthesis system (Thermal Fisher) following the supplier's protocol. Half of the cDNA (10 µl) was then used to generate the library using the Swift Normalase ^™ Amplicon Panel (SNAP) SARS-CoV-2 panel (Swift Biosciences) following the supplier's protocol. Sequencing was run on NextSeq (Illumina) with multiple paired reads with 2×150 cycles.

(VIII) RNAseq data analysis. RNAseq analysis was performed using the Array Studio software package platform (Omicsoft). Use the "RNA-Seq Data Kit Raw Data QC" to assess the quality of paired-end RNA Illumina reads. Calculate minimum and maximum read length, total nucleotide number, and GC%. Along each base pair, an overall quality report is generated summarizing the quality of all reads in each sample. Rapid amplicon whole RNA-seq reads were aligned to the SARS-CoV-2 reference genome Wuhan-Hu-1 (MN908947) using Omicsoft Sequence Aligner (OSA) version 4. Alignments were sorted by read name, and primers were cut using complementary Swiftbiosciences primer cutting software (v0.3.8). Use preset parameters to fine-tune reads by quality score (when the aligner encounters a nucleotide for a read with a quality score of 2 or less, it fine-tune the remainder of the read). Analyze and annotate OSA output using the Summary Variant Data and Annotation Variant Data packages (Omicsoft). The remainder of the analysis focused on the portion of the gene body encoding the spike protein. Use custom scripts to outline target coverage for each sample and calculate SNP calls. If the number of mutated reads relative to the total number of reads was higher than 1%, the virus mutation frequency inferred from the sequenced reads was calculated. Part A— Efficacy of Anti-SARS-CoV-2 Spiny Glycoprotein Antibodies in Rhesus Monkeys Infected with SARS-CoV-2

To determine the ability of spine antibodies to protect rhesus monkeys from SARS-CoV-2 challenge, the impact of high-dose antibody administration prior to viral challenge was assessed. A total of 12 untreated rhesus monkeys of Indian origin (purpose-bred, rhesus macaques ( Macaca mulatta )) were used in this study. Animals were distributed to treatment groups based on age distribution. Animals were administered anti-SARS-CoV-2 spike glycoprotein antibody via intravenous administration at a dose of 50 mg/kg and challenged with 1×10^5 PFU of virus via intranasal and intratracheal routes 3 days after antibody administration. Due to the relatively transient nature of SARS-CoV-2 infection in the rhesus monkey model, the survival portion of the study was limited to 5 days. To determine the impact of antibody prophylaxis on viral load in the upper and lower respiratory tract, daily nasopharyngeal swabs and bronchoalveolar lavage (BAL) fluid were collected on days 1, 3, and 5 postchallenge ( Fig. 1A ). Both genomic and subgenomic RNA were measured to assess the impact of antibody prophylaxis on the kinetics of viral replication. Viral replication kinetics in placebo-treated animals mirrored those previously reported, in which viral load peaked at day 2 post-challenge and then decreased rapidly, although most animals remained responsive to nasal swabs by day 5. The viral RNA was positive. The kinetics of sgRNA in nasal swabs and BAL were similar to those of gRNA, suggesting that both forms of RNA may be relevant to viral replication in this model, but sgRNA levels were significantly lower than gRNA levels, with a difference of approximately 2-log. In animals that received antibody prophylaxis, a reduction in viral load was observed in all measurements, including nasal swabs and BAL, indicating that prophylactic administration of antibodies reduced viral load in both the upper and lower respiratory tracts ( Figure 1B ). This is in contrast to previously reported effects on viral load in remdesivir-treated animals, where a reduction in viral load was only observed in the lower respiratory tract and no difference in rhinovirus RNA levels. Part B— Efficacy of Anti-SARS-CoV-2 Spiny Glycoprotein Antibodies in Rhesus Monkeys Infected with SARS-CoV-2 and Putative Escape Mutants

A secondary prevention study including high-dose and low-dose groups confirmed the ability of high-dose anti-SARS-CoV-2 spike glycoprotein antibodies to minimize viral replication, even when higher doses of virus (1.05×10^6 PFU) were used The same is true when attacking animals ( Figure 2A and Figure 2B ). Twenty-four (24) rhesus monkeys (13 females and 11 males) were used in this study and randomly assigned to one of six groups. Animal lines were obtained from the Southwest National Primate Research Center (SNPRC) colony and were between 2.5 and 6 years old and approximately 3 to 10 kg at the time of study inclusion. On study day 0, each animal was exposed to an Animal Biosafety Level 4 (ABSL-4) laboratory with a target dose of 1.05 × 10 ⁶ PFU of SARS-CoV-2 in a total volume of 500 µl (via the intranasal route 5.25 ×10 ⁵ PFU, 250 µl and via the intratracheal route 5.25 × 10 ⁵ PFU, 250 µl). Intranasal delivery is via a mucosal atomization device (Teleflex Intranasal Mucosal Nebulization Device LMA MAD Nasal Device), which allows IN delivery of aerosolized particles ranging in size from 30-100 microns, which simulates droplet transmission. Intratracheal delivery uses a tracheal mucosal nebulizer device (Teleflex Laryngo-tracheal mucosal nebulizer device LMA MADGIC). On day -3 relative to exposure, animals in the prevention group were sedated and received treatment. On day 1 (after viral exposure), animals in the treatment group were sedated and treated. Treatment is administered via intravenous injection over the course of approximately 90 seconds.

In this study, an increased effect of antibody treatment on viral load in oral and nasopharyngeal swabs was observed, suggesting that antibody treatment can differentially affect multiple physiological sources of viral replication. No protective effect of the antibodies was observed at the low dose of 0.3 mg/kg, where antibody-treated animals showed similar viral kinetics to placebo animals in both nasal and oral swabs.

Additionally, the impact of anti-SARS-CoV-2 spike glycoprotein antibodies in a therapeutic setting was assessed by administering 1 × 10^6 PFU of SARS-CoV-2 virus to animals challenged 1 day post-infection ( Figure 2A ) . By day 1 post-challenge, animals have reached peak viral loads as measured by both genomic and subgenomic RNA, simulating a likely clinical scenario, as it has been shown that most SARS-CoV-2-infected individuals Peak viral load is reached relatively early in the course of the disease and usually before or only at the onset of symptom onset. Animals treated with anti-SARS-CoV-2 spike glycoprotein antibodies showed faster viral clearance in nasopharyngeal and oral swab samples (including both genomic and subgenomic RNA samples) relative to placebo-treated animals rate ( Figure 2C ). Similar to the prophylaxis group, the reduction in viral load appeared to be more significant in oral swabs compared to NP swabs. Due to the small group size and higher day 1 viral load in the 150 mg/kg group, statistical conclusions regarding dose response in this study cannot be made. Upon antibody dosing, animals in the 150 mg/kg group showed approximately 1-log higher titers on day 1, thus potentially masking the potentiating effects of higher doses of antibody. Similar effects of antibody treatment on genomic and subgenomic RNA were observed for both NP and buccal samples, indicating that antibody treatment directly limits viral replication in these animals ( Fig . 2C ).

Pathological analysis of the lungs of the infected animals revealed that all four placebo monkeys exhibited evidence of lung damage characterized by interstitial pneumonitis in the septum, perivascular space, and/or pleura in three monkeys (Fig. 2D) Very little to mild infiltration of mononuclear cells (lymphocytes and macrophages). In these three animals, the lesion distribution was multifocal and involved 2-3 of the 4 lobes. Accompanying these changes are alveolar infiltration of lymphocytes, increase in alveolar macrophages and fusion cells. Type II pneumocyte hyperplasia has also been observed in sporadic alveoli. In the fourth placebo monkey, lung damage was limited to type II pneumocyte hyperplasia, suggesting secondary inflammatory repair processes. Overall, the histological lesions observed in placebo animals were consistent with acute SARS-CoV-2 infection.

In the prophylaxis group, 3 of 4 animals in the low-dose combination group and 1 of 4 animals in the low-dose combination group exhibited interstitial pneumonitis that was generally minimal and had fewer histologic features than the placebo group. signs (Table 16). In one infected high-dose combination animal, only 1 of the 4 lung lobes had minimal disease. In the therapeutic treatment group, 2 of 4 low-dose and 2 of 4 high-dose combination animals showed signs of interstitial pneumonia. In all infected low-dose and high-dose animals, only 1 of the 4 lung lobes had lesions. The incidence (number of animals and number of infected lung lobes) and severity of this interstitial pneumonia were reduced in both prophylactic and therapeutic treatment modalities compared with placebo. Table 16 below shows the pathology scores in individual animals treated with anti-SARS-CoV-2 spike protein antibodies or placebo.

［ Table 16. ] Pathological analysis of rhesus monkey lungs. prevention group placebo 0.3 mg/kg 50mg/kg animal number 1 2 3 4 5 6 7 8 9 10 11 12 Number of leaves to check 4 4 4 4 4 4 4 4 4 4 4 4 Number of leaves with inflammation 2 1 0 3 2 0 2 3 1 0 0 0 fever diaphragm 1 1 0 1 1 0 1 1 1 0 0 0 Alveoli 1 1 0 1 1 0 1 1 1 0 0 0 perivascular 1 1 0 2 1 0 1 0 0 0 0 0 pleura 0 1 0 1 1 0 1 0 0 0 0 0 fused cells 0 0 0 1 0 0 0 0 1 0 0 0 Hyperplasia, type II cells 0 1 1 1 0 0 0 1 0 0 0 0 Increased alveolar macrophages 1 1 1 1 1 1 1 1 0 0 1 1 ［ Table 16. Continued] treatment group placebo 25 mg/kg 150 mg/kg animal number 1 2 3 4 5 6 7 8 9 10 11 12 Number of leaves to check 4 4 4 4 4 4 4 4 4 4 4 4 Number of leaves with inflammation 2 1 0 3 0 1 1 0 1 0 1 0 fever diaphragm 1 1 0 1 0 1 1 0 1 0 2 0 Alveoli 1 1 0 1 0 0 1 0 0 0 1 0 perivascular 1 1 0 2 0 0 0 0 0 0 1 0 pleura 0 1 0 1 0 0 1 0 0 0 1 0 fused cells 0 0 0 1 0 0 1 0 0 0 1 0 Hyperplasia, type II cells 0 1 1 1 0 0 1 0 0 0 1 0 Increased alveolar macrophages 1 1 1 1 0 1 1 1 1 1 1 1

Two antibodies targeting non-overlapping sites on the spike protein have been shown to prevent selection of escape mutants that can be easily detected with single antibody treatment. To assess whether any signs of putative escape mutants could be observed in an in vivo setting using real SARS-CoV-2 viruses, RNAseq analysis was performed on all RNA samples obtained from all animals in this study. Analysis of the mutated spike gene sequences identified in animal samples that were not present in the inoculated virus ( Figure 3A and Figure 3B ) further demonstrated that the virus was actively replicating in these animals. No mutations unique to treated animals were observed, as all identified mutations were present in the inoculum or in both treated and placebo animals, suggesting that they may be selected as part of viral replication in animals and are not specific associated with antibody therapy. Part C— Efficacy of anti-SARS-CoV-2 spike glycoprotein antibodies in golden hamsters infected with SARS-CoV-2

A total of 50 male and female golden hamsters aged 6-8 weeks were used in this study. Animals were weighed before the start of the study. During the study period, animals were monitored twice daily for signs of COVID-19 disease (ruffled fur, hunched posture, difficulty breathing, etc.). Body weight was measured once daily during the study period. Antibodies are administered via intraperitoneal (IP) injection. Animals were challenged with 5.6 × 10^4 PFU of (USA-WA1/2020 (NR-52281; BEI Resources)) by dropwise administration of 0.05 ml of virus inoculum into each nostril. By collecting two small pieces from the lungs ( 0.1-0.2 g each) and tissue samples were taken for viral load analysis (4 slides total, 2 slides per tissue).

Unlike rhesus monkeys, which exhibit a mild clinical course of illness when infected with SARS-CoV-2 and mimic mild human disease, the golden hamster model is more severe, in which the animals demonstrate readily observable clinical disease, including concomitant lung disease. Extremely high viral load, rapid weight loss, and severe lung disease. Therefore, this model more closely simulates more severe diseases in humans. Preventing hamsters 2 days before challenge with SARS-CoV-2 virus at a dose of 5.6 × 10^4 produced significant protection against weight loss at all antibody doses administered (50 mg/kg to 0.5 mg/kg). This protection was accompanied by a reduction in viral load in the lungs at the end of the study. High gRNA and sgRNA levels were observed in the lungs of several treated animals; however, these individual animals did not exhibit any less protection from weight loss than animals with much lower viral loads. One explanation could be that antibody treatment may provide additional therapeutic benefit in this model that is not directly related to viral load reduction. Alternatively, increased viral RNA may not necessarily be associated with infectious virus. Because viral replication and lung pathology occur extremely rapidly in the hamster model, the therapeutic setting represents a high standard for demonstrating therapeutic efficacy. In animals treated with anti-SARS-CoV-2 spike protein antibody at doses of 50 mg/kg and 5 mg/kg, a clear therapeutic benefit was observed 1 day after viral challenge ( Figure 4B ). Although the 5 mg/kg treatment group showed the fastest recovery at the end of the study, this may be due to lower day 1 body weight loss in this group of animals and does not truly enhance the benefit of the lower dose ( Figure 4B ). result

In these studies, the in vivo efficacy of anti-SARS-CoV-2 antibody combinations in two animal models, one mild and one severe, was assessed in both preventive and therapeutic settings. Efficacy was demonstrated in both models, as measured by reduced viral load in the upper and lower respiratory tract and limited body weight loss in the hamster model. The impact of antibody prophylaxis on viral RNA levels in nasal and oral swabs may indicate not only preventing disease in exposed individuals but also limiting the potential for transmission.

Importantly, no signs of worsening of viral load or pathology in the presence of high or low doses of antibodies were observed in any animal model. The potential for antibody-dependent enhancement (ADE) of disease is an issue for antibody-based therapeutics and vaccines. ADE of viral infection can occur when antibodies bind to virions and infectivity increases due to internalization of the antibody/viral complex via the interaction of the antibody Fc domain with the Fcγ receptor (FCGR). Antibody-dependent enhancement can cause infection of cell types expressing FCGR, potentially causing enhanced viral replication, increased inflammation, or more severe disease. In vitro ADE studies confirmed that mAb10987 alone or in combination with mAb10933 mediates the entry of pVSV SARS-CoV-2 S pseudoparticles into FCGR2+ Raji and FCGR1+/FCGR2+ THP1 cells, but does not mediate other FCGR+ test cell lines (FCGR2+ IM9 and K562, and FCGR1+/ FCGR2+ U937), or any of the FCGR negative control cell lines (Ramos). mAb10933 alone did not mediate entry of pVSV SARS-CoV-2 S pseudoparticles into any of the test cell lines (R10933-PH-20101). These data demonstrate that mAb10987 may have the ability to enhance viral entry into certain FCGR+ cells in vitro. However, circulating IgG in vivo can compete with anti-SARS-CoV-2 S protein mAb for binding to FCGR, thereby inhibiting antibody-mediated virus entry. This is supported by studies in in vivo animal models, which showed no evidence of disease enhancement. Taken together, the data presented in this example provide compelling evidence that antibody-based therapies (e.g., using an antibody cocktail of mAb10987 + mAb10933) provide clinical benefit in the context of prevention and treatment of COVID-19 disease. Example 6. Clinical evaluation of repeated doses of anti-SARS-CoV-2 spike protein antibodies in adult volunteers.

The clinical study described below was a Phase 1, randomized, double-blind, placebo-controlled study that evaluated the efficacy of repeated subcutaneous doses of anti-Echinoplasma (S) SARS-CoV-2 monoclonal antibodies (mAb10933 + mAb10987) in adult volunteers. Safety, tolerability, pharmacokinetics and immunogenicity.

Research Objectives: The primary and secondary objectives of the research are stated below.

Primary Objectives —The primary objectives are: • To assess the occurrence of adverse events of particular interest (AESI) (for this study, AESI is defined as Grade 3 or higher ( NCI-CTCAE grade v5.0 ) injection site reaction or allergic reaction, including (but not limited to) anaphylaxis, laryngeal / pharyngeal edema, severe bronchospasm, chest pain, seizures, and severe Hypotension) • Assess changes in serum mAb10933 and mAb10987 concentrations over time following single and repeated SC administration

Secondary Objectives —Secondary objectives are: • To assess the safety and tolerability of repeated SC doses of mAb10933 + mAb10987 compared to placebo • To assess the achievement of target concentrations of mAb10933 and mAb10987 in serum following single and repeated SC dosing • Assessment of the immunogenicity of mAb10933 and mAb10987

Exploratory Objectives —The exploratory objectives are to: • Assess the occurrence of COVID-19 in subjects receiving repeated SC doses of mAb10933 + mAb10987 compared to placebo • Assess the occurrence of SARS-CoV-2 seroconversion • Determine the incidence of SARS-CoV-2 seroconversion in subjects receiving repeated SC doses of mAb10933 + mAb10987 and/or biomarkers and genomic factors related to the safety and exposure of SARS-CoV-2 infection

Study Design: This study is a Phase 1, randomized, double-blind, placebo-controlled study in adult volunteers designed to assess the safety and tolerability of multiple subcutaneous (SC) doses of mAb10933 + mAb10987. Subjects were randomized in a 3:1 ratio to receive up to 6 SC doses of mAb10933 + mAb10987 combination therapy or placebo.

Study Duration : This study consists of 3 phases: a screening/baseline period of up to 7 days, a treatment period of 24 weeks (or shorter if the subject develops symptomatic SARS-CoV-2 infection), and a 28-week treatment period if the subject develops symptomatic SARS-CoV-2 infection. symptoms of COVID-19, the follow-up period may be longer).

Study Population : The study included approximately 940 subjects. Subjects include male and female adult volunteers aged 18 to 90 years who are healthy or have a chronic but stable and well-controlled medical condition who screen negative for SARS-CoV-2 infection. Inclusion Criteria: Subjects are eligible for inclusion in the study if they meet the following criteria: 1. 18 to 90 years old (inclusive) at the time of signing the informed consent form 2. Healthy or suffering from a chronic medical condition considered stable and well-controlled by the investigator, and Unlikely to require medical intervention until the end of the study 3. On stabilizing medications for co-morbid conditions for at least 6 months prior to screening 4. Willing and able to comply with study visits and study-related procedures, including compliance with SARS-CoV-2 infection and transmission-related on-site prevention requirements 5. Willing and able to provide signed informed consent Exclusion criteria: Subjects who meet any of the following criteria will be excluded from the study: 1. A positive diagnostic test for SARS-CoV-2 infection in the randomized group ≤72 hours prior (This test is performed as part of screening. Samples for testing should be collected ≤72 hours before randomization, and results should be reviewed and confirmed negative prior to dosing). 2. The subject's reported clinical history of COVID-19 as determined by the investigator 3. The subject's reported history of previous positive diagnostic tests for SARS-CoV-2 infection 4. Active respiratory or non-respiratory symptoms suggestive of or consistent with COVID-19 Symptoms 5. Acute illness, systemic antibiotic use, or hospitalization for any reason within 30 days prior to screening (i.e., >24 hours) 6. Clinically significant abnormal laboratory results at the time of screening, such as from one of the following As defined by 1 or more of (can be repeated once): • HbA1c ≥8.0% • Hemoglobin <10 g/dL • Absolute neutrophil count <1.5 × 109/L • Platelet count <75 × 109/L • Serum creatinine >1.5×upper limit of normal (ULN) or estimated glomerular filtration rate ≤60 mL/min/1.73m2 • Abnormal liver function is defined as 1 or more of the following: - Aspartate aminotransferase (AST) and /or alanine aminotransferase (ALT) and/or alkaline phosphatase (ALP) >2× ULN - total bilirubin >1× ULN 7. Chronic lung disease in the past 6 months before screening (e.g., Acute exacerbation of chronic obstructive pulmonary disease [COPD], asthma exacerbation) 8. Abnormal blood pressure (BP) at screening, as defined by diastolic BP >100 mm Hg and/or systolic BP >160 mm Hg. Blood pressure measurement may be repeated once at screening 9. History of hospitalization for heart failure, diagnosis of myocardial infarction, stroke, transient ischemic attack, unstable angina, percutaneous or surgical revascularization procedure (coronary arterial, carotid or peripheral vascular) or intracardiac device placement (e.g., pacemaker) 10. Cancers other than non-melanoma skin cancer or cervical/anal in situ that currently require treatment or have been in the past 5 years11. A history of significant multiple and/or severe allergies (e.g., latex gloves) or allergic reactions to prescription or over-the-counter medications or foods. This is to avoid potential confusion of safety information and is not due to a specific safety risk. 12. Treated with another investigational drug within the last 30 days or 5 half-lives of the investigational drug (whichever is longer) prior to screening13. Receive an investigational or approved SARS-CoV-2 vaccine14. Receiving investigational or approved passive antibodies for prevention of SARS-CoV-2 infection (e.g., convalescent plasma or serum, monoclonal antibodies, hyperimmune globulin) 15. Use of RAD within 2 months prior to screening Civir, intravenous immune globulin (IVIG) or other anti-SARS virus agents16. Regularly drink ≥21 drinks per week17. Members of the clinical site research team and/or close relatives18. Pregnant or breastfeeding women19. In Women of childbearing potential (WOCBP)* who are unwilling to use highly effective contraception before the first dose/first treatment, during the study, and for at least 8 months after the last dose. Very effective contraceptive methods include: a. Steady use of combination (containing estrogen and progestin) hormonal contraception (oral, intravaginal, transdermal) or progestin-only hormonal contraception (oral, injectable, implantable) ), which is associated with suppression of ovulation that began 2 or more menstrual cycles before screening b. Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) c. Bilateral fallopian tube ligation *WOCBP is defined as menarche at menarche You will then be fertile until you become a postmenopausal woman, unless you become permanently infertile. Permanent sterilization methods include hysterectomy, bilateral fallopian tube resection, and bilateral oophorectomy. Postmenopausal status is defined as the absence of menstruation for 12 months without an alternative medical cause. Follicle-stimulating hormone (FSH) levels in the postmenopausal range can be used to confirm postmenopausal status in women who are not using hormonal contraception or hormone replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the onset of postmenopausal status. The above definitions are based on Clinical Trials Facilitation Group (CTFG) guidelines. Women who have had a documented hysterectomy or tubal ligation do not need a pregnancy test or birth control. 20. Sexually active men who are unwilling to use the following forms of medically acceptable birth control during the study drug follow-up period and for 8 months after the last dose of study drug: vasectomy, where the procedure is medically judged to be successful or ongoing use of insurance set. Sperm donation is prohibited during the study and for up to 8 months after the last dose of study drug.

Study Treatment : In the study, treatment consisted of co-administration of mAb10933 + mAb10987 1200 mg (600 mg + 600 mg)/subcutaneous (SC)/Q4W (once monthly) or placebo/SC/Q4W (once monthly).

Evaluation Metrics : Primary, secondary and exploratory evaluation metrics are defined below.

Main evaluation indicators—The main evaluation indicators are: • Incidence of AESI occurring within 4 days of SC administration of mAb10933 + mAb10987 or placebo at baseline and days 29, 57, 85, 113, and 141 • The concentration of mAb10933 and mAb10987 in serum changes over time

Secondary Evaluation Metrics—The secondary evaluation metrics are: • Proportion of subjects with treatment-emergent adverse events (TEAE) until the end of the study and severity of TEAEs • Proportion of subjects achieving or exceeding target serum concentrations of mAb10933 and mAb10987 (20 µg/mL) at the end of each 4-week dosing interval for mAb109333 + mAb10987 • Immunogenicity as measured by anti-drug antibodies (ADA) against mAb10933 and mAb10987 over time

Exploratory evaluation metrics—The exploratory evaluation metrics are: • Incidence and severity of symptomatic SARS-CoV-2 infection during treatment and follow-up periods • Proportion of baseline anti-SARS-CoV-2 seronegative subjects with post-baseline positive serology (anti-N protein) until study end

Procedure and Assessment :

Procedures performed at the time of screening only—Screening procedures include medical history (including chronic medical conditions), demographic information (including age, sex, race, weight, height), and assessment of SARS-CoV-2 infection (via nasopharyngeal [NP ] Central laboratory RT-PCR of swabs or by approved or authorized diagnostic analysis performed in accordance with site standards and procedures).

Procedures performed at baseline—Subjects underwent baseline RT-PCR assessment of SARS-CoV-2 infection via central laboratory NP swabs.

Safety Procedures and Assessments— Subjects are required to report all adverse events (AEs) and concomitant medications experienced from the time of informed consent until their last study visit. Performs targeted physical examination, vital signs, clinical laboratory testing, and clinical evaluation. During treatment, subjects were followed for AEs approximately 24 hours and 2 weeks after administration of each study drug. Assessment of SARS-CoV-2 infection (by central laboratory RT-PCR of NP swabs or by in accordance with site standards and procedures) in subjects who develop symptoms/symptoms of COVID-19 during the treatment period or follow-up period approved or authorized diagnostic analysis).

Pharmacokinetics, Immunogenicity and Serology—Blood samples were collected to assess serum concentrations of mAb10933 and mAb10987, the immunogenicity of mAb10933 and mAb10987, and anti-SARS-CoV-2 serology.

Statistics plan:

By the end of the study, approximately 940 subjects will have been enrolled (705 subjects in the mAb10933 + mAb10987 group and 235 subjects in the placebo group). Assuming approximately 80% of previously enrolled subjects return to the extended treatment period under protocol amendment 3, approximately 856 subjects are expected to be randomized over the 6-month treatment duration (642 subjects in the mAb10933 + mAb10987 group and 214 in the placebo group). name object).

Based on previous experience with subcutaneous (SC) administration of monoclonal antibodies (mAbs), the expected rates of injection site reactions (ISR) and anaphylaxis are approximately 10% and <1%, respectively. If the number of subjects observed with ISA is ≤54, a sample size of 705 subjects in the mAb10933 + mAb10987 group would exclude the risk of an ISR >10%. Similarly, a ≥1% risk of anaphylaxis (grade ≥3) will be excluded if such events occur in fewer than 2 subjects in the study.

Results —This study demonstrates that multiple subcutaneous (SC) doses of mAb10933 + mAb10987 are safe and well tolerated. Example 7. Clinical evaluation of the virological efficacy of anti-SARS-CoV-2 spike glycoprotein antibodies with different dosing regimens in outpatients with SARS-CoV-2 infection.

The clinical study described below was a Phase 2, randomized, double-blind, placebo-controlled, parallel-group study evaluating a single intravenous (IV) or single subcutaneous (SC) dose in outpatients with SARS-CoV-2 infection. Dose-response profile of mAb10933 + mAb10987.

Research Objectives: The primary and secondary objectives of the research are stated below.

Primary objective —The primary objective is to assess the virological efficacy of mAb10933 + mAb10987 at various intravenous and subcutaneous doses compared with placebo.

Secondary Objectives —Secondary objectives are: • To assess additional measures of virological efficacy of mAb10933 + mAb10987 compared to placebo • To assess the safety and tolerability of mAb10933 + mAb10987 compared to placebo • To assess serum levels of mAb10933 and mAb10987 Changes in concentration over time • Evaluate the immunogenicity of mAb10933 and mAb10987

Exploratory Objectives —The exploratory objectives are: • To explore the occurrence of all-cause hospitalization, emergency room (ER) visit, or death in patients treated with mAb10933 + mAb10987 compared to patients treated with placebo • To explore the occurrence of all-cause hospitalizations, emergency room (ER) visits, or death in patients treated with mAb10933 + mAb10987 compared with patients treated with placebo Occurrence of COVID-19 related medical visits (MAVs) in patients treated with mAb10933 + mAb10987 compared to patients treated (COVID-19 related medical visits will be defined as follows: hospitalization, ER visit, urgent care visit, physician Office visit or telemedicine visit where the primary reason for the visit is COVID-19) • Assess viral genetic variation in patients with positive SARS-CoV-2 quantitative reverse transcription polymerase chain reaction (RT-qPCR) • Explore the relationship between mAb10933 + mAb10987 exposure and selected efficacy measures, safety measures, and/or biomarkers

Study Design: This study is a randomized, double-blind, placebo-controlled, parallel-group study evaluating a single intravenous (IV) or single subcutaneous (SC) dose of REGN10933+ in outpatients with SARS-CoV-2 infection. Dose-response profile of REGN10987. An overview of the study is shown in Figure 57 .

Eligible patients will be randomized to receive a single dose of mAb10933 + mAb10987 or placebo via IV or SC route. On the day of administration, patients collected NP swabs for SARS-CoV-2 RT-qPCR testing and blood draws for safety, drug concentration, immunogenicity and serological analyses. Following study drug administration, patients underwent postdose blood sampling (either at the end of the intravenous infusion or at least 1 hour after subcutaneous administration). Monitor patients for at least 1 hour after study drug administration and then release from the study site when medically appropriate.

Record information related to safety and COVID-19-related medical visits during planned study visits. Patients are also asked to inform researchers of any medical visits as soon as possible. TEAEs collected during the study may vary depending on the time period of the study. For more information on reporting TEAEs and treatment-induced laboratory abnormalities, refer to the Safety Reporting section of the protocol.

Patients collected NP swabs and blood samples every other day during the first week of the study. Additional NP swab samples were collected weekly for 2 weeks to assess potential persistence of viral load. Telephone interviews were conducted during the fourth week to collect safety information.

After the first month, patients visit approximately once a month for another 4 months. The penultimate visit was for in-person blood sample collection for drug concentration and immunogenicity. The final visit (EOS) is a telephone call.

Study Duration : The study duration for each patient is 170 days.

Study population : This study included adult non-hospitalized patients with a positive diagnostic test for SARS-CoV-2. The protocol calls for enrolling up to approximately 1,400 patients by the end of the study. Inclusion Criteria: Patients must meet the following criteria to be eligible for inclusion in the study: 14. Male or female ≥18 years old (or national legal age of majority) at the time of randomization Note: an upper age limit may apply; refer to other inclusion criteria. 15. Use validated SARS-CoV-2 antigen, RT-PCR or other molecular diagnostic assays and appropriate samples (such as nasopharyngeal (NP), nose, oropharynx (OP) or saliva), ≤72 hours before randomization Samples collected for positive diagnostic testing for SARS-CoV-2 NOTE: A history of positive results is acceptable as long as the sample was collected ≤72 hours before randomization. 16. Low-risk symptomatic patients: Have symptoms consistent with COVID-19 onset ≤7 days prior to randomization (as determined by the investigator) and meet all of the following 8 criteria: a. Age ≤50 b. Not obese, obesity is defined as BMI ≥30 kg/m ² c. Not suffering from cardiovascular disease or hypertension d. Not suffering from chronic lung disease or asthma e. Not suffering from type 1 or type 2 diabetes f. Not suffering from chronic kidney disease , with or without dialysisg. Not with chronic liver diseaseh. Non-pregnant or asymptomatic patients: No symptoms consistent with COVID-19 at any time <2 months prior to randomization (as confirmed by investigator determined) 17. Maintain room air with _O2 saturation ≥93% 18. Willing and able to provide informed consent signed by the study patient or a legally acceptable representative 19. Willing and able to comply with study procedures, including providing Sample exclusion criteria for viral shedding testing: Patients who meet any of the following criteria will be excluded from the study: 1. Admitted to the hospital with COVID-19 before randomization, or hospitalized for any reason at the time of randomization (inpatients) 2. Known positive SARS-CoV-2 serological test 3. Positive SARS-CoV-2 antigen or molecular diagnostic test in sample collected >72 hours before randomization 4. Immunosuppressed, based on investigator's assessment : Examples include cancer treatment, bone marrow or organ transplantation, immune deficiencies, HIV (if poorly controlled or evidence of AIDS ), sickle cell anemia, thalassemia, and long-term use of immune-weakening drugs. 5. Participated or are participating in the evaluation of COVID-19 convalescent plasma, anti-SARS-CoV-2 mAb, or intravenous immunoglobulin within 3 months or 5 half-lives of the investigational product (whichever is longer) before the screening visit Clinical studies of (IVIG) 6. Previous, current or planned future use of any of the following treatments: COVID-19 convalescent plasma, anti-SARS-CoV-2 mAb (e.g., bamlanivimab), IVIG (any indication), systemic corticosteroids (any indication), or COVID-19 treatment (authorized, approved, or investigational) Note: Prior use is defined as the past 30 days since screening or within more than 5 investigational product half-lives within (whichever is longer). 7. Previous use (before randomization), current use (at the time of randomization), or planned use (within the period given in accordance with CDC guidelines, but no earlier than 22 days after the study drug is administered) of any authorized or approved SARS-CoV-2 vaccine8. Known active infection with influenza or other non-SARS-CoV-2 respiratory pathogens, confirmed by diagnostic testing9. Known allergy or anaphylaxis to components of the study drug10. Already Discharged from the hospital, or planning to be discharged to an isolation center 11. Participated, is participating, or plans to participate in a clinical study evaluating any authorized, approved, or investigational SARS-CoV-2 vaccine 12. Is a member of the clinical site study team or is a member of the site study team immediate family members

Study Treatment : In the study, treatment consisted of co-administration of mAb10933 + mAb10987 via intravenous or subcutaneous administration in a single dose selected from: IV single dose Co-administered mAb10933 + mAb10987 combination therapy intravenous (IV) single dose: • 2400 mg (1200 mg per monoclonal antibody [mAb]) • 1200 mg (600 mg per mAb) • 600 mg (300 mg per mAb) • 300 mg (150 mg per mAb) • Placebo IV single dose SC single dose Co-administered mAb10933 + mAb10987 combination therapy subcutaneous (SC) single dose • 1200 mg (600 mg per mAb) • 600 mg (300 mg per mAb) • Placebo SC single dose

Evaluation Metrics : Primary, secondary and exploratory evaluation metrics are defined below.

Primary outcome measure—The primary outcome measure was viral load (log ₁₀ copies/ml) from day 1 to day 7 relative to Time-weighted average daily change from baseline, as measured by RT-qPCR in NP swab samples.

Secondary Endpoints—Secondary endpoints are: • Time-weighted average daily change from baseline in viral load (log ₁₀ copies/ml) from Day 1 to Day 5 • From Day 1 to Day 7, with Time-weighted viral load (log ₁₀ copies/ml) relative to baseline in patients with high viral load (>10 ⁴ copies/ml, >10 ⁵ copies/ml, >10 ⁶ copies/ml, >10 ⁷ copies/ml) Mean daily changes • from day 1 to day 5 among patients with high viral load (>10 ⁴ copies/ml, >10 ⁵ copies/ml, >10 ⁶ copies/ml, >10 ⁷ copies/ml) Time-weighted average daily change in viral load (log ₁₀ copies/ml) from baseline • High viral load at each visit (>10 ⁴ copies/ml, >10 ⁵ copies/ml, >10 ⁶⁷ copies/ml) Proportion of patients • Proportion of patients with viral load below the detection limit at each visit • Proportion of patients with viral load below the lower limit of quantification at each visit • Cycle threshold (Ct) from day 1 to day 7 Time-weighted average daily change from baseline, as measured by RT-qPCR in NP samples • Time-weighted average daily change in Ct from day 1 to day 5, as measured by RT-qPCR Measured in NP samples • Change in Ct from baseline at each visit, as by RT-qPCR Measured in NP samples • Change in viral load from baseline at each visit, as by RT-qPCR Measured by qPCR in NP samples • Proportion of patients with treatment-initiated SAEs up to day 29 • Proportion of patients with infusion-related reactions (grade ≥ 2) up to day 4 • Injection site reactions (grade ≥ 3) up to day 4 Proportion of patients • Proportion of patients with allergic reactions (grade ≥ 2) up to day 29 • Concentrations of mAb10933 and mAB10987 in serum over time • Neutralization by anti-drug antibodies (ADA) and antibodies against mAb10933 and mAb10987 Immunogenicity as measured by antibodies (NAb)

Exploratory evaluation metrics—The exploratory evaluation metrics are: • Cumulative incidence of COVID-19-related medical visits (through days 29 and 169) or all-cause mortality • Cumulative incidence of COVID-19-related hospitalizations, emergency room visits (through days 29 and 169), or all-cause mortality • Cumulative incidence of COVID-19-related hospitalization (through days 29 and 169) or all-cause mortality • Cumulative incidence of COVID-19-related emergency room visits (through days 29 and 169) or all-cause mortality • Proportion of patients with ≥1 COVID-19-related medical visit (through days 29 and 169) or all-cause mortality • Proportion of patients with ≥1 COVID-19-related medical visit by visit type (inpatient, emergency room visit, urgent care, physician office visit, and/or telemedicine visit) (through Day 29 and 169 days) • Proportion of patients with ≥2 COVID-19-related medical visits (through days 29 and 169) or all-cause mortality • Number of days hospitalized due to COVID-19 • Proportion of patients admitted to the intensive care unit (ICU) due to COVID-19 (as of day 29 and day 169) • Proportion of patients requiring supplemental oxygen due to COVID-19 (as of day 29 and day 169) • Proportion of patients requiring mechanical ventilation due to COVID-19 (as of day 29 and day 169) • Total number of COVID-19 related MAVs up to days 29 and 169 • Cumulative incidence of all-cause hospitalizations, emergency room visits (through days 29 and 169), or mortality • All-cause mortality as of day 29 and day 169 • Proportion of patients with treatment-induced SAEs up to day 169

Procedure and Assessment :

Procedures and assessments include: • NP swabs for SARS-CoV-2 RT-qPCR • Medical visits related to COVID-19 • TEAEs, treatment-emergent SAEs, and treatment-emergent AESI (grade ≥2 infusion-related reactions, grade ≥3 Injection site reactions, grade ≥2 anaphylaxis, and any TEAE resulting in hospitalization or emergency room visit, regardless of whether the visit is related to COVID-19) • Target concomitant medications, safety laboratories, vital signs, and pregnancy status

Statistics plan:

The primary virological efficacy variable was the time-weighted average change from baseline in viral load from day 1 to day 7, as measured by RT-qPCR in NP swab samples. The primary analysis was performed in the seronegative modified full analysis set (mFAS) population.

mFAS includes all randomized patients with a central laboratory-confirmed positive SARS-CoV-2 RT-qPCR result from a randomized NP swab sample and is based on treatment received (if treated). Seronegative mFAS is the subset of patients within the mFAS population who are seronegative at baseline.

Results —This study demonstrated that mAb10933 + mAb10987 at various intravenous and subcutaneous doses provided virological efficacy compared to placebo ( Figure 74 ). All doses tested met the primary outcome measure, rapidly and significantly reducing patients' viral load (log ₁₀ copies/ml) compared to placebo (p≤0.001). With an initial cohort of 816 patients, this study demonstrated significant and comparable viral reduction through day 7 in patients who were SARS-CoV-2 PCR+ and seronegative at baseline across all 6 REGEN-COV doses tested. Although there were small numerical differences in mean viral reduction between the 2400 mg group and the other treatment groups, these were not considered to be statistically significant or clinically significant. In fact, REGEN-COV significantly and substantially reduced viral load at all doses tested, down to a single dose of 300 mg intravenously or 600 mg subcutaneously ( Figure 47 ). Furthermore, these results are comparable to those of Example 2, although the doses in this study were lower ( Figures 48 and 51 ; the Example 2 study is labeled "2067" and this study is labeled "20145"). There was also a dose-proportional increase in REGEN-COV serum concentrations in IV and SC patients ( Figure 75 ). Treatment was generally well tolerated, with no deaths and only two serious adverse events, both of which were assessed as not related to COVID-19 or REGEN-COV ( Figure 49 and Figure 50 ). An overview of the demographics and baseline characteristics of seronegative intravenous and subcutaneous patients (modified full analysis set) is shown in Figure 45 and Figure 46 , respectively.

[Table 17 ]: Time-weighted average daily change in viral load (log 10 copies/ ml) from baseline (day 1 ) to day 7 _among PCR-positive and seronegative patients at baseline Pre-specified test levels compare LS average 95% CI p value REGEN-COV 2400 mg IV (n=61) vs combined placebo (n=74) -0.71 (-1.05, -0.38) <0.0001 REGEN-COV 1200 mg IV (n=67) vs combined placebo (n=74) -0.56 (-0.89, -0.24) 0.0007 REGEN-COV 1200 mg SC (n=71) vs combined placebo (n=74) -0.56 (-0.87, -0.24) 0.0007 REGEN-COV 600 mg IV (n=66) vs combined placebo (n=74) -0.66 (-0.99, -0.34) <0.0001 REGEN-COV 600 mg SC (n=71) vs combined placebo (n=74) -.056 (-0.88, -0.24) 0.0006 REGEN-COV 300 mg IV (n=76) vs combined placebo (n=74) -0.57 (-0.88, -0.25) 0.0004 CI, confidence interval; IV, intravenous; LS, least squares; PCR, polymerase chain reaction; SC, subcutaneous Example 8 : Evaluation of anti-SARS-CoV-2 spike protein monoclonal antibodies as pre-exposure prophylaxis to prevent immune function Phase 3 Study of Efficacy and Safety of COVID-19 in Incomplete Patients

Available evidence indicates that some immunocompromising conditions, such as certain primary or secondary immunodeficiencies, may result in reduced production of endogenous antibodies against SARS-CoV-2. Individuals with these conditions may be at greater risk of becoming infected or experiencing prolonged infection, potentially resulting in increased morbidity and mortality, and may also have significantly impaired protective immune responses to COVID-19 vaccination . Individuals at such risk may benefit from the prophylactic use of exogenous anti-SARS-CoV-2 mAb administered prior to infection or exposure to the virus (i.e., pre-exposure prophylaxis), thereby providing increased levels of passive immunity to supplement Insufficient endogenous immune response from previous SARS-CoV-2 infection or vaccination.

This example describes a randomized, double-blind, placebo-controlled Phase 3 study in adults and adolescents to evaluate the efficacy of casirimab + idelimumab (mAb10933 and mAb10987, respectively) according to the study eligibility criteria. Safety and efficacy as prophylaxis against symptomatic COVID-19 in immunocompromised individuals defined by recurrent and secondary immunodeficiency. Research Objectives Main Objectives

The primary objective of the study is to evaluate the effect of casirumab plus idelimumab compared with placebo in preventing symptomatic SARS-CoV-2 infection in immunocompromised participants. secondary goals

The secondary objectives of the research are: • Evaluate the safety and tolerability of repeated subcutaneous (SC) injections of casirimab + idelimumab in the study population; • Characterize changes in serum concentrations of casirimab and idelimumab over time; and • Evaluate the immunogenicity of casirimab and idelimumab exploratory goals

The exploratory objectives of the study were: • To evaluate the clinical efficacy and additional measures of disease prevention of casirimab + idelimumab compared to placebo; • To evaluate the clinical efficacy and disease prevention of casirimab + idelimumab compared to placebo; The role of agents in preventing SARS-CoV-2 infection with elevated viral loads; • Explore predicting and/or indicating the safety and/or efficacy of casirimab + idelimab, COVID-19 vaccine responses, SARS - Biomarkers of CoV-2 infection and immune responses, COVID-19 disease progression, and clinical outcomes with casirumab + idelimab; • Exploring the impact of baseline immune responses to COVID-19 vaccination on casirumab Impact of anti+idelimumab responses and clinical outcomes; and • Characterizing viral variants by sequencing SARS-CoV-2 among participants experiencing post-baseline infection. hypothesis

Pre-exposure prophylaxis with an anti-SARS-CoV-2 mAb (casirimab + idelimumab) will prevent symptomatic SARS-CoV-2 infection in immunocompromised individuals who do not respond effectively to vaccination. Fundamental Basic principles of research design research community

In the absence of a universal clinical definition, this study defined immunocompromised states based on discrete sets of primary and secondary immunodeficiencies used as eligibility criteria.

Immunocompromised conditions: Certain immunocompromised conditions can negatively impact the production of endogenous antibodies to SARS-CoV-2, particularly in response to vaccination. This study therefore aimed to evaluate the use of the anti-SARS-CoV-2 mAb therapy casirimab + idelimumab in immunocompromised individuals aged ≥12 years.

Definition of immunocompromised participants for study inclusion and guidelines for conditions and treatments related to moderate to severe immunocompromise as described in the August 2021 Advisory Committee on Immunization Practices (ACIP) CDC Vaccine Recommendations Meeting consistent. The guidelines provided during this meeting were as follows (ACIP, 2021): • Active or recent treatment of solid tumors and hematological malignancies • Receiving a solid organ or recent hematopoietic stem cell transplant • Severe primary immunodeficiency • Advanced or untreated HIV infection • Aggressive treatment with immunosuppressive or immunomodulatory high-dose corticosteroids, alkylating agents, antimetabolites, tumor necrosis (TNF) blockers, and other biologic agents • Chronic medical conditions, such as asplenia and chronic kidney disease, some of which may be associated with varying degrees of immune deficiency

The above criteria are presented in the context of identifying individuals for whom COVID-19 vaccine booster doses may be considered. The guidelines described in this study were modified to take into account the experience of the research community in the clinical development program of casirimab + idelimumab, other government, academic, and industry publications and briefings, as well as information from the field and other clinical Suggestions for testing.

Prior non-response to COVID-19 vaccination: To ensure that the study population is included at a proven risk for future SARS-CoV-2 infection despite being vaccinated, studies require inclusion that participants have previously received a COVID-19 vaccination. Complete course (unless medically disqualified or contraindicated) and confirmed non-response to COVID-19 vaccination (i.e., lack of circulating anti-S protein IgG antibodies).

Nonresponse was further retrospectively and quantitatively assessed through central analysis of baseline samples, and the results of this analysis were used to define the primary efficacy analysis population (modified intention to treat). The quantitative cutoff used as an upper limit for the definition of nonresponse in the primary analysis was a value derived from an ongoing clinical trial assessing immune response to a COVID-19 booster vaccine (NCT05000216).

Because the study was conducted in an at-risk group, participants who were infected with SARS-CoV-2 at any time point during the study were offered additional treatment with casirimab + idelimab on site.

Centralized inclusion: Studies are conducted in areas experiencing COVID-19 outbreaks and active community transmission of COVID-19, further ensuring that the scientific goals of prevention in assessing individuals at risk can be achieved. double-blind design

The double-blind design is used to reduce potential bias introduced by knowledge of study drug allocation. The comparison group in this study will be placebo because approved or authorized pre-exposure prophylaxis is not currently available in the area where the study is being conducted. clinical efficacy

The primary outcome measure of this study was the occurrence of symptomatic, laboratory-confirmed SARS-CoV-2 infection. This metric is similar to the primary metric used in COVID-19 vaccine trials and is therefore intended to assess efficacy in the pre-exposure prophylaxis setting.

In this study, participants were asked to immediately report any potential signs or symptoms of COVID-19 so that symptoms could be clinically confirmed before any laboratory testing for SARS-CoV-2 infection. However, participants may obtain incidental testing outside of the study during the standard course of care for their immunocompromised condition or for other personal reasons. Therefore, the study considered participants who received external positive test results for SARS-CoV-2 infection and who underwent additional protocol-limited laboratory virus testing. Because these participants could be asymptomatic at the time of laboratory-confirmed infection according to the protocol, the study additionally assessed (as an exploratory assessment measure) the incidence of confirmed infection without symptoms.

The clinical development program of casirimab + idelimumab includes several controlled phase 3 studies, which have demonstrated consistent clinical efficacy of treatment across the SARS-CoV-2/COVID-19 spectrum. -19 disease spectrum spans from uninfected individuals, to asymptomatic SARS-CoV-2 infected individuals, to non-hospitalized and hospitalized COVID-19 patients. In the outpatient setting, treatment with casirimab + idelimumab demonstrated efficacy on clinically meaningful measures, including the risk of COVID-19-related hospitalization and/or all-cause death through study day 29 reduce. Although study participants received additional casirumab + idelimumab on-site following laboratory-confirmed SARS-CoV-2 infection, it is necessary to evaluate whether prior prophylactic administration conferred clinical benefit following subsequent infection. Therefore, several clinical outcome measures derived from outpatient care settings were evaluated as exploratory assessments. Virological efficacy

The study was conducted in an exploratory manner to assess measures of viral load among participants with symptoms of COVID-19. Virological efficacy has been evaluated in all clinical efficacy studies in the casirimab + idelimumab program and has been used as a proximal indicator of pharmacological activity to demonstrate the relationship between disease burden following SARS-CoV-2 infection and High viral loads were associated, and the virological efficacy of casirimab + idelimab was consistently correlated with clinical efficacy. Basic principles of dose selection

Three dosing regimens of casirimab + idelimumab (casirumab and idelimumab co-administered in a 1:1 ratio) were evaluated in the study: 1200 mg Sc starting dose + 600 mg SC Q4W×5 maintenance dose; 300 mg SC Q4W×6; and 300 mg SC Q12W×2 (SC: subcutaneous, Q4W: every four weeks; Q12W: every 12 weeks). For post-exposure prophylaxis, a single 1200 mg SC casirumab + idelimab dose demonstrated a statistically and clinically meaningful benefit in preventing SARS-CoV-2 infection. In the long-term prevention setting, the United States authorizes a starting dose of 1200 mg Sc + a maintenance dose of 600 mg SC Q4W for post-exposure prophylaxis in individuals at high risk of progression to severe COVID-19. The maintenance arm (600 mg SC Q4W) is expected to maintain serum trough concentrations of casirumab and idelimab at steady state (Ctrough,ss), similar to day 29 concentrations after a single 1200 mg SC dose.

Using a conservative estimate of serum to respiratory fluid penetration of 1%, as early as 4.8 hours after dose and up to 28 days after dose, for currently circulating variants of concern/variants of concern (alpha, beta, delta, gamma, κ, λ, and µ), it is estimated that the serum concentration of the combination casirimab + idelimab in a single 1200 mg SC dose exceeds the serum concentration required to achieve 90% neutralization concentration (IC90) in respiratory fluids (Cs, target). For Casirimab + Idemumab 1200 mg Sc starting dose + 600 mg SC Q4W maintenance dose regimen, for reference SARS-CoV-2 virus (Wuhan, D614G) and currently circulating variants of concern/concern Variant, median population PK estimate Ctrough,ss for casirumab + idelimab combination is approximately 14× to 35× Cs,target. In outpatients at low risk for severe COVID-19, nasopharyngeal ( The time-weighted average change in NP) viral load from baseline was significantly and comparably reduced relative to placebo, indicating that all doses were in the plateau of the dose-response curve for NP viral load reduction. Because all of these doses were most effective in reducing viral load in COVID-19 outpatients, these results warrant the evaluation of lower doses in both treatment and prevention settings.

In addition to the 1200 mg SC starting dose + 600 mg SC Q4W × 5 maintenance dose regimen, two additional dosing regimens will be evaluated to see whether lower doses and/or lower doses with extended dosing intervals will be effective in preventing immunity SARS-CoV-2 infection in dysfunctional individuals. Median population PK estimates 12 hours after first dose for reference SARS-CoV-2 virus and currently circulating variants of concern/variants of concern for intermediate dosing regimen of 300 mg SC Q4W × 6 The serum concentration of cilizumab + idelimumab exceeded Cs,target, and the expected Ctrough,ss of the 1200 mg SC starting dose + 60 0 mg SC Q4W maintenance dose regimen was 50%. This is expected based on the in vitro efficacy of casirimab + idelimab against the reference SARS-CoV-2 virus and currently circulating variants of concern/variants of concern and the moderate exposure reduction of 300 mg SC Q4W × 6 The intermediate dosing regimen will be effective in preventing SARS-CoV-2 infection. For the low-dose regimen of 300 mg SC Q12W × 2, the population PK estimate median Ctrough,ss for casirimab + idelimab is approximately 7 times the Ctrough,ss for 1200 mg SC starting dose + 600 mg SC Q4W %, and exploration is ongoing to evaluate the efficacy of more convenient Q12W dosing regimens.

Because the lower end of the proposed weight range (≥40 kg) for adolescent subjects aged ≥12 years falls within the expected adult weight range, exposure between these 2 groups is expected to be similar for each dosing regimen. Evaluation indicators Main evaluation indicators

The primary assessment metric is the cumulative incidence of symptomatic (broadly termed) RT-PCR-confirmed SARS-CoV-2 infection cases during the efficacy assessment period (EAP). Secondary evaluation metrics

Secondary evaluation indicators are: • Proportion of participants with grade ≥3 treatment-emergent adverse events (TEAE) during EAP and follow-up periods • Proportion of participants with TEAEs leading to study drug endpoints during EAP and follow-up periods • Proportion of participants with treatment-emergent serious adverse events (SAE) during EAP and follow-up periods • Incidence of Adverse Events of Special Interest (AESI) during EAP • Concentration of each mAb (applicable to treatment group) over time • The incidence and titer of anti-drug antibodies (ADA) and the incidence of neutralizing antibodies (NAb) for each mAb (applicable to treatment groups) over time exploratory evaluation metrics

Exploratory assessment indicators were: • Cumulative incidence of symptomatic (broadly termed), RT-PCR-confirmed SARS-CoV-2 infections during the follow-up period • RT-PCR-confirmed SARS-CoV-2 during the EAP period Cumulative incidence of infection cases (regardless of symptoms) • Proportion of participants with ≥1 moderate COVID-19 symptom (broad term) during the EAP and follow-up periods • Post-diagnosis COVID-19 signs and symptoms (broad term) Weeks of duration • Proportion of participants with COVID-19-related hospitalization, emergency room visit, urgent care center visit, or death during the EAP and follow-up period • Participation with a COVID-19-related hospitalization or death during the EAP and follow-up period Proportion of participants • Proportion of participants requiring supplemental oxygen due to COVID-19 during the EAP and follow-up period • Proportion of participants admitted to the intensive care unit (ICU) due to COVID-19 during the EAP and follow-up period • Proportion of participants requiring supplemental oxygen due to COVID-19 during the EAP and follow-up period Proportion of participants with -19 requiring mechanical ventilation • Proportion of symptomatic (broadly termed) participants with viral load >4 log10 copies/ml in NP swab samples collected at COVID-19 diagnosis • Proportion of symptomatic (broadly termed) participants with an episode during EAP? Maximum SARS-CoV-2 RT-qPCR viral load in NP swab sample (log10 copies/ml) among 1 individual with a positive RT-qPCR test • Among symptomatic (broad term) participants during EAP, Number of weeks with viral load >4 log10 copies/ml in NP swab samples Study description and duration of viral variant characterization of SARS-CoV-2 among participants infected after baseline

This example describes a randomized, double-blind, placebo-controlled phase 3 study to assess the immune function of casirimab + idelimumab as defined in primary and secondary immunodeficiency as outlined in the study eligibility criteria Safety and efficacy as pre-exposure prophylaxis against symptomatic COVID-19 in incomplete individuals.

The study consists of three phases: a screening period of up to 14 days, an efficacy assessment period (EAP) of approximately 6 months, and a follow-up period of 3 months.

In addition to the main study, optional immunological substudies may be conducted outside the protocol. Assessment of symptomatic SARS-CoV-2 infection

The study's primary outcome measure assessed cases of symptomatic SARS-CoV-2 infection. The conditions for symptomatic SARS-CoV-2 infection are as follows: • The study clinician (investigator or designee) confirms at least 1 sign or symptom (broadly defined term) related to COVID-19, and • Positive SARS-CoV-2 RT-PCR result (local or central analysis), where • Date of onset of symptoms/symptoms and date of positive sample collection within ±7 days

The primary outcome measure analyzed symptomatic SARS-CoV-2 infection during the efficacy assessment period (EAP).

The broad term COVID-19 signs and symptoms includes fever ≥38.0°C and 23 signs/symptoms designed to be consistent with the COVID-19 Symptom Evolution (SE-C19) instrument. Study Period Screening/Baseline

Participants were assessed for study eligibility after they provided informed consent. Screening includes negative RT-PCR test results. Prior to dosing, a baseline nasopharyngeal swab sample was collected for retrospective central laboratory confirmation of SARS-CoV-2 negativity by RT-qPCR.

Participants who are unable to complete the screening requirements within the screening period will be allowed to re-screen after consulting with the sponsor. Treatment and Efficacy Assessment Period (EAP)

On Day 1, participants were randomized to receive repeated subcutaneous administrations of study drug or placebo.

Study visits occur every 4 weeks during the EAP period. During these visits, dosing and study information collection occurs, including assessment of any possible signs or symptoms of COVID-19. Clinicians (investigators or designees) assess signs and symptoms and use them to assess symptomatic SARS-COV-2 infection (i.e., the primary outcome measure).

After the first dose, monitor participants for at least 15 minutes and then release from the study site as medically appropriate. Dosing continues for the duration of EAP, with the last visit in EAP occurring approximately one month after the final dose.

Blood samples are collected during selected EAP visits for assessment of drug concentration, immunogenicity, serum antibody concentration, or exploratory studies. tracking period

Participants continued to be visited every 4 weeks during the follow-up period. These visits may be conducted in person, by telephone, or by other means of communication as necessary. These visits are used to collect safety information and track any COVID-19 signs/symptoms as described in the event timeline. The final study visit occurred at 9 months (by telephone). Monitoring and treating suspected COVID-19 Monitoring and treating suspected COVID-19

Participants will be monitored for suspected COVID-19 symptoms throughout the study. Provide participants (or their caregivers, when applicable) with contact information for the clinical study site and provide written and verbal instructions to call site staff as soon as possible if they experience any change in health status. This may include any symptoms or signs that may be related to COVID-19 or if they observe any new feelings of discomfort. Assessing suspected COVID-19

Participants with suspected COVID-19 receive a symptom assessment by a study clinician (investigator or designee ) as soon as possible (within 48 hours of symptom onset, if feasible). To ensure timely assessment, unscheduled visits are preferred unless the scheduled study visit is the fastest visit available. Post-infection treatment of participants with confirmed positive SARS-CoV-2 RT-PCR

Participants with confirmed positive SARS-CoV-2 RT-PCR at any time during the study (documented locally, at the center, or outside the study) should be treated with standard care in accordance with local practice and at the discretion of the investigator. Alternatively, participants may be offered casirimab + idelimab as post-infectious therapy if deemed medically appropriate in the investigator's judgment.

If post-infectious treatment with casirimab + idelimumab is deemed medically appropriate, treatment should be provided through the most expeditious mechanism available. For this reason, casirimab + idelimumab may be administered through off-study mechanisms in regions where it is approved or authorized. Where regional approval or authorization is available, casirimab + idelimumab should be administered at the approved or authorized dose.

For participants who are able to receive post-infection care at the study site, casirimab + idelimab may also be provided to participants as part of the study. For example, this could be used if casirimab + idelimumab is not regionally approved or authorized for the treatment of SARS-CoV-2 infection, or if the treatment cannot be provided in an expedited manner through an approved or authorized mechanism. mechanism.

The following study dose levels will be provided as part of the study and when medically indicated at the discretion of the investigator: • No hospitalization due to COVID-19 and no need for supplemental oxygen or increased baseline oxygen flow rate due to COVID-19: 1200 mg (600 mg per mAb) administered intravenously or subcutaneously • Hospitalized with COVID-19 but not requiring supplemental oxygen due to COVID-19, or requiring supplemental oxygen due to COVID-19: 2400 mg (1200 mg per mAb) intravenously • Hospitalized with COVID-19 and requiring high-intensity supplemental oxygen due to COVID-19 or mechanical ventilation due to COVID-19: 8000 mg (4000 mg per mAb) intravenously

If feasible, treatment with casirimab + idelimumab should be offered within 48 hours of obtaining a positive RT-PCR result.

Post-infectious therapy administered with casirumab + idelimumab will not require unblinded randomization of participants. Time course of events in participants with positive SARS-CoV-2 RT-PCR

Participants with a positive SARS-CoV-2 RT-PCR (from local or central testing) will have study drug assigned at randomization discontinued and enter the follow-up period. This includes any participant who was offered post-infectious treatment with casirumab + idelimab but was declined or otherwise not accepted by the participant or investigator.

All participants with positive SARS-CoV-2 RT-PCR have additional assessment and sample collection outlined below: • NP swab samples are collected for central laboratory RT-qPCR analysis during unscheduled visits every 7 days (±1 day) until 2 consecutive negative test results are obtained. During these visits, the investigator or designee also assesses COVID-19 signs and symptoms. • Information about COVID-19 related medical visits (MAVs) will be recorded, and participants will be asked to notify study staff as soon as possible if they occur. Study end definition

Study end was defined as the date when the last participant completed the last study visit, dropped out of the study draw, or was lost to follow-up (i.e., the participant may no longer be contacted by the study site). research community

To be included in this study, participants must have an immunocompromised condition, documented evidence of nonreactivity to COVID-19 vaccination, a negative SARS-CoV-2 RT-PCR test result, and must have completed the full standard of care for COVID-19 vaccination duration (regional definition) and documented evidence of nonresponse unless medically disqualified or contraindicated. inclusion criteria

Participants must meet the following criteria to be eligible for study inclusion: • Age ≥12 years old at the time of randomization ○ Note: Participants under the age of 18 will only be included if local requirements permit. • Satisfies ≥1 of the following criteria: ○ Solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT) recipients receiving immunosuppressive drugs ○ Active hematological malignancies ○ Solid organ malignancies receiving active treatment using T cell or B cell immunosuppressive therapy ○ Primary immunodeficiency (such as hypogammaglobulinemia, common variable immunodeficiency, severe combined immunodeficiency) ○ HIV and CD4 <200 cells/microliter ○ Patients with rheumatic diseases, autoimmune diseases or multiple sclerosis receive Th1, Th17 modulation, anti-TNF such as infliximab (infliximab), adalimumab (adalimumab), etanercept (etanercept) ) or B cell response immunosuppressive therapy ○ Currently receiving any of the following immunosuppressive drugs: § T-cell inhibitors (eg, during >3 weeks, ?5 mg prednisone equivalent/day § Proteasome inhibitors (such as bortezomib, lenalidomide), alemtuzumab, antithymocyte globulin, CAR-T therapy, calcineurin inhibitors) § Alkylating agents and anthracyclines §Antimetabolites and purine analogues such as mycophenolate mofetil, fludarabine or cladribine § B cell targeted therapies such as rituximab, ocrelizumab, CD19/CD20 and BTK inhibitors § mTOR inhibitors § JAK/STAT pathway inhibitors • Receiving full standard of care COVID-19 vaccination in accordance with regional guidelines, or deemed medically ineligible or contraindicated to receive full standard of care COVID-19 vaccination • In anti-SARS-CoV-2 spike (S) protein IgG clinical testing (including (but not limited to) RBD-specific testing), or in the ?50 U/mL Elecsys® SARS-CoV-2 S total Ig test, Documented negative (based on test reference value) serology/antibody response. Testing should be done on samples collected at least 2 weeks after the final dose of COVID-19 vaccine and 3 months before randomization ○ Note: Lateral flow immunoassay (LFIA) results will not be accepted. Tests should be deemed acceptable for clinical use according to local standards (approved or with an EUA issued by the US FDA or equivalent local health authority). • Samples collected ≥72 hours before randomization have SARS-CoV-2 negative RT-PCR using local analytical and sample collection and analysis standards ○ Note: A history of negative results is acceptable as long as the sample is collected ≥72 hours before randomization. Nasopharyngeal swab samples are excellent but other sample types meeting local standards (such as nasal, oropharyngeal [OP] or saliva) are acceptable. • Willing and able to: ○ Provide informed consent signed by the research participant or a legally acceptable representative ○  Comply with procedures related to clinic visits and research, including providing samples for viral load testing • Determined by the investigator to be in stable health based on medical history, physical examination, vital sign measurements, and laboratory measurements taken at other times prior to screening and/or administration of study drug Exclusion criteria

Participants who met any of the following criteria were excluded from the study: • Life expectancy less than 2 years • Weight <40 kg (only for participants aged ≥12 to <18 years) • Have any medical condition consistent with COVID-19 Signs or symptoms (as determined by the investigator) • History of SARS-CoV-2 infection within 90 days prior to randomization • Planned use of any investigational drug within 90 days of last dose of study drug (or in accordance with current CDC recommendations) , authorizing or approving COVID-19 vaccines (CDC, 2021) • Previous, current, or planned use of any of the following treatments: COVID-19 convalescent plasma, other monoclonal antibodies against SARS-CoV-2 (banizumab and etesevimab, sotovimab) or any COVID-19 treatment (authorized, approved or investigational) ○ Note: Prior use is defined as the past 30 days since screening or within the 5 within the half-life of the study product (whichever is longer). • Plan to start intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) therapy, plan to change the existing IVIG or SCIG regimen, or have received a long-term stable dose of their IVIG or SCIG regimen less than 90 days before screening. • Have any known acute active respiratory infection • No documented laboratory blood chemistry and hematology (including differential) results within 6 months prior to randomization • Have persistent (refractory to treatment for ≥14 days) bacterial or Fungal infection • Known allergy or anaphylactic reaction to a component of the study drug • Discharged from the hospital, or planned to be discharged to an isolation center • Studying investigational and reference treatments for a member of the clinical site study team or their close relatives

Eligible participants will be randomly divided into the following groups in a 1:1:1:1 allocation ratio: • Co-administer casirimab + idelimumab combination therapy, 1200 mg (600 mg per mAb) on day 1, then 600 mg (300 mg per mAb) SC Q4W • Co-administered casirimab + idelimumab combination therapy, 300 mg (150 mg per mAb) SC Q4W • Co-administered casirimab + idelimumab combination therapy, 300 mg (150 mg per mAb) SC Q12W • Placebo SC Q4W

To maintain blinding, additional placebo injections were administered so that all participants received the same number of injections and the same dosing frequency (Q4W).

For administration of study drug requiring multiple SC injections, it is recommended to use different quarters of the abdomen (avoiding the navel and waist area), front and upper outer thighs, or dorsal areas of the outer area above the arms. During dosing, each injection must be in a different anatomical location (e.g., 1 injection in the lower right side of the abdomen, another in the lower left side of the abdomen, etc.). Anesthetic cream should not be used at the injection site as this will interfere with the safety assessment, that is, the assessment of injection site reactions.

statistical plan

This chapter provides the basis for the statistical analysis plan (SAP) of the study. The SAP will be revised prior to study completion to accommodate modifications to the clinical study protocol and to account for unanticipated problems with study conduct and data that may affect planned analyses. The final SAP will be released before the first interim analysis. Statistical Planning Statistical Assumptions

For the primary objective, the study's null hypothesis was that the antibody efficacy (AbE) of casirimab + idelimumab in preventing symptomatic SARS-CoV-2 infection was 0% compared with placebo.

The statistical assumptions (virtual and alternative) for any panel of antibodies can be stated as:

H ₀ : HR = 1 versus H ₁ : HR < 1 , where HR is the hazard ratio of the antibody group relative to placebo.

Likewise, the null and alternative hypotheses can be stated as:

H ₀ : AbE = 0% vs. H ₁ : AbE > 0% , where AbE = 100 × (1-HR).

Therefore, when comparing the incidence of symptomatic SARS-CoV-2 infection using a time-to-event analysis approach, antibody efficacy was defined as the percentage reduction in the hazard ratio for the antibody group relative to placebo.

For the alternative hypothesis, it is assumed that the target antibody efficacy of group 1 (casirimab + idelimumab 1200 mg (Day 1) SC, then 600 mg SC Q4W) is at least 60% (i.e., HR=0.4); AbE Can be the same as or lower than the other 2 antibody groups, such as 55% (HR=0.55), 45% (HR=0.45) analysis set power analysis set

The intention-to-treat (ITT) population was defined as all randomly assigned participants.

The primary efficacy analysis population was the modified intention-to-treat (mITT) population, defined as all randomized participants who received at least one dose of study drug and baseline (Day 1): • Has tested negative for RT-qPCR (central laboratory result), and • Center serology test results (Elecsys® anti-S RBD total Ig) ≤50 U/mL.

Participants who are considered medically ineligible or contraindicated to receive the full standard of care COVID-19 vaccine are also included in the mITT.

Analyzes were performed according to study drug assignment (eg, randomization).

Both the ITT and mITT populations were used to summarize the demographics and baseline characteristics of the participants. Statistical methods

For continuous variables, descriptive statistics include the following information: number of participants (n) reflected in the calculation, mean, standard deviation, Q1, median, Q3, minimum, and maximum.

For categorical or ordinal data, show frequencies and percentages for each category.

Subgroups are defined by key baseline factors (e.g., demographics, disease characteristics). Conduct subgroup analysis on efficacy evaluation indicators and safety evaluation indicators as needed. Details are described in the Statistical Analysis Plan (SAP).

Statistical analysis was performed using Statistical Analysis Software (SAS) version 9.4 or later. Participant tendencies

The following are provided: • Total number of screened participants who signed informed consent • Total number of participants in random groups: random numbers received • Total number of participants who discontinued the study and reasons for discontinuation • Total number of participants who discontinued study treatment and reasons for discontinuation • Summary of analysis sets, including ITT, mITT, SAF, PK and AAS Demographics and Baseline Characteristics

A descriptive overview of participant demographics and baseline characteristics will be provided by treatment group and all combinations. power analysis

The mITT population is the main efficacy analysis population. The ITT population was also used for power analysis. Participant data were analyzed according to randomized groups. main efficacy analysis

The primary outcome measure of the study was the cumulative incidence of symptomatic (broadly termed) RT-PCR-confirmed SARS-CoV-2 infection during the efficacy assessment period (EAP).

EAP is defined as visits from day 2 to day 169. The cumulative incidence of cases during EAP was estimated using the Kaplan-Meier method, and antibody efficacy (AbE) was estimated as a percentage risk reduction (i.e., 100×[1-HR), where HR is used to compare antibody group relative Hazard ratio relative to placebo case incidence). Stratified Cox proportional hazards regression models using treatment group as a fixed effect and adjusting for stratification factors before screening: age category, region, and stable IVIG or SCIG regimen use were used to estimate hazard ratios and 95% CIs (two-sided).

For the primary analysis, cases were counted from day 2 to day 176 (i.e., day 169 + 7 days) to allow for the increase in cases until the end of the EAP visit range according to the event schedule. The time of symptomatic SARS-CoV-2 infection is earlier than the date of onset of symptoms/symptoms or the date of sample collection with positive RT-PCR results (local or central).

Two-sided p values are reported using a log rank test for pairwise comparisons between each antibody group and placebo.

The main analysis group is the mITT group. The ITT population is also used to analyze key evaluation indicators.

Details of the supporting analysis and subgroup analysis used for the key evaluation indicators are provided in SAP. multiplicity control

The overall Type 1 error rate was strictly controlled at 0.025 (one-sided) due to multiple hypothesis testing of each antibody arm versus placebo, the planned interim power analysis, and other testing detailed in the Statistical Analysis Plan (SAP).

Hypothesis testing of the primary outcome measure was performed first to compare Group 1 (casirimab + idelimumab 1200 mg SC [Day 1], then 600 mg SC Q4W) to placebo, and then to compare Group 2 (casirumab + idelimumab 1200 mg SC [Day 1], followed by 600 mg SC Q4W). cisrelimab + idelimumab 300 mg SC Q4W) and Group 3 (casirimab + idelimumab 300 mg SC Q12W) versus placebo. The overall testing strategy for all testing is described in SAP.

A Lan-DeMets implementation of the O'Brien-Fleming alpha cost function was applied to control the false-positive error rate to 0.025 (one-sided) in the interim power analysis and primary analysis. Example 9 : Neutralization of SARS-CoV-2 variant O spike protein

To test whether anti-SARS-CoV-2 spike protein antibodies could neutralize SARS-CoV-2 variant O, these antibodies were screened against a panel of VSV pseudotyped viruses expressing wild-type and variant spike proteins. The emergence of recombinant VSV

Non-replicating pseudoparticles were generated using the VSV genome encoding firefly luciferase and GFP genes instead of the native viral glycoprotein (VSV-G). Infectious particles supplemented with VSV-G (VSV-ΔG-Fluc-2A-GFP/VSV-G) were recovered and produced using standard techniques with minor modifications. HEK293T cells (ATCC CRL-3216) were plated on polylysine-treated culture plates in DMEM without glutamine (Life Technologies), 10% fetal calf serum (Life Technologies), and 1% penicillin/ Incubate overnight in streptomycin/L-glutamine (Life Technologies). The next day, use Lipofectamine LTX reagent (Life Technologies) using a pure strain of the VSV genome driven by the T7 promoter and a helper plasmid expressing VSV-N, VSV-P, VSV-G, VSV-L, and T7 RNA polymerase. transfected cells. 48 hours later, the transfected cells and BHK-21 cells (ATCC CCL-10) transfected with VSV-G using SE cell line 4D-Nucleofector X Kit L (Lonza) were cultured in a gluten-free solution (Life Technologies ) were cultured in DMEM, 3% fetal calf serum (Life Technologies) and 1% penicillin/streptomycin/L-glutamine (Life Technologies). Cells were monitored for expression of GFP or cytopathic effect (CPE) indicative of viral replication. Next, viral plaques were purified, amplified, and titrated in BHK-21 cells transiently expressing VSV-G. Fully replicating VSV-SARS-CoV-2-S virus was generated by replacing the VSV glycoprotein with the native SARS-CoV-2 sequence encoding residues 1-1255 of the spike protein (NCBI accession number MN908947.3). VSV-SARS-CoV-2 echinovirus was recovered as described above, but instead HEK293T cells were co-cultured with VSV-G and hACE2-transfected BHK-21 cells. VSV-SARS-CoV-2-S virus was plaque purified and titrated in Vero cells (ATCC CCL-81) and amplified in Vero E6 cells (ATCC CRL-1586). After collection, stocks of both viruses were clarified by centrifugation at 3000xg for 5 minutes, sucrose buffered to concentrate 10 times, aliquoted, and frozen at -80°C. Pseudotyping of VSV

Non-replicating pseudoparticles were generated as previously described (Baum et al., Science 2020). Human codon-optimized SARS-CoV-2 spine (NCBI accession number MN908947.3) was selected and cloned into expression plasmids. A total of 1.2×107 HEK293T cells (ATCC CRL-3216) were cultured in glutamine-free solution containing 10% heat-inactivated fetal calf serum (Life Technologies) and penicillin-streptomycin-L-glutamine (Life Technologies). Acid (Life Technologies) was inoculated into 15-cm culture dishes in DMEM overnight. The next day, cells were transfected with 15 µg of echinoplast using Lipofectamine LTX (Life Technologies) following the manufacturer's protocol. 24 hours after transfection, cells were washed with phosphate buffered saline (PBS) and treated with VSV-ΔG-Fluc-2A-GFP/VSV-G virus diluted in 10 mL Opti-MEM (Life Technologies) at MOI 1 for infection. Cells were incubated at 37°C and 5% CO2 for 1 hour. Cells were washed three times with PBS to remove residual input virus and washed with glutamine-containing (Life Technologies) containing 0.7% IgG-free BSA (Sigma), sodium pyruvate (Life Technologies), and gentamycin (Life Technologies). Technologies) DMEM coverage. After 24 hours at 37°C and 5% _CO2 , the supernatant containing pseudoparticles was collected, centrifuged at 3000xg for 5 minutes to clarify, aliquoted, and frozen at -80°C. Variants were selected into spinoplasts using site-directed mutagenesis, and pseudoparticles were generated as described above. Use VSV -based false particle neutralization analysis.

Vero cells (ATCC: CCL-81) were cultured at 20,000 cells/well 24 hours before analysis in a solution containing 10% heat-inactivated fetal calf serum (Life Technologies) and 1X penicillin/streptomycin/L-glutamine ( Gluten-free DMEM from Life Technologies was inoculated into 96-well black transparent bottom tissue culture-treated plates (Corning: 3904). Allow cells to reach approximately 85% confluence before use for analysis. Antibodies were diluted in infection medium containing DMEM containing glutamine (Life Technologies), 0.7% low IgG BSA (Sigma), 1X sodium pyruvate (Life Technologies), and 0.5% gentamycin (Life Technologies). 2X assay concentration and diluted 3x in infection medium for use in an 11-point dilution curve in assays starting at 3 µg/mL (20 nM). Antibody dilutions and pseudoparticles were mixed 1:1 at room temperature for 30 minutes before addition to Vero cells. Cells were incubated at 37°C, 5% CO _for 24 h. The supernatant was removed from the cells and then lysed with 100 µL Glo lysis buffer (Promega). Then 100 µL of resuspended Bright Glo substrate (Promega) was added and luminescence was read on a Spectramax i3x (Molecular Devices). Exported values were analyzed using GraphPad Prism (v8.4.1).

Determination in Vero cells against Wuhan-Hu-1 (NCBI accession number MN908947.3) sequence encoding spike protein (S-wt) or D614G spike protein variant (SEQ ID NO: 94) or Omik BA.2 spike Performance of the protein variant (SEQ ID NO: 95) The half inhibitory concentration (IC50) and 90% inhibitory concentration (IC90) of individual monoclonal antibodies of the pseudovirus VSV-SARS-CoV-2 spike protein (S). Neutralizing efficacy varies depending on the strain of SARS-CoV-2 spike protein, but in general, BA.2 SARS-CoV-2 spike protein reduces neutralizing efficacy.

[Table 18 ]: Casirimab, Idemumab and Kasirumab of pVSV-SARS-CoV-2 pseudotyped into Vero cells using the complete S protein sequence of the Ο BA.2 lineage or the reference sequence (D614G) Overview of IC50 and IC90 values for siretimab + idelimab-mediated neutralization Analysis number ^a Casirimab Idemumab IC ₅₀ [M] IC ₉₀ [M] Fold change in IC ₅₀ relative to reference virus IC ₅₀ [M] IC ₉₀ [M] Fold change in IC ₅₀ relative to reference virus Ο BA.2 ^b 1 6.80E-09 8.04E-08 461.82 2.19E-09 1.99E-08 158.12 2 NC NC ＞7407.41 ^c 2.03E-09 1.85E-08 362.50 3 NC NC ＞ ^3938.56c 2.49E-09 1.60E-08 268.80 4 4.63E-09 1.97E-08 620.33 1.89E-09 1.17E-08 242.27 5 1.96E-08 4.49E-07 1973.99 2.42E-09 2.57E-08 189.65 6 NC NC ＞ ^1706.48c 7.89E-09 5.23E-07 568.25 7 2.51E-08 4.65E-07 1476.19 1.81E-09 1.43E-08 109.33 8 4.29E-09 1.17E-07 296.48 5.93E-09 2.35E-07 535.29 9 NT NT NT NT NT NT average value N ^D N ^D N ^D 3.33E-09 1.08E-07 293 D614G (reference virus) 1 1.47E-11 2.70E-10 Reference virus 1.39E-11 2.91E-10 Reference virus 2 2.70E-12 8.76E-11 5.59E-12 1.29E-10 3 5.08E-12 1.33E-10 9.27E-12 2.50E-10 4 7.47E-12 1.90E-10 7.80E-12 2.48E-10 5 9.92E-12 3.03E-10 1.28E-11 1.39E-10 6 1.17E-11 4.06E-10 1.39E-11 1.89E-10 7 1.70E-11 2.73E-10 1.65E-11 2.27E-10 8 1.45E-11 1.50E-10 1.11E-11 2.27E-10 9 NT NT NT NT NT NT average value 1.04E-11 2.27E-10 Reference virus 1.14E-11 2.33E-10 Reference virus [Table 18 continued] Analysis number ^a Casirimab + Idemumab IC ₅₀ [M] IC ₉₀ [M] Fold change in IC ₅₀ relative to reference virus Ο BA.2 ^b 1 2.60E-09 1.82E-08 190.26 2 2.33E-09 1.48E-08 394.67 3 3.03E-09 3.43E-08 432.12 4 4.20E-09 2.29E-07 650.64 5 2.70E-09 1.59E-08 227.23 6 2.82E-09 1.85E-08 154.38 7 2.66E-09 1.73E-08 173.52 8 3.60E-09 3.11E-08 475.16 9 6.20E-09 2.28E-07 655.87 average value 3.35E-09 485 ng/mL 6.75E-08 9,760 ng/mL 315 D614G (reference virus) 1 1.37E-11 1.33E-10 Reference virus 2 5.89E-12 5.30E-11 3 7.01E-12 7.51E-11 4 6.45E-12 5.58E-11 5 1.19E-11 7.88E-11 6 1.83E-11 1.45E-10 7 1.53E-11 8.68E-11 8 7.57E-12 8.97E-11 9 9.45E-12 4.72E-11 average value 1.06E-11 8.49E-11 Reference virus Each column corresponds to ^an individual replicate. The analysis number columns are 1 to 9 to identify replicate values obtained for the BA.2 and D614G reference viruses. Analysis numbers are assigned chronologically by the date the analysis was performed, with number 1 being the first analysis run (analysis date January 26, 2022). ^B evaluates the complete S protein sequence of the BA.2 lineage, including the following substitutions: T19I, del24-26, A27S, G142D, V213G, G339D, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, S477N, T478K, E484A, Q493R, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, N969K ^c In cases where the IC50 may not be accurately calculated, by dividing by the maximum antibody concentration tested (20nM) Changes in mAb potency in the presence of each variant were calculated based on the calculated IC50 values for casirimab in the presence of reference pVSV-SARS-CoV-2-S pseudoparticles. ^D The average value of the neutralizing activity of casirimab against BA.2 was not calculated because the IC50 of several replicates could not be accurately calculated. NC, not calculated due to poor or lack of neutralization; NT, not tested. Casirimab, idelimumab and casirimab + idelimumab were tested at concentrations ranging from approximately 300 fM to 20 nM. By dividing the IC50 value for an antibody call in the presence of a specific variant by the IC50 for an antibody call in the presence of a reference virus (pVSV-SARS-CoV-2 pseudotyped with the D614G variant S protein) from the same analysis value to calculate the fold change relative to the reference (ref) virus. The different columns for reference virus D614G represent data collected on separate analysis dates. Values for fold changes in D614G are not provided as these columns contain neutralization data useful for reference to the virus itself.

To predict the potentially effective dose of REGEN-COV IV against Ο BA.2, serum concentrations of casirimab, idelimumab, and casirimab and idelimumab combinations were calculated, which were predicted to target pulmonary The site [lung epithelial lining fluid (ELF)] achieved sufficient neutralizing activity (IC90) against Ο BA.2, also known as target modulated IC90 against Ο BA.2 (ta-IC90). This method is based on modeled simulated population PK (PopPK) concentrations of casirimab and idelimumab in serum over time and reports the most conservative estimate of serum to lung ELF penetration of other IgG1 mAbs.

PopPK Modeling: Population PK modeling was based on an analysis of 5,152 (casirumab) and 5,153 (idelimumab) participants from four single-dose studies of REGEN-COV. Briefly, the PopPK model for casirimab and idelimumab was developed using the same 2-compartment modeled structure with linear elimination and first-order absorption in subcutaneous (SC) administration. Stochastic simulations were performed to predict exposure measures for individuals receiving REGEN-COV. For the following REGENCOV dosing regimen for the treatment of outpatients with COVID-19, empirical Bayesian estimates of PK parameters for the final model for casirimab and idelimumab were used to generate casirimab. And the concentration-time profile of Idemumab: • 1200 mg (600 mg per mAb) IV single dose • 2400 mg (1200 mg per mAb) IV single dose • 8000 mg (4000 mg per mAb) IV single dose

The following exposure measures [median (5th, 95th percentile)] are derived from the simulated concentration-time curves generated above: • Concentration after 1 hour of infusion (i.e. 1/24th day) • Concentrations on Day 7, Day 14 and Day 28

The concentrations of casirumab and idelimumab at each simulated time point were combined to obtain the concentration of casirumab and idelimumab combination in serum. Observed Linear PK of Casirimab and Idemumab Based on 300 mg IV (150 mg per mAb) to 8000 mg IV (4000 mg per mAb) for a single IV dose of 4800 mg (2400 mg per mAb) , serum concentrations of casirimab, idelimumab, and casirimab and idelimumab combinations were determined by doubling the 2400 mg (1200 mg per mAb) IV dose.

Targeted modulation IC90 against Ο BA.2 (ta-IC90): Casirimab, idelimab and casirirumab required to achieve in vitro neutralizing potency IC90 against Ο BA.2 variants in lung ELF Serum concentrations of MAb + Idemumab were calculated as the ratio of in vitro neutralization IC90 against BA.2 to serum to lung ELF penetration. For simplicity, this concentration is also referred to herein as target modulated IC90 (ta-IC90). In the absence of measured serum to lung ELF penetration data for casirimab, idelimumab, and casirimab + idelimumab, we utilized the results of two other IgG1 mAbs, ASN-1 and ASN-2. The penetration value range reported in the literature (2.6% to 20%). Since casirimab and idelimumab are also IgG1 mAbs, it is reasonable to assume a similar distribution in pulmonary ELF.

Comparison of serum concentrations over time of casirimab, idelimumab, and casirimab + idelimumab combination with ta-IC90 for Ο BA.2: comparing casirimab, idelimumab The estimated median (5th, 95th percentile) PopPK concentrations of detumabine and casirimab + idelimumab were significantly different at the end of infusion and across the REGEN-COV IV dose range (1200 mg, 2400 mg, 4800 mg and 8000 mg) and serum to lung ELF penetration values (2.6%, 5% and 10%) ta-IC90 against Ο BA.2 on days 7, 14 and 28 after administration values are compared. For these comparisons, the average IC90 values for casirumab, idelimumab, and casirumab + idelimumab combination against Ο BA.2 were used in the primary analysis. Using the minimum and maximum values from the range of nine replicate IC90 values reported for casirumab, idelimumab and REGEN-COV (casirumab + idelimumab combination) against O BA.2 value for sensitivity analysis (see Table 18).

The results in Table 19 provide serum to lung ELF penetration with targeted regulatory IC90 (ta-IC90) over O BA.2 variants up to 28 days after administration of REGEN-COV doses ranging from 1200 mg to 8000 mg IV Overview of the degree of casirumab + idelimab combination concentration in percentage of subjects. The ta-IC90 value of Ο BA.2 was derived from the average IC90 (9 replicates) of Ο BA.2 variants.

[Table 19 ]: Casirimab+ Idemumab serum concentration ≥Ο BA.2 ta-EC90 % of objects Penetration value REGEN-COV IV Dosage(mg) C _Serum >ta-EC ₉₀ Object% 14th sky No. 28 sky 2.6 1200 <5% <5% 2400 <5% <5% 4800 ＞50 to ＜95% ＞5 to ＜50% 5 1200 <5% <5% 2400 ＞50 to ＜95% <5% 4800 ＞95% ＞50 to ＜95% 10 1200 ＞50 to ＜95% <5% 2400 ＞95% ＞50 to ＜95% 4800 ＞95% ＞95%

Using the most conservative estimate of serum-to-pulmonary ELF penetration (2.6%), for the 2400 mg IV dose of REGEN-COV, ≥95% of subjects had a concentration of the casirimab + idelimab combination above Ο at the end of the infusion BA.2 of ta-IC90. For the 4800 mg IV dose with 2.6% penetration, serum concentrations exceeded the ta-IC90 in ≥95% of subjects by 7 days postdose, >50% to <95% of subjects by day 14, and >5 to <50 % of objects until the 28th day. For the 8000 mg IV dose with 2.6% penetration, serum concentrations exceeded the ta-IC90 in ≥95% of subjects by day 14 postdose, and by day 28 in >50% to <95% of subjects.

As expected, the percentage of subjects with serum concentrations exceeding the ta-IC90 for the casirimab + idelimab combination and the duration of drug serum concentration exceeding the ta-IC90 increased with the degree of serum-to-pulmonary ELF penetration. Using the most conservative estimate of serum-to-pulmonary LF penetration (2.6%), these results suggest that the 4800 mg and 8000 mg IV doses can achieve >95% Clinically effective drug concentrations for Ο BA.2 are provided in the subjects. Assuming 5% penetration, the 4800 mg and 8000 mg IV doses provided clinically effective drug concentrations against BA.2 in >95% of subjects on day 14 (4800 mg) or day 28 (8000 mg). Of note, in the outpatient treatment trial, nearly all events (i.e., COVID-19 hospitalization or death from any cause) occurred on or before study day 15 (most within 7 days), indicating maintenance of effective concentrations To 28 days is a conservative target.

As expected, sensitivity analysis showed that the percentage of subjects with drug serum concentrations exceeding ta-IC90 and the duration of drug serum concentrations exceeding ta-IC90 increased and decreased the observed minimum and maximum IC90 values, respectively.

Taken together, the results of these analyzes indicate that REGEN-COV IV doses of 4800 mg to 8000 mg can be clinically effective against BA.2 even at the most conservative estimate of serum to lung ELF penetration of 2.6%.

The scope of the invention is not limited by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the accompanying patent application.

[Table 20]: Sequences excluded from the ST.26 formatted sequence list SEQ ID NO: sequence 13 gctgcatcc 14 AAS 33 gatgtcagt 34 DVS 84 ggtaacagc 85 GNS

[ Figure 1A ] and [ Figure 1B ] show an overview of the study design to evaluate the preventive efficacy of anti-SARS-CoV-2 spike glycoprotein antibodies in a rhesus macaque model of SARS-CoV-2 infection (Figure 1A), and anti-SARS -The impact of CoV-2 spike glycoprotein antibody prophylaxis on viral genomic RNA (gRNA) and subgenomic RNA (sgRNA) in nasopharyngeal swabs and bronchoalveolar lavage (BAL) fluid (Figure 1B).

[ Figure 2A ] , [ Figure 2B ] , [ Figure 2C ], and [ Figure 2D ] show the evaluation of the preventive and therapeutic efficacy of anti-SARS-CoV-2 spike glycoprotein antibodies in the rhesus macaque model of SARS-CoV-2 infection. Overview of the study design (Figure 2A); Effects of anti-SARS-CoV-2 spine glycoprotein antibody prophylaxis on viral gRNA and sgRNA in nasopharyngeal swabs and oral swabs (Figure 2B); Anti-SARS-CoV-2 spine glycoprotein antibody Effects of protein antibody treatment on viral gRNA and sgRNA in nasopharyngeal swabs and oral swabs (Figure 2C); and representative images of lung histopathology in treated animals and placebo animals (Figure 2D).

[ Figure 3A ] and [ Figure 3B ] show the results of RNA sequence analysis of viral RNA from the studies shown in Figures 2A to 2D. Figure 3A shows the frequency of all amino acid changes identified in the spike protein across all viral sequences; each point represents the frequency of the corresponding amino acid change in a specific viral sample, and the samples are grouped based on treatment: isotype control (placebo) , therapeutic antibodies administered before (prevention) or after (treatment) viral challenge. Figure 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 was calculated and these frequencies were calculated as the number of amino acid changes in the input virus. The viral population is presented as a percentage or as a frequency range (lowest to highest %) in the viral population isolated from the placebo, prophylaxis, and treatment groups.

[ Figure 4A ] , [ Figure 4B ] , and [ Figure 4C ] show an overview of the study design to evaluate the therapeutic and preventive efficacy of anti-SARS-CoV-2 spike glycoprotein antibodies in the golden Syrian hamster model of SARS-CoV-2 infection. (Figure 4A); the effect of anti-SARS-CoV-2 spike glycoprotein antibody treatment or prevention on weight loss (Figure 4B); and the effect of anti-SARS-CoV-2 spike glycoprotein antibody therapy on lung gRNA and sgRNA levels.

[ Figure 5 ] is a schematic overview of the research design discussed in Example 2.

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

[ Figure 7 ] shows the relationship between baseline serum antibody status and baseline viral load in the placebo group of the study discussed in Example 2.

[ Figure 8 ] Viral load over time in the placebo group is shown by baseline serum antibody status in the study discussed in Example 2.

[ Figure 9 ] shows the proportion of patients with ≥1 Covid-19 related medical visit (MAV) in the placebo group through day 29 in the study discussed in Example 2.

[ Figure 10A ] and [ Figure 10B ] show the time-weighted average (TWA) diurnal change (forest plot) relative to baseline in viral load (log10 copies/ml) treated with REGEN-COV in the study discussed in Example 2.

[ Figure 11 ] shows the daily change in TWA (plot) relative to baseline in viral load (log ₁₀ copies/ml) treated with REGEN-COV in the study discussed in Example 2. Presented in the total population (modified full analysis set that excludes 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 Change from baseline in mean viral load (measured as log10 copies/ml) at each visit on day 7 in groups defined by baseline antibody status and baseline viral load. The bars in panel C indicate standard errors. The lower detection limit (dashed line) is 714 copies/ml (2.85 log10 copies/ml). IV, intravenous; SE, standard error.

[ Figure 12 ] shows the duration of negative RT-qPCR for baseline viral load categories in the study discussed in Example 2.

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

[ Figure 14A ] , [ Figure 14B ] , and [ Figure 14C ] show the proportion of patients with Covid-19-associated MAV in the study discussed in Example 2.

[ Figure 15A ] , [ Figure 15B ] , and [ Figure 15C ] show viral load through day 29 in patients with and without ≥1 Covid-19-associated MAV in the study discussed in Example 2.

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

[ Figure 17 ] shows that among COVID-19 hospitalized patients receiving low-flow supplemental oxygen, seropositive patients had a lower cumulative incidence of death or mechanical ventilation compared with seronegative patients.

[ Figure 18 ] The clinical results of Group 1 are shown by serum status and viral load. Patients who were seronegative at baseline or had higher viral loads at baseline had worse clinical outcomes.

[ Figure 19 ] shows the seamless Phase 1/2/3 study design in COVID-19 hospitalized patients.

[ Figure 20 ] shows that in the full analysis set (FAS), viral load > 10 ⁶ or modified full analysis set (mFAS) with viral load > 10 ⁷ , seronegative, seropositive or with borderline results or missing data ("Other ") number of patients.

[ Figure 21 ] shows the mean viral load among seronegative patients (circles), seropositive patients (squares), and other patients (borderline results or missing data; triangles). TWA, time weighted average; CI, confidence interval.

[ Figure 22 ] Shows 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) .

[ Figure 23 ] Shows 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) Change from baseline. The diagram shows patients divided by viral load: >10 ⁴ copies/ml, >10 ⁵ copies/ml, >10 ⁶ copies/ml and >10 ⁷ copies/ml.

[ Figure 24 ] Shows results 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) Average viral load. Graphically divided patients by baseline viral load: >10 ⁴ copies/ml, >10 ⁵ copies/ml, >10 ⁶ copies/ml and >10 ⁷ copies/ml.

[ Figure 25 ] Shows seronegative or seropositivity following intravenous treatment 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) Average viral load in patients over time. Graphical representation of patients by serostatus and clinical trial: 2066 (inpatient study; Example 1) and 2067 (ambulatory/outpatient study; Example 2).

[ Figure 26 ] Shows 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) Change from baseline. Graphical representation of patients by serostatus and clinical trial: 2066 (inpatient study; Example 1) and 2067 (ambulatory/outpatient study; Example 2).

[ Figure 27 ] Shows results 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) Average viral load. Graphical breakdown of patients by baseline viral load and clinical trial: 2066 (inpatient study; Example 1) and 2067 (ambulatory/outpatient study; Example 2).

[ Figure 28 ] Shows 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) Change from baseline. Graphical breakdown of patients by baseline viral load and clinical trial: 2066 (inpatient study; Example 1) and 2067 (ambulatory/outpatient study; Example 2).

[ Figure 29 ] shows the performance of mAb10933 alone (REGN10933), mAb10987 alone (REGN10987), and the combination of mAb10933 + mAb10987 (REGN10933 + REGN10987) against the B.1.1.7 SARS-CoV-2 variant (also known as "UK Neutralization % of pseudotyped VSV (UK variant)”. Antibodies neutralize viruses individually and in combination.

[ Figure 30 ] Shows the weekly viral load of individual symptomatic subjects (filled symbols) and asymptomatic subjects (open symbols) in the two treatment groups of the placebo group and the mAb10933 + mAb10987 (also collectively referred to as REGEN-COV ^™ ) group . 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.

[ Figure 31 ] Schematic diagram showing a phase 3 study of non-hospitalized patients treated with REGEN-COV or placebo.

[ Figure 32 ] shows the modification for phase 3 cohort inclusion, modifying the trial to include the 2400 mg and 1200 mg doses.

[ Figure 33 ] shows the clinical efficacy of REGEN-COV to compare the therapeutic effects of placebo, 2400 mg and 1200 mg intravenous treatment groups. Treatment significantly reduced COVID-19-related hospitalization or all-cause death and symptom duration, with similar treatment effects at both doses (confidence in the point estimate was higher at the 2400 mg dose due to the larger event size).

[ Figure 34 ] Shows Phase 3 Cohort 1 mFAS (SARS-CoV at baseline) for outpatients treated with 8000 mg REGEN-COV, 2400 mg REGEN-COV, 1200 mg REGEN-COV, or placebo (PBO) Balanced baseline demographics among -2 PCR-positive patients ≥18 years of age with ≥1 risk factor for severe covid-19. Stage 3 patients had higher baseline viral load and higher baseline seronegative disease than high-risk stage 1/2 patients.

[ Figure 35 ] Shows COVID-19 related hospitalization or all-cause death through day 29 after administration of 1200 mg mAb10933 + -1200 mg mAb10987 (iv) in subjects with ≥ 1 risk factor for severe COVID-19 Kaplan-Meier curve of time. The risk of COVID-19 hospitalization or death from any cause was reduced by 71% compared with placebo in the entire modified full analysis set (mFAS) population.

[ Figure 36 ] Shows COVID-19 related hospitalization or all-cause death through day 29 after administration of 600 mg mAb10933 + -600 mg mAb10987 (iv) in subjects with ≥ 1 risk factor for severe COVID-19 Kaplan-Meier curve of time. The risk of COVID-19 hospitalization or death from any cause was reduced by 71% compared with placebo in the entire modified full analysis set (mFAS) population.

[ Figure 37 ] shows that in subjects with ≥ 1 risk factor for severe COVID-19, up to day 29 Days, number of hospitalizations or all-cause deaths related to COVID-19. Results were consistent between the two treatment groups.

[ Figure 38 ] Kaplan-Meier curve showing time to resolution of symptoms consistent with COVID-19 in patients with ≥ 1 risk factor for severe COVID-19. HR: hazard ratio. The 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.

[ Figure 39 ] shows time to symptom resolution in outpatients with ≥ 1 risk factor for severe COVID-19. Improvement in symptom resolution was consistent between the modified full analysis set (mFAS) population and those with higher viral load or seronegative status at baseline.

[ Figure 40 ] Shows serious adverse events (SAEs) and specific outcomes in Phase 3 Cohort 1 outpatients treated intravenously with 1200 mg REGEN-COV, 2400 mg REGEN-COV, 8000 mg REGEN-COV or placebo (PBO). Adverse events of concern (SAEI). Safety was acceptable in all treatment groups and no serious safety issues were identified. Specifically, SAEs and AESI occurred more frequently in the placebo group compared with any REGEN-COV treatment group, and no safety imbalances were found between REGEN-COV dose groups. No safety signal was observed in hematology), more patients had treatment-emergent adverse events (TEAEs) with fatal outcomes in the placebo group than in any REGEN-COV treatment group, and in all REGEN-COV dose groups Rarely, patients experience infusion-related reactions (IRR) and anaphylaxis AESI.

[ Figure 41 ] shows serious adverse events (SAE) in Phase 3 Cohort 1 outpatients treated intravenously with 1200 mg REGEN-COV, 2400 mg REGEN-COV, 8000 mg REGEN-COV, or placebo (PBO). Occurred in >1 patient in any treatment group. SAEs occurred more frequently in the placebo group compared with any REGEN-COV dose group, more frequently reported events were consistent with COVID-19 and related complications, and lower frequency of events in the REGEN-COV dose group was associated with treatment benefit consistent.

[ Figure 42 ] Shows Adverse Events of Particular Interest (AESI) in Phase 3 Cohort 1 outpatients treated intravenously with 1200 mg REGEN-COV, 2400 mg REGEN-COV, 8000 mg REGEN-COV, or placebo (PBO) ) (e.g., infusion-related reaction or anaphylaxis) that occurred in >1 patient in any treatment group. There was a low rate of infusion-related reactions or anaphylaxis in all dose groups.

[ Figure 43 ] shows the change from baseline in viral load (log10 copies/ml) at day 7 after treatment with mAb10933 and mAb10987 in outpatients with 1 or more risk factors for severe COVID-19.

[ Figure 44 ] shows the change from baseline in viral load (log10 copies/ml) at day 7 after 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: Modification of the 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.

[ Figure 45 ] shows the demographics and baseline characteristics of seronegative IV patients (seronegative mFAS). The groups are well balanced.

[ Figure 46 ] Shows the demographics and baseline characteristics of seronegative SC patients (seronegative mFAS). The groups are well balanced.

[ Figure 47 ] shows the least square mean of change in viral load from baseline over time in patients treated with mAb10933 + mAb10987 intravenously (IV) or subcutaneously (SC).

[ Figure 48 ] shows changes in viral load from baseline in seronegative patients in the 2067 (Example 2; Outpatient) Phase 1/2 and 3 trials and the 20145 (Example 7; Dose Range-Discovery) trial. Changes in viral load from baseline were comparable between studies.

[ Figure 49 ] shows safety data from the clinical trial described in Example 7. All treatment groups were well tolerated and no safety signals were identified.

[ Figure 50 ] shows treatment-emergent adverse events in patients treated subcutaneously in the clinical trial described in Example 7. All doses were well tolerated, with minimal treatment-emergent adverse events. Of the incidents observed, they were not serious.

[ Figure 51 ] shows 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 were provided before and after revisions that changed dose groups from 2400 mg and 8000 mg to 1200 mg and 2400 mg (initial Ph3 and revised Ph3, respectively). Analysis of the change in viral load (log10 copies/ml) from baseline to day 7 demonstrated similar reductions in viral load before and after correction for changes and across all doses.

[ Figure 52 ] shows the average viral load in patients with and without hospitalization/death outcomes. Viral load in patients treated with placebo (PBO), 2.4 g of REGEN-COV, or 8.0 g of REGEN-COV was previously demonstrated on PA 6. PA 6 or subsequently demonstrated viral load in patients treated with PBO, 1.2 g of REGEN-COV, or 2.4 g of REGEN-COV.

[ Figure 53 ] Detailed plot showing viral load for individual patients with and without hospitalization/death outcome (placebo, 1.2 g REGEN-COV, and 2.4 g REGEN-COV).

[ Figure 54 ] Detailed plot showing viral load for individual patients with and without hospitalization/death outcome (placebo, 2.4 g REGEN-COV, and 8.0 g REGEN-COV).

[ Figure 55 ] Box plot showing viral load at baseline and day 7 post-treatment for patients with and without hospitalization/death outcome (placebo, 1.2 g REGEN-COV, and 2.4 g REGEN-COV) COV).

[ Figure 56 ] Box plot showing viral load at baseline and day 7 post-treatment for patients with and without hospitalization/death outcome (placebo, 2.4 g REGEN-COV, and 8.0 g REGEN-COV COV).

[ Figure 57 ] shows an overview of the clinical trial described in Example 7.

[ Figure 58 ] shows changes in viral load on day 7 after treatment in all patients, that is, seronegative patients and seropositive patients (divided between patients with and without COVID-19 related events). Placebo patients with events had higher baseline viral levels and cleared virus more slowly, whereas seropositive patients with events had similarly high baseline viral levels and delayed clearance, indicating that they may have had an ineffective antibody response.

[ Figure 59 ] shows the hierarchy of hypothesis testing in the phase 3 prevention trial described in Example 4 and the treatment effect of each evaluation index. REGEN-COV significantly prevents infection, improves disease progression and reduces viral load.

[ Figure 60 ] shows the symptomatic infection assessment metrics in the Phase 3 prevention trial described in Example 4. REGEN-COV significantly reduces symptomatic COVID-19 by all three definitions.

[ Figure 61 ] shows the cumulative incidence of symptomatic infection in the Phase 3 prevention trial described in Example 4. Beginning 1 day after dosing, REGEN-COV prevents the onset of symptomatic infection.

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

[ Figure 63 ] shows the significant reduction in weeks of symptomatic infection by REGEN-COV in the Phase 3 prevention trial described in Example 4.

[ Figure 64 ] shows the significant reduction in weeks of symptomatic infection by REGEN-COV in the Phase 3 prevention trial described in Example 4.

[ Figure 65 ] shows the number of weeks in which overall infections were significantly reduced by REGEN-COV in the Phase 3 prevention trial described in Example 4.

[ Figure 66 ] shows the hierarchy of hypothesis testing in the phase 3 preemptive treatment trial described in Example 4. REGEN-COV significantly prevents the progression of asymptomatic infection and reduces viral load. The treatment is more effective in the first three days.

[ Figure 67 ] Shows viral load over time in asymptomatic patients (2069) in the Phase 3 preemptive treatment trial described in Example 4 compared with symptomatic patients (2067) in the modified Phase 3 trial in Example 2 time average. Early treatment with REGEN-COV provides greater viral load reduction over time.

[ Figure 68 ] shows the mean concentrations of mAb10933 and mAb10987 in the serum of the sentinel and safety groups over time following a single 1200 mg dose in the phase 3 preemptive treatment trial described in Example 4.

[ Figure 69 ] shows that REGEN-COV has an acceptable and well-tolerated safety profile, with no major or serious safety issues in the Phase 3 trial of Example 4.

[ Figure 70 ] shows treatment-emergent adverse events occurring in ≥2% of any treatment group in the Phase 3 trial of Example 4.

[ Figure 71 ] shows that serious adverse events were rare, with no COVID-related serious adverse events in patients treated with REGEN-COV.

[ Figure 72 ] shows the cumulative incidence of symptomatic infection on study days in clinical trials assessing the ability of REGEN-COV to prevent symptoms of COVID-19. Subcutaneous administration of REGEN-COV reduces the risk of symptomatic SARS-CoV-2 infection by 81.4%.

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

[ Figure 74 ] shows the average viral load over time in patients who were PCR positive and seronegative at baseline in the clinical trial described in Example 7.

[ Figure 75 ] shows the mean concentration of total REGEN-COV in the serum of ambulatory PCR-positive patients after single intravenous (IV) and subcutaneous (SC) administration in the clinical trial described in Example 7.

[ Figure 76 ] shows the number of patients assigned to different treatment groups in a clinical trial designed to study REGEN-COV treatment in non-hospitalized patients.

[ Figure 77A ] , [ Figure 77B ] and [ Figure 77C ] : Figure 77A shows the clinical efficacy of 1200 mg IV dose of REGEN-COV on hospitalization or all-cause death. Treatment significantly reduced hospitalization or all-cause death. Figure 77B shows 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. Figure 77C shows the clinical efficacy of REGEN-COV at the 1200 mg IV dose and the 2400 mg IV dose on time to symptom resolution. Treatment reduced the median number of days to symptom resolution by 4 days.

[ Figure 78 ] shows the demographics and baseline medical characteristics of patients assigned to different treatment groups in a clinical trial designed to study REGEN-COV treatment in non-hospitalized patients.

[ Figure 79 ] shows the effects of different treatment groups in each of the Phase 3 clinical trial evaluation metrics in non-hospitalized adult patients with COVID-19.

[ Figure 80 ] shows a summary of serious adverse events and adverse events of particular concern in patients treated intravenously with 1200 mg REGEN-COV, 2400 mg REGEN-COV, 8000 mg REGEN-COV, or placebo.

[ Figure 81 ] shows a schematic overview of the study design to evaluate REGEN-COV treatment in adult non-hospitalized patients with COVID-19.

[ Figure 82 ] Viral load over time in the placebo group is shown by baseline serum antibody status.

[ Figure 83A ] , [ Figure 83B ], and [ Figure 83C ] : Figure 83A shows a forest plot demonstrating COVID-19 through day 29 in non-hospitalized adults with one or more severe COVID-19 risk factors. Relevant hospitalization or death from any cause. Figure 83B breaks down the data by scenario-defined risk factors, and Figure 83C breaks down the data by other risk factor combinations.

[ Figure 84A ] and [ Figure 84B ] : Figure 84A shows the number of patients with COVID-19 related hospitalization or all-cause death from day 4 to day 29 in patients treated with a single intravenous dose of 1200 mg REGEN-COV proportion of patients. Figure 84B shows 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.

[ Figure 85 ] shows 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.

[ Figure 86A ] , [ Figure 86B ], and [ Figure 86C ] : Figure 86A shows an outpatient clinic with 1 or more risk factors for severe COVID-19 treated with 1200 mg REGEN-COV or 2400 mg REGEN-COV intravenously. Viral load in patients over time. Both doses significantly reduced viral load compared with placebo. Figure 86B shows viral load over time in these patients, broken down by baseline serum antibody status (seronegative vs. seropositive). Figure 86C shows viral load over time in these patients, by baseline viral load category (>10 ⁴ copies/ml, >10 ⁵ copies/ml, >10 ⁶ copies/ml and >10 ⁷ copies/ml) Segmentation.

[ Figure 87 ] Shows viral load (log10 copies/ml) on 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 Change from baseline.

[ Figure 88A ] , [ Figure 88B ], and [ Figure 88C ] : Figure 88A shows an outpatient clinic with 1 or more risk factors for severe COVID-19 treated with 2400 mg REGEN-COV or 8000 mg REGEN-COV intravenously. Viral load in patients over time. Both doses significantly reduced viral load compared with placebo. Figure 88B shows viral load over time in these patients, broken down by baseline serum antibody status (seronegative vs. seropositive). Figure 88C shows viral load over time in these patients, by baseline viral load category (>10 ⁴ copies/ml, >10 ⁵ copies/ml, >10 ⁶ copies/ml and >10 ⁷ copies/ml) Segmentation.

[ Figure 89 ] shows the primary hierarchical analysis test sequence indicating in which order the primary and secondary evaluation indicators are evaluated.

[ Figure 90 ] shows protocol-defined risk factors for severe COVID-19 in the clinical trial evaluating REGEN-COV in non-hospitalized patients.

[ Figure 91 ] Shows the demographics and baseline medical characteristics of patients receiving 8000 mg of REGEN-COV or placebo.

[ Figure 92 ] The proportion of patients in the placebo group with at least 1 COVID-19-related hospitalization or all-cause death is shown by baseline viral load category.

[ Figure 93 ] shows viral load (hospitalization/death, no hospitalization/death, and baseline serum antibody status) in the placebo group.

[ Figure 94 ] shows the proportion of patients with one or more COVID-19-related hospitalizations and/or all-cause death.

[ Figure 95 ] shows the proportion of patients with one or more medical visits or all-cause death after treatment with REGEN-COV.

[ Figure 96 ] shows results for patients hospitalized during the course of the clinical trial among outpatients with 1 or more risk factors for severe COVID-19.

[ Figure 97 ] shows the proportion of patients with one or more COVID-19-related hospitalizations, emergency room visits, or all-cause death among patients treated with 1200 mg REGEN-COV, 2400 mg REGEN-COV, or placebo.

[ Figure 98 ] shows the proportion of patients with one or more COVID-19 related hospitalizations or all-cause death among patients treated with 8000 mg REGEN-COV or placebo.

[ Figure 99 ] shows the proportion of patients with one or more COVID-19 related medical visits or all-cause death among patients treated with 8000 mg REGEN-COV or placebo.

[ Figure 100 ] Shows treatment-emergent adverse events leading to death in patients treated with 1200 mg REGEN-COV, 2400 mg REGEN-COV, 8000 mg REGEN-COV, or placebo

[ Figure 101 ] shows an overview of treatment-emergent serious adverse events and adverse events of particular concern in patients treated with 1200 mg REGEN-COV, 2400 mg REGEN-COV, 8000 mg REGEN-COV, or placebo.

[ Figure 102 ] Shows adverse events of particular concern that require medical attention in a health care setting in patients treated with 1200 mg REGEN-COV, 2400 mg REGEN-COV, 8000 mg REGEN-COV, or placebo .

[ Figure 103 ] shows 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.

[ Figure 104 ] and [ Figure 105 ] show symptomatic SARS-CoV-2 infections (Figure 104) and all infections (none) during the 8-month study period for REGEN-COV versus placebo participants as discussed in Example 4. Symptomatic and symptomatic) (Figure 105).

[ Figure 106 ] and [ Figure 107 ] show symptomatic SARS-CoV-2 infections (Figure 106) and all infections (none) during the 8-month study period for REGEN-COV versus placebo participants as discussed in Example 4. symptomatic and symptomatic) (Figure 107).

TW202337896A_111142431_SEQL.xml

Claims (134)

A method for improving one or more clinical parameters of COVID-19, the method comprising administering to a subject in need thereof a therapeutic composition, wherein the therapeutic composition comprises at least one SARS-CoV-2 binding O(omicron) ) Antigen-binding molecules of surface proteins of variants. The method of claim 1, wherein the subject is a human patient with laboratory-confirmed SARS-CoV-2 infection and one or more COVID-19 symptoms. The method of claim 2, wherein the one or more COVID-19 symptoms include fever, cough, or shortness of breath. The method of claim 2 or claim 3, wherein the subject is selected from the group consisting of: (a) human COVID-19 patients requiring low-flow oxygen supply; (b) requiring high-intensity oxygen therapy but not mechanical Ventilated human COVID-19 patients; and (c) Human COVID-19 patients requiring mechanical ventilation. The method of any one of claims 1 to 4, wherein the subject is hospitalized due to one or more symptoms of COVID-19. The method of claim 1 to 4, wherein the subject is an outpatient. A method for preventing SARS-CoV-2 infection or COVID-19 in a subject, the method comprising administering to the subject a prophylactic composition, wherein the prophylactic composition comprises at least one surface protein that binds SARS-CoV-2 Antigen-binding molecules. The method of claim 7, wherein the subject is an uninfected individual at high risk of SARS-CoV-2 infection. The method of claim 8, wherein the subject at high risk for SARS-CoV-2 infection is a health care worker, a first responder, or a family member of an individual who has tested positive for SARS-CoV-2 infection. The method of any one of claims 1 to 9, wherein the therapeutic or preventive composition comprises a first antigen-binding molecule that binds to a first epitope on the surface protein of SARS-CoV-2 O, and binds to SARS- A second antigen-binding molecule for a second epitope on the surface protein of CoV-2 O, wherein the first epitope and the second epitope do not overlap in structure. The method of claim 10, wherein the therapeutic or preventive composition further comprises a third antigen-binding molecule that binds a third epitope on the surface protein of SARS-CoV-2 O, wherein the third epitope is structurally Does not overlap with the first epitope and the second epitope. The method of any one of claims 1 to 9, wherein the therapeutic or preventive composition comprises a first antigen-binding molecule that binds to a first epitope on the surface protein of SARS-CoV-2 O, and binds to SARS- A second antigen-binding molecule for a second epitope on the surface protein of CoV-2, wherein the first antigen-binding molecule and the second antigen-binding molecule can simultaneously bind to the surface protein of SARS-CoV-2. The method of claim 12, wherein the therapeutic or preventive composition further comprises a third antigen-binding molecule that binds to a third epitope on the surface protein of SARS-CoV-2 O, wherein the first antigen-binding molecule, the The second antigen-binding molecule and the third antigen-binding molecule can simultaneously bind to the surface protein of SARS-CoV-2. Such as requesting the method of any one of items 10 to 13, wherein: a) The first antigen-binding molecule includes three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained in the heavy chain variable region (HCVR), which is described in SEQ ID NO. : The amino acid sequence in 2; and the three light chain complementarity determining regions (CDRs) (LCDR1, LCDR2 and LCDR3) contained in the light chain variable region (LCVR), which is described in SEQ ID NO: Amino acid sequence in 10; b) The second antigen-binding molecule includes three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained in the heavy chain variable region (HCVR), which is described in SEQ ID NO. : The amino acid sequence in 22; and the three light chain complementarity determining regions (CDRs) (LCDR1, LCDR2 and LCDR3) contained in the light chain variable region (LCVR), which is described in SEQ ID The amino acid sequence in NO: 30; and c) The third antigen-binding molecule includes three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained in the heavy chain variable region (HCVR), which is described in SEQ ID NO. : The amino acid sequence in 73; and the three light chain complementarity determining regions (CDRs) (LCDR1, LCDR2 and LCDR3) contained in the light chain variable region (LCVR), which is described in SEQ ID Amino acid sequence in NO: 81. The method of any one of claims 1 to 13, wherein the surface protein of SARS-CoV-2 O is a spike (S) protein comprising a receptor binding domain, the receptor binding domain comprising at least SEQ ID NO: 59 80% identical amino acid sequence. The method of any one of claims 1 to 15, wherein the antigen-binding molecule is an anti-SARS-CoV-2 spike glycoprotein antibody or an antigen-binding fragment thereof, which includes a heavy chain variable region (HCVR) and a light chain variable region. The amino acid sequence of the variable region (LCVR) contains three heavy chain complementarity determining regions (HCDR) and three light chain complementarity determining regions (LCDR) HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3. This amino acid The sequence pair includes an amino acid sequence selected from the group consisting of: SEQ ID NO: 2/10, 22/30, 42/50, and 73/81. The method of claim 16, wherein the anti-SARS-CoV-2 O-thorn glycoprotein antibody or antigen-binding fragment comprises HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3, which respectively comprise an amine group selected from the group consisting of: Acid sequence: SEQ ID NO: 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. The method of claim 17, wherein the anti-SARS-CoV-2 O-thorn glycoprotein antibody or antigen-binding fragment includes an HCVR/LCVR amino acid sequence pair, which includes an amino acid sequence selected from the group consisting of: SEQ ID NO: 2/10, 22/30, 42/50, and 73/81. The method of any one of claims 16 to 18, wherein the anti-SARS-CoV-2 spike glycoprotein antibody comprises a human IgG heavy chain constant region. The method of claim 19, wherein the anti-SARS-CoV-2 spike glycoprotein antibody comprises a heavy chain constant region of IgG1 or IgG4 isotype. The method of claim 19, wherein the anti-SARS-CoV-2 O-thorn glycoprotein antibody comprises a pair of heavy chain and light chain amino acid sequences selected from the group consisting of: SEQ ID NO: 18/20, 38/ 40, 56/58, and 89/91. The method of any one of claims 1 to 15, wherein the antigen-binding molecule is an anti-SARS-CoV-2 O having the same binding and/or blocking properties as a reference antibody comprising the HCVR/LCVR amino acid sequence pair Spiny glycoprotein antibody, the HCVR/LCVR amino acid sequence pair includes an amino acid sequence selected from the group consisting of: SEQ ID NO: 2/10, 22/30, 42/50, and 73/81. The method of any one of claims 1 to 15, wherein the antigen-binding molecule is an anti-SARS-CoV-1 antibody with the same binding and/or blocking properties as a reference antibody comprising a pair of heavy chain and light chain amino acid sequences. 2. A spine glycoprotein antibody, the heavy chain and light chain amino acid sequence pairs are selected from the group consisting of: SEQ ID NO: 18/20, 38/40, 56/58, and 89/91. The method of claim 10 or claim 12, wherein the first antigen-binding molecule includes six complementarity determining regions contained within the amino acid sequence pair of the heavy chain variable region (HCVR) and the light chain variable region (LCVR). The first anti-SARS-CoV-2 O-thorn glycoprotein antibody or antigen-binding fragment thereof of HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3, the amino acid sequence pair comprising the amino acid sequence of SEQ ID NO: 2/10 , and the second antigen-binding molecule includes six complementarity determining regions HCDR1-HCDR2-HCDR3-LCDR1-LCDR2- included in the amino acid sequence pair of the heavy chain variable region (HCVR) and the light chain variable region (LCVR). The second anti-SARS-CoV-2 O-thorn glycoprotein antibody of LCDR3 or its antigen-binding fragment, the amino acid sequence pair includes the amino acid sequence of SEQ ID NO: 22/30. The method of claim 24, wherein the first anti-SARS-CoV-2 O-thorn glycoprotein antibody or antigen-binding fragment includes six complementarity determining regions HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3, which respectively include SEQ ID NO. : the amino acid sequence of 4-6-8-12-14-16, and the second anti-SARS-CoV-2 O-thorn glycoprotein antibody or antigen-binding fragment contains six complementarity determining regions HCDR1-HCDR2-HCDR3-LCDR1 -LCDR2-LCDR3, which respectively comprise the amino acid sequence of SEQ ID NO: 24-26-28-32-34-36. The method of claim 25, wherein the first anti-SARS-CoV-2 O-thorn glycoprotein antibody or antigen-binding fragment comprises: an HCVR/LCVR amino acid sequence pair comprising the amino acid sequence of SEQ ID NO: 2/10 , and the second anti-SARS-CoV-2 O-thorn glycoprotein antibody or antigen-binding fragment includes: an HCVR/LCVR amino acid sequence pair including the amino acid sequence of SEQ ID NO: 22/30. The method of any one of claims 24 to 26, wherein the first and the second anti-SARS-CoV-2 spike glycoprotein antibodies comprise human IgG heavy chain constant regions. The method of claim 27, wherein the first and the second anti-SARS-CoV-2 spike glycoprotein antibodies comprise heavy chain constant regions of IgG1 or IgG4 isotype. The method of claim 27, wherein the first anti-SARS-CoV-2 O-thorn glycoprotein antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 20 The light chain; and the second anti-SARS-CoV-2 spike glycoprotein antibody includes: a heavy chain including the amino acid sequence of SEQ ID NO: 38 and a light chain including the amino acid sequence of SEQ ID NO: 40. The method of claim 10 or 12, wherein the first antigen-binding molecule is a first anti-SARS-CoV-2 O having the same binding and/or blocking properties as a reference antibody comprising the HCVR/LCVR amino acid sequence pair Spiny glycoprotein antibody or antigen-binding fragment thereof, the HCVR/LCVR amino acid sequence pair includes the amino acid sequence of SEQ ID NO: 2/10, and the second antigen-binding molecule has and includes the HCVR/LCVR amino acid sequence. A second anti-SARS-CoV-2 O-thorn glycoprotein antibody or an antigen-binding fragment thereof having the same binding and/or blocking properties as the reference antibody in the sequence pair, the HCVR/LCVR amino acid sequence pair comprising SEQ ID NO: 22/ 30 amino acid sequences. The method of claim 10 or 12, wherein the first antigen-binding molecule is a first anti-SARS-CoV-2 O-thorn sugar having the same binding and/or blocking properties as a reference antibody comprising a heavy chain and a light chain pair Protein antibody or antigen-binding fragment thereof, the heavy chain and light chain pair comprise the amino acid sequence of SEQ ID NO: 18/20, and the second antigen-binding molecule is the same as the reference antibody comprising the heavy chain and light chain pair A second anti-SARS-CoV-2 O-thorn glycoprotein antibody or an antigen-binding fragment thereof with binding and/or blocking properties, the heavy chain and light chain pair comprising the amino acid sequence of SEQ ID NO: 38/40. The method of any one of claims 1 to 9, wherein the antigen-binding molecule is an anti-SARS-CoV-2 spike glycoprotein antibody or an antigen-binding fragment thereof, which includes: the amino acid sequence of SEQ ID NO: 42 The heavy chain variable region (HCVR) and the light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO: 50 contain six complementarity determining regions HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3. The method of claim 32, wherein the anti-SARS-CoV-2 O-thorn glycoprotein antibody or antigen-binding fragment includes six complementarity determining regions HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3, which respectively include SEQ ID NO: 44 -Amino acid sequence of 46-48-52-34-54. The method of claim 33, wherein the anti-SARS-CoV-2 O-thorn glycoprotein antibody or antigen-binding fragment comprises: an HCVR comprising the amino acid sequence of SEQ ID NO: 42 and an amino acid comprising SEQ ID NO: 50 Sequential LCVR. The method of any one of claims 32 to 34, wherein the anti-SARS-CoV-2 spike glycoprotein antibody comprises a human IgG heavy chain constant region. The method of claim 35, wherein the anti-SARS-CoV-2 spike glycoprotein antibody comprises a heavy chain constant region of IgG1 or IgG4 isotype. The method of claim 35, wherein the anti-SARS-CoV-2 O-thorn 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. chain. The method of any one of claims 1 to 9, wherein the antigen-binding molecule is an anti-SARS-CoV-2 O having the same binding and/or blocking properties as a reference antibody comprising the HCVR/LCVR amino acid sequence pair Spiny glycoprotein antibody, the HCVR/LCVR amino acid sequence pair includes the amino acid sequence of SEQ ID NO: 42/50. The method of any one of claims 1 to 9, wherein the antigen-binding molecule is an anti-SARS-CoV-2 O-thorn sugar having the same binding and/or blocking properties as a reference antibody comprising a heavy chain and a light chain pair Protein antibody, the heavy chain and light chain pair comprise the amino acid sequence of SEQ ID NO: 56/58. The method of any one of claims 1 to 39, wherein the therapeutic composition contains 1 mg to 10 g of the antigen-binding molecule. The method of any one of claims 1 to 21 or 24 to 29, wherein the therapeutic composition includes about 1.2 g of mAb10933 and about 1.2 g of mAb10987. The method of claim 41, wherein the therapeutic composition further comprises about 1.2 g of mAb10985. The method of any one of claims 1 to 21 or 24 to 29, wherein the therapeutic composition includes about 150 mg of mAb10933 and about 150 mg of mAb10987. The method of claim 43, wherein the therapeutic composition further comprises about 150 mg of mAb10985. The method of any one of claims 1 to 21 or 24 to 29, wherein the therapeutic composition includes about 300 mg of mAb10933 and about 300 mg of mAb10987. The method of claim 45, wherein the therapeutic composition further comprises about 300 mg of mAb10985. The method of any one of claims 1 to 21 or 24 to 29, wherein the therapeutic composition includes about 600 mg of mAb10933 and about 600 mg of mAb10987. The method of claim 47, wherein the therapeutic composition further comprises about 600 mg of mAb10985. The method of any one of claims 1 to 21 or 24 to 29, wherein the therapeutic composition includes 150 mg to 1200 mg of mAb10933 and 150 mg to 1200 mg of mAb10987. The method of claim 49, wherein the therapeutic composition further comprises 150 mg to 1200 mg of mAb10985. The method of any one of claims 1 to 21 or 24 to 29, wherein the therapeutic composition includes 1200 mg to 5000 mg of mAb10933 and 1200 mg to 5000 mg of mAb10987. The method of claim 51, wherein the therapeutic composition includes 2400 mg of mAb10933 and 2400 mg of mAb10987. The method of claim 51, wherein the therapeutic composition includes 4000 mg of mAb10933 and 4000 mg of mAb10987. The method of any one of claims 1 to 53, wherein the therapeutic or prophylactic composition is administered to the subject by intravenous infusion or subcutaneous injection. The method of any one of claims 1 to 6 or 10 to 54, wherein after administration of the therapeutic composition, the subject exhibits one or more efficacy parameters selected from the group consisting of: (a) Reduction in SARS-CoV-2 viral shedding relative to baseline; (b) At least 1 point improvement in clinical status using a 7-point ordinal scale; (c) Reduce or eliminate the need for supplemental oxygen; (d) Reduce or eliminate the need for mechanical ventilation; (e) Prevent COVID-19 related deaths; (f) Prevent all-cause mortality; and (g) Changes in serum concentrations of one or more disease-related biomarkers. For example, the method of request item 55, where the 7-point ordinal scale is: [1] Death; [2] Hospitalization, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation; [3] Hospitalization requiring non-invasive ventilation or high-flow oxygen device; [4] Hospitalized, requiring supplemental oxygen; [5] Hospitalization, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); [6] Hospitalization, no supplemental oxygen required - no longer requiring ongoing medical care; and [7] Not hospitalized. The method of claim 55 or 56, wherein the one or more efficacy parameters are measured 21 days after administration of the first dose of the therapeutic composition. The method of claim 55 to 57, wherein the reduction in SARS-CoV-2 viral shedding relative to baseline is determined by real-time quantitative PCR (RT-qPCR) in a nasopharyngeal swab sample, a nasal sample, or a saliva sample . The method of any one of claims 55 to 57, wherein 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. Claim the method of Item 6, wherein after administration of the therapeutic composition, the subject exhibits fewer than 5 COVID-19 related medical visits, telemedicine visits, hospitalizations, and/or intensive care unit (ICU) admissions. Claim the method of Item 60, wherein the subject exhibits fewer than 5 COVID-19 related medical visits, telemedicine visits, hospitalizations, and/or intensive care unit visits within 29 days after administration of the first dose of the therapeutic composition (ICU) admission. If the method of item 60 or 61 is requested, wherein the subject exhibits less than 4, less than 3, less than 2, or less than 1 COVID-19 related medical visits, telemedicine visits, hospitalizations, and/or Admission to the intensive care unit (ICU). The method of any one of claims 55 to 62, wherein the subject tests negative for SARS-CoV-2 within 2 days to 3 weeks after the first administration of the therapeutic composition. The method of claim 63, wherein a negative test for SARS-CoV-2 is determined by RT-qPCR in a nasopharyngeal swab sample, nasal sample, or saliva sample. Claim the method of any one of items 1 to 6 or 10 to 65, further comprising administering to the subject an additional therapeutic agent. The method of claim 65, wherein the additional therapeutic agent is an antiviral compound. The method of claim 66, wherein the antiviral compound is remdesivir. The method of claim 65, wherein the additional therapeutic agent is an IL-6 or IL-6R blocker. The method of claim 68, wherein the additional therapeutic agent is tocilizumab or sarilumab. The method of claim 65, wherein the additional therapeutic agent is a steroid. The method of any one of claims 65 to 70, wherein the additional therapeutic agent is administered before the therapeutic composition. The method of any one of claims 65 to 70, wherein the additional therapeutic agent is administered after or concurrently with the therapeutic composition. The method of any of the above claims, wherein the subject is seronegative for SARS-CoV-2 infection. A method for improving one or more clinical parameters of SARS-CoV-2 O infection, the method comprising administering a therapeutic composition to a subject suffering from SARS-CoV-2 O infection, wherein the therapeutic composition comprises A first anti-SARS-CoV-2 O-thorn glycoprotein antibody or an antigen-binding fragment thereof, which includes three heavy chains contained within a heavy chain variable region (HCVR) and a light chain variable region (LCVR) amino acid sequence pair Complementarity determining region (HCDR) and three light chain complementarity determining regions (LCDR), the amino acid sequence pair includes the amino acid sequence of SEQ ID NO: 2/10; and the second anti-SARS-CoV-2 O spinose Protein antibody or antigen-binding fragment thereof, which includes three HCDRs and three LCDRs contained in an amino acid sequence pair of HCVR and LCVR, and the amino acid sequence pair includes the amino acid sequence of SEQ ID NO: 22/30, wherein The therapeutic composition reduces at least one symptom of SARS-CoV-2 O infection more rapidly when administered to a population of seronegative subjects than to a comparable population of seronegative subjects administered placebo. A method for improving one or more clinical parameters of SARS-CoV-2 O infection, the method comprising administering a therapeutic composition to a subject suffering from SARS-CoV-2 O infection, wherein the therapeutic composition comprises A first anti-SARS-CoV-2 O-thorn glycoprotein antibody or an antigen-binding fragment thereof, which includes three heavy chains contained within a heavy chain variable region (HCVR) and a light chain variable region (LCVR) amino acid sequence pair Complementarity determining region (HCDR) and three light chain complementarity determining regions (LCDR), the amino acid sequence pair includes the amino acid sequence of SEQ ID NO: 2/10; and the second anti-SARS-CoV-2 O spinose Protein antibody or antigen-binding fragment thereof, which includes three HCDRs and three LCDRs contained in an amino acid sequence pair of HCVR and LCVR, and the amino acid sequence pair includes the amino acid sequence of SEQ ID NO: 22/30, wherein The therapeutic composition reduces at least one symptom of SARS-CoV-2 O infection more rapidly when administered to a population of seronegative subjects compared to a comparable population of seropositive subjects. A method for improving one or more clinical parameters of SARS-CoV-2 O infection, the method comprising administering a therapeutic composition to a subject suffering from SARS-CoV-2 O infection, wherein the therapeutic composition comprises A first anti-SARS-CoV-2 O-thorn glycoprotein antibody or an antigen-binding fragment thereof, which includes three heavy chains contained within a heavy chain variable region (HCVR) and a light chain variable region (LCVR) amino acid sequence pair Complementarity determining region (HCDR) and three light chain complementarity determining regions (LCDR), the amino acid sequence pair includes the amino acid sequence of SEQ ID NO: 2/10; and the second anti-SARS-CoV-2 O spinose Protein antibody or antigen-binding fragment thereof, which includes three HCDRs and three LCDRs contained in an amino acid sequence pair of HCVR and LCVR, and the amino acid sequence pair includes the amino acid sequence of SEQ ID NO: 22/30, wherein The therapeutic composition reduced the viral load in the subject population 7 days after administration (Day 7) compared to the day of administration (Day 0). A method for improving one or more clinical parameters of SARS-CoV-2 O infection, the method comprising administering a therapeutic composition to a subject suffering from SARS-CoV-2 O infection, wherein the therapeutic composition comprises A first anti-SARS-CoV-2 O-thorn glycoprotein antibody or an antigen-binding fragment thereof, which includes three heavy chains contained within a heavy chain variable region (HCVR) and a light chain variable region (LCVR) amino acid sequence pair Complementarity determining region (HCDR) and three light chain complementarity determining regions (LCDR), the amino acid sequence pair includes the amino acid sequence of SEQ ID NO: 2/10; and the second anti-SARS-CoV-2 O spinose Protein antibody or antigen-binding fragment thereof, which includes three HCDRs and three LCDRs contained in an amino acid sequence pair of HCVR and LCVR, and the amino acid sequence pair includes the amino acid sequence of SEQ ID NO: 22/30, wherein The therapeutic composition reduces viral load in a subject population. A method for improving one or more clinical parameters of SARS-CoV-2 O infection, the method comprising administering a therapeutic composition to a subject suffering from SARS-CoV-2 O infection, wherein the therapeutic composition comprises A first anti-SARS-CoV-2 O-thorn glycoprotein antibody or an antigen-binding fragment thereof, which includes three heavy chains contained within a heavy chain variable region (HCVR) and a light chain variable region (LCVR) amino acid sequence pair Complementarity determining region (HCDR) and three light chain complementarity determining regions (LCDR), the amino acid sequence pair includes the amino acid sequence of SEQ ID NO: 2/10; and the second anti-SARS-CoV-2 O spinose Protein antibody or antigen-binding fragment thereof, which includes three HCDRs and three LCDRs contained in an amino acid sequence pair of HCVR and LCVR, and the amino acid sequence pair includes the amino acid sequence of SEQ ID NO: 22/30, wherein The therapeutic composition was administered with 0.6 g of the first anti-SARS-CoV-2 O-thorn glycoprotein antibody and 0.6 g of the second anti-SARS-CoV-2 O-thorn glycoprotein compared to a comparable population of subjects treated with placebo. Protein antibodies 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 will alleviate symptoms (defined as symptoms becoming mild) or does not exist) is reduced by a median of 4 days. For example, claim the method of any one of items 78 to 85, wherein the subjects and/or the subject group include subjects who are not hospitalized due to COVID-19. The method of any one of claims 1 to 79, wherein the SARS-CoV-2 O is a BA.2 variant. A method of reducing the risk of contracting a symptomatic SARS-CoV-2 infection, the method comprising administering to a subject a combination of at least two antibodies that bind to the SARS-CoV-2 spine glycoprotein, wherein at least one of the administered single doses is The combination of two antibodies reduces the subject's risk of contracting a symptomatic SARS-CoV-2 infection for at least two months. The method of claim 81, wherein the method continues for at least 3 months, at least 4 months, at least 5 months, at least 6 months, or at least 7 months after administration of a single dose of the combination of at least two antibodies Reduce the risk of this object every month. The method of claim 81, wherein the method reduces the risk in the subject for at least 8 months following administration of a single dose of the combination of at least two antibodies. The method of claim 81, wherein the method continues for up to 3 months, up to 4 months, up to 5 months, up to 6 months, or up to 7 months after administration of a single dose of the combination of at least two antibodies Reduce the risk of this object every month. The method of claim 81, wherein the method reduces the risk in the subject for up to 8 months after administration of a single dose of the combination of at least two antibodies. The method of claim 81, wherein the method continues for at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks after administration of a single dose of the combination of at least two antibodies, At least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 20 weeks, at least 21 weeks, at least 22 weeks, at least 23 weeks weeks, at least 24 weeks, at least 25 weeks, at least 26 weeks, at least 27 weeks, at least 28 weeks, at least 29 weeks, at least 30 weeks, at least 31 weeks, at least 32 weeks, at least 33 weeks, at least 34 weeks, at least 35 weeks, reducing the risk in the subject for at least 36 weeks, at least 37 weeks, at least 38 weeks, at least 39 weeks, or at least 40 weeks. The method of claim 81, wherein the method reduces the risk in the subject for at least 32 weeks after administration of a single dose of the combination of at least two antibodies. The method of claim 81, wherein the method continues for up to 5 weeks, up to 6 weeks, up to 7 weeks, up to 8 weeks, up to 9 weeks, up to 10 weeks after administration of a single dose of the combination of at least two antibodies, Up to 11 weeks, Up to 12 weeks, Up to 13 weeks, Up to 14 weeks, Up to 15 weeks, Up to 16 weeks, Up to 17 weeks, Up to 18 weeks, Up to 19 weeks, Up to 20 weeks, Up to 21 weeks, Up to 22 weeks, Up to 23 weeks weeks, up to 24 weeks, up to 25 weeks, up to 26 weeks, up to 27 weeks, up to 28 weeks, up to 29 weeks, up to 30 weeks, up to 31 weeks, up to 32 weeks, up to 33 weeks, up to 34 weeks, up to 35 weeks, Reducing the risk for the subject by up to 36 weeks, up to 37 weeks, up to 38 weeks, up to 39 weeks, or up to 40 weeks. The method of claim 81, wherein the method reduces the risk in the subject for up to 32 weeks after administration of a single dose of the combination of at least two antibodies. The method of any one of claims 81 to 89, wherein the spine glycoprotein is a wild-type SARS-CoV-2 spine glycoprotein comprising the amino acid sequence of SEQ ID NO: 92. The method of any one of claims 81 to 89, wherein the spine glycoprotein is a variant SARS-CoV-2 spine glycoprotein comprising the amino acid sequence of SEQ ID NO: 93. The method of any one of claims 81 to 91, wherein each of the at least two antibodies is administered at a dose of 1 g to 10 g. The method of claim 92, wherein each of the at least two antibodies is administered at a dose of 1.2 g. The method of any one of claims 81 to 93, wherein the risk is reduced by at least 80% relative to a subject not administered the combination of at least two antibodies. The method of any one of claims 81 to 94, wherein the combination includes an antibody that binds to the SARS-CoV-2 spike glycoprotein and includes amines comprising SEQ ID NOs: 4, 6, and 8 respectively. The three heavy chain complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3 of the amino acid sequences, and the three light chain CDRs LCDR1, LCDR2, and the amino acid sequences of SEQ ID NOs: 12, 14, and 16 respectively. LCDR3. The method of any one of claims 81 to 94, wherein the combination includes an antibody that binds to the SARS-CoV-2 spike glycoprotein and includes amines comprising SEQ ID NOs: 24, 26, and 28 respectively. The three heavy chain complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3 of the amino acid sequences, and the three light chain CDRs LCDR1, LCDR2, and the amino acid sequences of SEQ ID NOs: 32, 34, and 36 respectively. LCDR3. Such as requesting the method of any one of items 81 to 94, wherein the combination includes: (a) A first antibody that binds to the SARS-CoV-2 spike protein and includes three heavy chain complementarity determining regions (CDRs) HCDR1 including the amino acid sequences of SEQ ID NO: 4, 6, and 8 respectively. , HCDR2, and HCDR3, and three light chain CDRs LCDR1, LCDR2, and LCDR3 respectively comprising the amino acid sequences of SEQ ID NO: 12, 14, and 16; and (b) A second antibody that binds to the SARS-CoV-2 spike protein and includes three heavy chain complementarity determining regions (CDRs) HCDR1 that respectively include the amino acid sequences of SEQ ID NO: 24, 26, and 28. , HCDR2, and HCDR3, and three light chain CDRs LCDR1, LCDR2, and LCDR3 respectively comprising the amino acid sequences of SEQ ID NO: 32, 34, and 36. The method of claim 97, wherein the first antibody comprises: a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 10. variable region (LCVR), and the second antibody includes: HCVR including the amino acid sequence of SEQ ID NO: 22 and LCVR including the amino acid sequence of SEQ ID NO: 30. The method of claim 98, wherein the first antibody, the second antibody, or both the first antibody and the second antibody comprise human IgGl of a human IgG4 heavy chain constant region. The method of any one of claims 81 to 99, wherein administering the single dose of the combination comprises administering a single dosage form containing the at least two antibodies. The method of any one of claims 81 to 99, wherein administering the single dose of the combination comprises administering each of the at least two antibodies in separate dosage forms within 24 hours of each other. A method of reducing the risk of contracting a symptomatic SARS-CoV-2 infection, the method comprising administering to a subject a combination of two antibodies that bind to the SARS-CoV-2 spike protein, wherein after administration of a single dose of the combination , the combination continues to reduce the risk of the object for at least two months, where the combination includes: (a) A first antibody that binds to the SARS-CoV-2 spike protein and includes three heavy chain complementarity determining regions (CDRs) HCDR1 that respectively include the amino acid sequences of SEQ ID NO: 4, 6, and 8. , HCDR2, and HCDR3, and three light chain CDRs LCDR1, LCDR2, and LCDR3 respectively comprising the amino acid sequences of SEQ ID NO: 12, 14, and 16; and (b) A second antibody that binds to the SARS-CoV-2 spike protein and includes three heavy chain complementarity determining regions (CDRs) HCDR1 that respectively include the amino acid sequences of SEQ ID NO: 24, 26, and 28. , HCDR2, and HCDR3, and three light chain CDRs LCDR1, LCDR2, and LCDR3 respectively comprising the amino acid sequences of SEQ ID NO: 32, 34, and 36. The method of claim 102, wherein the first antibody comprises: a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 10. variable region (LCVR), and the second antibody includes: HCVR including the amino acid sequence of SEQ ID NO: 22 and LCVR including the amino acid sequence of SEQ ID NO: 30. The method of claim 103, wherein the first antibody, the second antibody, or both the first antibody and the second antibody comprise human IgGl of a human IgG4 heavy chain constant region. The method of any one of claims 102 to 104, wherein the spike protein is a wild-type SARS-CoV-2 spike protein comprising the amino acid sequence of SEQ ID NO: 92, or the spike protein is a spike protein comprising SEQ ID NO: 93 amino acid sequence variants of SARS-CoV-2 spike protein. The method of any one of claims 102 to 105, wherein each of the two antibodies is administered at a dose of 1.2 g. The method of any one of claims 102 to 106, wherein administering the single dose of the combination comprises administering a single dosage form containing the two antibodies. The method of any one of claims 102 to 107, wherein the risk is reduced by at least 80% relative to a subject not administered the combination. The method of any one of claims 102 to 108, wherein the method reduces the risk in the subject for at least eight months after administration of a single dose of the combination. The method of any one of claims 81 to 109, wherein the combination of antibodies is in a pharmaceutical composition formulated for subcutaneous administration. The method of any one of claims 81 to 110, wherein the antibodies are administered subcutaneously to the subject. The method of claim 111, wherein the antibodies are administered to the subject in four subcutaneous injections. The method of any one of claims 81 to 112, wherein the subject is immunocompromised. The method of any one of claims 81 to 113, wherein each of the two antibodies is administered at a dose of 600 mg. A method for long-term COVID-19 prevention, the method comprising administering to a subject a combination of at least two antibodies that bind to SARS-CoV-2 spike protein, wherein a single dose of the at least two antibodies is administered. The combination continues to reduce the subject's risk of symptomatic SARS-CoV-2 infection for at least two months after combination. The method of claim 115, wherein the method continues for at least 3 months, at least 4 months, at least 5 months, at least 6 months, or at least 7 months after administration of a single dose of the combination of at least two antibodies Monthly prevention of COVID-19 in this subject. The method of claim 115, wherein the method prevents COVID-19 in the subject for at least 8 months after administration of a single dose of the combination. The method of any one of claims 115 to 117, wherein the spine glycoprotein is a wild-type SARS-CoV-2 spine glycoprotein comprising the amino acid sequence of SEQ ID NO: 92. The method of any one of claims 115 to 117, wherein the spine glycoprotein is a variant SARS-CoV-2 spine glycoprotein comprising the amino acid sequence of SEQ ID NO: 93. The method of any one of claims 115 to 119, wherein each of the at least two antibodies is administered at a dose of 1 g to 10 g. The method of claim 120, wherein each of the at least two antibodies is administered at a dose of 1.2 g. The method of any one of claims 115 to 121, wherein the risk is reduced by at least 80% relative to a subject not administered the combination of at least two antibodies. The method of any one of claims 115 to 122, wherein the combination includes an antibody that binds to the SARS-CoV-2 spike protein and includes amines including SEQ ID NOs: 4, 6, and 8 respectively. The three heavy chain complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3 of the amino acid sequences, and the three light chain CDRs LCDR1, LCDR2, and the amino acid sequences of SEQ ID NOs: 12, 14, and 16 respectively. LCDR3. The method of any one of claims 115 to 123, wherein the combination includes an antibody that binds to the SARS-CoV-2 spike protein and includes amines including SEQ ID NOs: 24, 26, and 28 respectively. The three heavy chain complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3 of the amino acid sequences, and the three light chain CDRs LCDR1, LCDR2, and the amino acid sequences of SEQ ID NOs: 32, 34, and 36 respectively. LCDR3. Such as requesting the method of any one of items 115 to 124, wherein the combination includes: (a) A first antibody that binds to the SARS-CoV-2 spike protein and includes three heavy chain complementarity determining regions (CDRs) HCDR1 including the amino acid sequences of SEQ ID NO: 4, 6, and 8 respectively. , HCDR2, and HCDR3, and three light chain CDRs LCDR1, LCDR2, and LCDR3 respectively comprising the amino acid sequences of SEQ ID NO: 12, 14, and 16; and (b) A second antibody that binds to the SARS-CoV-2 spike protein and includes three heavy chain complementarity determining regions (CDRs) HCDR1 that respectively include the amino acid sequences of SEQ ID NO: 24, 26, and 28. , HCDR2, and HCDR3, and three light chain CDRs LCDR1, LCDR2, and LCDR3 respectively comprising the amino acid sequences of SEQ ID NO: 32, 34, and 36. The method of claim 125, wherein the first antibody comprises: a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 10. variable region (LCVR), and the second antibody includes: HCVR including the amino acid sequence of SEQ ID NO: 22 and LCVR including the amino acid sequence of SEQ ID NO: 30. The method of claim 115 to 126, wherein the antibodies are administered subcutaneously to the subject. The method of claim 127, wherein the antibodies are administered to the subject in four subcutaneous injections. The method of claim 115 to 128, wherein each of the two antibodies is administered at a dose of 600 mg. The method of claim 115 to 129, wherein the subject is immunocompromised. The method of claim 130, wherein the subject has primary immunodeficiency. The method of claim 130, wherein the subject has secondary immunodeficiency. Such as the method of claim 130, wherein the subject has not responded effectively to COVID-19 vaccination. For example, the method of request item 130, wherein the object meets ≥ 1 of the following criteria: a. Solid organ transplant (SOT) or hematopoietic cell transplant (HSCT) recipients receiving any immunosuppressive agents b. Active hematological malignancy or treatment has been completed within 3 months c. Solid organ malignancies receive active treatment using T cell or B cell immunosuppressive therapy d. Moderate or severe primary immunodeficiency (such as hypogammaglobulinaemia, common variable immunodeficiency, severe combined immunodeficiency) e. HIV and CD4 <200 cells/microliter f. Patients with rheumatic diseases, autoimmune diseases, or multiple sclerosis receive immunosuppressive therapy to modulate Th1, Th17, or B cell responses g. Receiving any of the following immunosuppressive medications for more than 3 weeks: − T cell inhibitors (e.g., ≥5 mg prednisone equivalent/day for >3 weeks), proteasome inhibitors (such as bortezomib, lenalidomide), alemtuzumab ( alemtuzumab), antithymocyte globulin, CAR-T therapy, calcineurin inhibitor) − Alkylating agent − Purine analogues, such as fludarabine or cladribine − B cell depleting agents, such as rituximab and ocrelizumab − mTOR inhibitors − Anti-metabolites such as mycophenolate mofetil − JAK inhibitors.