Methods for treating or preventing SARS-CoV-2 infection and COVID-19 using anti-SARS-CoV-2 spike glycoprotein antibodies

Abstract

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

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application is a compilation of U.S. Provisional Applications No. 63 / 034,348 filed on June 3, 2020, No. 63 / 036,956 filed on June 9, 2020, No. 63 / 038,274 filed on June 12, 2020, No. 63 / 043,336 filed on June 24, 2020, No. 63 / 060,592 filed on August 3, 2020, No. 63 / 062,961 filed on August 7, 2020, No. 63 / 065,799 filed on August 14, 2020, and No. 63 / 065,799 filed on September 29, 2020, under Section 119(e) of the U.S. Patent Act. Filings No. 63 / 084,881, No. 63 / 085,066 filed on September 29, 2020, No. 63 / 089,399 filed on October 8, 2020, No. 63 / 090,690 filed on October 12, 2020, No. 63 / 094,133 filed on October 20, 2020, No. 63 / 105,779 filed on October 26, 2020, No. 63 / 106,696 filed on October 28, 2020, No. 63 / 112,140 filed on November 10, 2020, and November 20, 2020 The same No. 63 / 116,773 filed on November 30, 2020, the same No. 63 / 119,593 filed on December 1, 2020, the same No. 63 / 120,065 filed on December 14, 2020, the same No. 63 / 124,980 filed on December 29, 2020, the same No. 63 / 131,627 filed on December 29, 2020, the same No. 63 / 141,423 filed on January 25, 2021, the same No. 63 / 141,952 filed on January 26, 2021, the same No. 63 / 142,471 filed on January 27, 2021, the same No. Filings No. 63 / 144,789, No. 63 / 150,978 filed on February 18, 2021, No. 63 / 162,504 filed on March 17, 2021, No. 63 / 162,996 filed on March 18, 2021, No. 63 / 164,488 filed on March 22, 2021, No. 63 / 165,654 filed on March 24, 2021, No. 63 / 166,187 filed on March 25, 2021, No. 63 / 173,468 filed on April 11, 2021, and No. 63 / 185 filed on May 6, 2021.Claiming the interests of Patent No. 301 and Patent No. 63 / 186,029 filed on 7 May 2021, each of which is incorporated herein by reference in whole for all purposes.

[0002] (Federal government-funded research or development) This invention was made with government support under contract HHSO100201700020C, certified by the USDepartment of Health and Human Services. The government has certain rights in this invention.

[0003] (Reference to the sequence list) This application incorporates reference to a sequence listing file 10807WO01-Sequence, prepared on June 2, 2021, and submitted in computer-readable format, containing 72,328 bytes.

[0004] (Field of invention) The present invention belongs to the field of pharmaceuticals and relates to methods and pharmaceutical compositions for treating SARS-CoV-2 infection and COVID-19 by administering antigen-binding molecules that bind to the surface protein of SARS-CoV-2 (e.g., anti-SARS-CoV-2 spike glycoprotein antibodies and their antigen-binding fragments, or combinations of such antibodies or antigen-binding fragments). [Background technology]

[0005] Coronaviruses are a family of enveloped single-stranded RNA viruses. In the last decade or so, two highly pathogenic strains of coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), have been identified in humans. These viruses have been found to cause severe, sometimes fatal, respiratory illnesses.

[0006] In December 2019, a cluster of patients with pneumonia of unknown cause was identified in Wuhan City, China. A novel enveloped RNA beta-coronavirus (SARS-CoV-2) was identified in these patients, and the disease caused by SARS-CoV-2 infection was later named Coronavirus Disease 2019 (COVID-19) by the World Health Organization. As of May 2020, there were reported to be more than 55 million confirmed cases of COVID-19 worldwide. Its rapid spread and global pandemic prompted the declaration of COVID-19 as a pandemic of international concern and a public health emergency.

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

[0008] Coronaviruses possess an RNA genome packaged in a nucleocapsid (N) protein surrounded by an outer membrane. The envelope consists of membrane (M) and envelope (E) proteins involved in viral assembly, as well as a spike (S) protein that mediates entry into host cells. The S protein forms a large trimer projection, giving coronaviruses their characteristic cucrown-like appearance. The S protein trimer binds to the host receptor and mediates host-viral membrane fusion after priming by cellular proteases. The S protein appears to be central to the infectivity of SARS-CoV-2. The SARS-CoV-2 S protein binds to the host receptor angiotensin-converting enzyme 2 (ACE2) with high affinity, allowing ACE2 to be utilized as a functional receptor for host cell entry in cell assays and animal models.

[0009] Given the potential central role of the S protein in the pathogenesis of SARS-CoV-2, several efforts have already been made to develop antibodies and vaccines targeting this protein. [Overview of the project]

[0010] This disclosure provides methods for improving one or more clinical parameters of COVID-19. In some cases, the method comprises doing so to a subject requiring the administration of a therapeutic composition, the therapeutic composition comprising at least one antigen-binding molecule that binds to the surface protein of SARS-CoV-2. In some embodiments, the subject is a human patient having SARS-CoV-2 confirmed by testing and one or more symptoms of COVID-19. In some cases, one or more symptoms of COVID-19 include fever, cough, or shortness of breath.

[0011] In some embodiments, subjects are selected from a group consisting of (a) human COVID-19 patients requiring low-flow oxygen supplementation, (b) human COVID-19 patients requiring high-intensity oxygen therapy but not receiving mechanical ventilation, and (c) human COVID-19 patients requiring mechanical ventilation. In some cases, subjects are hospitalized due to one or more COVID-19 symptoms. In some cases, subjects are outpatients (i.e., treated as outpatients).

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

[0013] In some embodiments, the subjects are uninfected individuals at high risk of SARS-CoV-2 infection. In some embodiments, subjects at high risk of SARS-CoV-2 infection are healthcare workers, first responders, or family members of individuals who have tested positive for SARS-CoV-2 infection.

[0014] In some embodiments, the therapeutic or prophylactic composition comprises a first antigen-binding molecule bound to a first epitope on the surface protein of SARS-CoV-2, and a second antigen-binding molecule bound to a second epitope on the surface protein of SARS-CoV-2, wherein the first and second epitopes do not structurally overlap.

[0015] 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 third epitope does not structurally overlap with the first and second epitopes.

[0016] In some embodiments, the therapeutic or prophylactic composition comprises a first antigen-binding molecule bound to a first epitope on the surface protein of SARS-CoV-2, and a second antigen-binding molecule bound to a second epitope on the surface protein of SARS-CoV-2, wherein the first and second antigen-binding molecules can bind to the surface protein of SARS-CoV-2 simultaneously. In some embodiments, the therapeutic or prophylactic composition further comprises a third antigen-binding molecule bound to a third epitope on the surface protein of SARS-CoV-2, wherein the first, second, and third antigen-binding molecules can bind to the surface protein of SARS-CoV-2 simultaneously. In some embodiments, a) the first antigen-binding molecule comprises three chain complementarity determining regions (CDRs) (HCDR1, HCDR2, and HCDR3) contained within a heavy chain variable region (HCVR) containing the amino acid sequence described in SEQ ID NO: 2, and a light chain variable region (CDRs) containing the amino acid sequence described in SEQ ID NO: 10. a) The second antigen-binding molecule includes three light chain complementarity-determining regions (CDRs) (LCDR1, LCDR2, and LCDR3) contained within the heavy chain variable region (HCVR) containing the amino acid sequence described in SEQ ID NO: 22, and three light chain complementarity-determining regions (CDRs) (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) containing the amino acid sequence described in SEQ ID NO: 30, and c) The third antigen-binding molecule includes three heavy chain complementarity-determining regions (CDRs) (HCDR1, LCDR2, and LCDR3) contained within the heavy chain variable region (HCVR) containing the amino acid sequence described in SEQ ID NO: 73, and three light chain complementarity-determining regions (CDRs) (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) containing the amino acid sequence described in SEQ ID NO: 81.

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

[0018] In some embodiments, the antigen-binding molecule is an anti-SARS-CoV-2 spike glycoprotein antibody or its antigen-binding fragment, comprising six complementarity-determining regions, HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3, contained within a heavy chain variable region (HCVR) and light chain variable region (LCVR) amino acid sequence pair, which include an amino acid sequence selected from the group consisting of SEQ ID NOs: 2 / 10, 22 / 30, 42 / 50, and 73 / 81. In some cases, the anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment includes six complementarity-determining regions, HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3, each containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 4-6-8-12-14-16, 24-26-28-32-34-36, 44-46-48-52-34-54, and 75-77-79-83-85-87. In some cases, the anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment includes an HCVR / LCVR amino acid sequence pair, each containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 2 / 10, 22 / 30, 42 / 50, and 73 / 81. In some embodiments, the anti-SARS-CoV-2 spike glycoprotein antibody includes a human IgG heavy chain constant region. In some cases, the anti-SARS-CoV-2 spike glycoprotein antibody contains a heavy chain constant region of the IgG1 or IgG4 isotype. In some cases, the anti-SARS-CoV-2 spike glycoprotein antibody contains a heavy chain and light chain amino acid sequence pair selected from the group consisting of SEQ ID NOs: 18 / 20, 38 / 40, 56 / 58, and 89 / 91.

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

[0020] In some embodiments, the first antigen-binding molecule is a first anti-SARS-CoV-2 spike glycoprotein antibody or its antigen-binding fragment, comprising six complementarity-determining regions, HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3, contained within a heavy chain variable region (HCVR) and light chain variable region (LCVR) amino acid sequence pair comprising the amino acid sequence of SEQ ID NO: 2 / 10, and the second antigen-binding molecule is a second anti-SARS-CoV-2 spike glycoprotein antibody or its antigen-binding fragment, comprising six complementarity-determining regions, HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3, contained within a heavy chain variable region (HCVR) and light chain variable region (LCVR) amino acid sequence pair comprising the amino acid sequence of SEQ ID NO: 22 / 30. In some cases, the first anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment contains six complementarity-determining regions, HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3, each containing the amino acid sequences of SEQ ID NOs: 4-6-8-12-14-16, 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, each containing the amino acid sequences of SEQ ID NOs: 24-26-28-32-34-36. In some cases, the first anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment contains an HCVR / LCVR amino acid sequence pair containing the amino acid sequence of SEQ ID NOs: 2 / 10, and the second anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment contains an HCVR / LCVR amino acid sequence pair containing the amino acid sequences of SEQ ID NOs: 22 / 30. In some embodiments, the first and second anti-SARS-CoV-2 spike glycoprotein antibodies include a human IgG heavy chain constant region. In some cases, the first and second anti-SARS-CoV-2 spike glycoprotein antibodies include a heavy chain constant region of IgG1 or IgG4 isotype.In some cases, the first anti-SARS-CoV-2 spike glycoprotein antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 18 and a light chain containing the amino acid sequence of SEQ ID NO: 20, and the second anti-SARS-CoV-2 spike glycoprotein antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 38 and a light chain containing the amino acid sequence of SEQ ID NO: 40.

[0021] In some embodiments, the first antigen-binding molecule is a first anti-SARS-CoV-2 spike glycoprotein antibody or its antigen-binding fragment having the same binding and / or blocking properties as the reference antibody, comprising an HCVR / LCVR amino acid sequence pair comprising the amino acid sequence of SEQ ID NO: 2 / 10, and the second antigen-binding molecule is a second anti-SARS-CoV-2 spike glycoprotein antibody or its antigen-binding fragment having the same binding and / or blocking properties as the reference antibody, comprising an 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 its antigen-binding fragment having the same binding and / or blocking properties as the reference antibody, comprising a heavy chain and light chain pair comprising the amino acid sequence of SEQ ID NO: 18 / 20, and the second antigen-binding molecule is a first anti-SARS-CoV-2 spike glycoprotein antibody or its antigen-binding fragment having the same binding and / or blocking properties as the reference antibody, comprising a heavy chain and light chain pair comprising the amino acid sequence of SEQ ID NO: 38 / 40.

[0022] In some embodiments, the antigen-binding molecule is an anti-SARS-CoV-2 spike glycoprotein antibody or its antigen-binding fragment, comprising six complementarity-determining regions, HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3, contained within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 42 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 50. In some cases, the anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment comprises six complementarity-determining regions, HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3, each comprising the amino acid sequences of SEQ ID NOs: 44-46-48-52-34-54. In some cases, the anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 42 and an LCVR comprising the amino acid sequence of SEQ ID NO: 50. In some embodiments, the anti-SARS-CoV-2 spike glycoprotein antibody comprises a human IgG heavy chain constant region. In some cases, anti-SARS-CoV-2 spike glycoprotein antibodies contain a heavy chain constant region of the IgG1 or IgG4 isotype. In some cases, anti-SARS-CoV-2 spike glycoprotein antibodies contain a heavy chain containing the amino acid sequence of SEQ ID NO: 56 and a light chain containing the amino acid sequence of SEQ ID NO: 58.

[0023] In some embodiments, the antigen-binding molecule is an anti-SARS-CoV-2 spike glycoprotein antibody having the same binding and / or blocking properties as the reference antibody, comprising an HCVR / LCVR amino acid sequence pair containing 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 having the same binding and / or blocking properties as the reference antibody, comprising a heavy chain and light chain pair containing the amino acid sequence of SEQ ID NO: 56 / 58.

[0024] In any of the various embodiments of the methods described above or herein, the therapeutic or prophylactic composition contains 1 mg to 10 g of antigen-binding molecules. In some cases, the therapeutic or prophylactic composition contains 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 contains about 4.0 g of mAb10933 and about 4.0 g of mAb10987. In some cases, the therapeutic or prophylactic composition contains 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 contains 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 contains about 600 mg of mAb10933 and about 600 mg of mAb10987. In some cases, the therapeutic or prophylactic composition contains about 600 mg of mAb10985. In some cases, the therapeutic or prophylactic composition contains 150 mg to 1200 mg of mAb10933 and 150 mg to 1200 mg of mAb10987. In some cases, the therapeutic or prophylactic composition further contains 150 mg to 1200 mg of mAb10985. In some cases, the therapeutic or prophylactic composition contains about 1.2 g of mAb10989.

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

[0026] In any of the various embodiments, the subject exhibits one or more efficacy parameters selected from the group consisting of (a) reduction from baseline in SARS-CoV-2 virus shedding, (b) improvement of at least 1 point on a 7-point ordinal scale in clinical status, (c) reduction or elimination of the need for oxygen supplementation, (d) reduction or elimination of the need for mechanical ventilation, (e) prevention of COVID-19-related death, (f) prevention of all-cause death, and (g) change in serum concentration of one or more disease-related biomarkers after administration of the therapeutic composition. 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 a high-flow oxygen device, [4] hospitalization requiring oxygen supplementation, [5] hospitalization not requiring oxygen supplementation but requiring ongoing medical care (COVID-19-related or not), [6] hospitalization not requiring oxygen supplementation and no longer requiring ongoing medical care, and [7] no hospitalization. In some cases, one or more efficacy parameters are measured 21 days after administration of a first dose of the therapeutic composition. In some cases, a reduction from baseline in SARS-CoV-2 virus shedding is determined by real-time quantitative PCR (RT-qPCR) of nasopharyngeal swab, nasal cavity, or saliva samples. In some cases, changes in serum concentrations of one or more disease-related biomarkers include changes in C-reactive protein, lactate dehydrogenase, D-dimer, or ferritin.

[0027] In any of the various embodiments, the subject represents fewer than five visits, telemedicine visits, hospitalizations, and / or intensive care unit (ICU) admissions requiring COVID-19-related medical intervention after administration of the therapeutic composition. In some cases, fewer than five visits, telemedicine visits, hospitalizations, and / or intensive care unit (ICU) admissions requiring COVID-19-related medical intervention are indicated by the subject within 29 days after administration of the first dose of the therapeutic composition. In some cases, the subject represents fewer than four, three, two, or one visit, telemedicine visit, hospitalization, and / or intensive care unit (ICU) admissions requiring COVID-19-related medical intervention.

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

[0029] In some embodiments, the method further includes administering an additional therapeutic agent to the subject. In some cases, the additional therapeutic agent is an antiviral compound. In some embodiments, the antiviral compound is remdesivir. In some cases, the additional therapeutic agent is an IL-6 or IL-6R antagonist. In some embodiments, the additional therapeutic agent is tocilizumab or sarilumab. In some embodiments, the additional therapeutic agent is a steroid. In some embodiments, the additional therapeutic agent is administered before 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 described above or herein, the subject may be seronegative for SARS-CoV-2 infection.

[0030] In one embodiment, 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 having SARS-CoV-2 infection, the therapeutic composition comprising a first anti-SARS-CoV-2 spike glycoprotein antibody or its antigen-binding fragment, comprising three heavy chain complementarity-determining regions (HCDRs) and three light chain complementarity-determining regions (LCDRs) contained within a heavy chain variable region (HCVR) and light chain variable region (LCVR) amino acid sequence pair comprising the amino acid sequence of SEQ ID NO: 2 / 10, and a second anti-SARS-CoV-2 spike glycoprotein antibody or its antigen-binding fragment, comprising three HCDRs and three LCDRs contained within an HCVR and LCVR amino acid sequence pair comprising the amino acid sequence of SEQ ID NO: 22 / 30, wherein, when administered to a seronegative control population, the therapeutic composition more rapidly alleviates at least one symptom of SARS-CoV-2 infection compared to an equivalent seronegative control population administered a placebo.

[0031] In one embodiment, 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 having SARS-CoV-2 infection, the therapeutic composition comprising a first anti-SARS-CoV-2 spike glycoprotein antibody or its antigen-binding fragment comprising three heavy chain complementarity-determining regions (HCDRs) and three light chain complementarity-determining regions (LCDRs) contained within a heavy chain variable region (HCVR) and light chain variable region (LCVR) amino acid sequence pair comprising the amino acid sequence of SEQ ID NO: 2 / 10, and a second anti-SARS-CoV-2 spike glycoprotein antibody or its antigen-binding fragment comprising three HCDRs and three LCDRs contained within an HCVR and LCVR amino acid sequence pair comprising the amino acid sequence of SEQ ID NO: 22 / 30, wherein, when administered to a seronegative control population, the therapeutic composition more rapidly alleviates at least one symptom of SARS-CoV-2 infection compared to an equivalent seropositive control population.

[0032] In one embodiment, 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 having SARS-CoV-2 infection, the therapeutic composition comprising a first anti-SARS-CoV-2 spike glycoprotein antibody or its antigen-binding fragment, comprising three heavy chain complementarity-determining regions (HCDRs) and three light chain complementarity-determining regions (LCDRs) contained within a heavy chain variable region (HCVR) and light chain variable region (LCVR) amino acid sequence pair comprising the amino acid sequence of SEQ ID NO: 2 / 10, and a second anti-SARS-CoV-2 spike glycoprotein antibody or its antigen-binding fragment, comprising three HCDRs and three LCDRs contained within an HCVR and LCVR amino acid sequence pair comprising the amino acid sequence of SEQ ID NO: 22 / 30, wherein the therapeutic composition reduces the viral load in the target population by 7 days after administration (day 7) compared to the day of administration (day 0).

[0033] In some embodiments, the time-weighted mean change from baseline nasopharyngeal (NP) viral load up to day 7 in a seronegative control population was at least 0.86 log10 copies / mL greater (p<0.0001) in patients treated with 0.6 g of a first anti-SARS-CoV-2 spike glycoprotein antibody and 0.6 g of a second anti-SARS-CoV-2 spike glycoprotein antibody compared to an equivalent control population treated with placebo.

[0034] In some embodiments, the change from baseline nasopharyngeal (NP) viral load up to day 7 in a seronegative control population was at least 1.04 log10 copies / mL greater (p<0.0001) in patients treated with 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 compared to an equivalent control population treated with placebo.

[0035] In some embodiments, the mean change from baseline nasopharyngeal (NP) viral load up to day 7 in the control population was at least 0.71 log10 copies / mL greater (p<0.0001) in patients treated with 0.6 g of a first anti-SARS-CoV-2 spike glycoprotein antibody and 0.6 g of a second anti-SARS-CoV-2 spike glycoprotein antibody compared to an equivalent control population treated with placebo.

[0036] In some embodiments, the mean change from baseline nasopharyngeal (NP) viral load up to day 7 in the control population was at least 0.86 log10 copies / mL greater (p<0.0001) in patients treated with 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 compared to an equivalent control population treated with placebo.

[0037] In one embodiment, 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 having SARS-CoV-2 infection, the therapeutic composition comprising a first anti-SARS-CoV-2 spike glycoprotein antibody or its antigen-binding fragment, comprising three heavy chain complementarity-determining regions (HCDRs) and three light chain complementarity-determining regions (LCDRs) contained within a heavy chain variable region (HCVR) and light chain variable region (LCVR) amino acid sequence pair comprising the amino acid sequence of SEQ ID NO: 2 / 10, and a second anti-SARS-CoV-2 spike glycoprotein antibody or its antigen-binding fragment, comprising three HCDRs and three LCDRs contained within an HCVR and LCVR amino acid sequence pair comprising the amino acid sequence of SEQ ID NO: 22 / 30, the therapeutic composition reduces the viral load in the target population.

[0038] In some embodiments of the methods described above or herein, the administration of the therapeutic composition comprises administering 0.6 g of a first anti-SARS-CoV-2 spike glycoprotein antibody and 0.6 g of a second anti-SARS-CoV-2 spike glycoprotein antibody, the administration resulting in an average reduction of at least 3.00 log10 copies / mL of viral load on day 7 post-administration compared to the baseline viral load measured on day 0 prior to administration. In some cases, the reduction is at least 3.50 log10 copies / mL. In some cases, the reduction is at least 3.90 log10 copies / mL.

[0039] In some embodiments, administration of 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, which results in an average reduction of at least 3.50 log10 copies / mL of viral load on day 7 post-administration compared to the baseline viral load measured on day 0 prior to administration. In some cases, the reduction is at least 3.75 log10 copies / mL. In some cases, the reduction is at least 4.09 log10 copies / mL.

[0040] In one embodiment, 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 having SARS-CoV-2 infection, the therapeutic composition comprising a first anti-SARS-CoV-2 spike glycoprotein antibody or its antigen-binding fragment, comprising three heavy chain complementarity-determining regions (HCDRs) and three light chain complementarity-determining regions (LCDRs) contained within the heavy chain variable region (HCVR) and light chain variable region (LCVR) amino acid sequence pair comprising the amino acid sequence of SEQ ID NO: 2 / 10, and three contained within the HCVR and LCVR amino acid sequence pair comprising the amino acid sequence of SEQ ID NO: 22 / 30 The therapeutic composition comprises a second anti-SARS-CoV-2 spike glycoprotein antibody or its antigen-binding fragment, comprising HCDR and three LCDRs, and reduces the median duration of symptom relief (defined as mild or absent symptoms) by 4 days in a target population treated with 0.6 g of a first anti-SARS-CoV-2 spike glycoprotein antibody and 0.6 g of a second anti-SARS-CoV-2 spike glycoprotein antibody, or 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, compared to an equivalent target population treated with placebo. In some embodiments, the target and / or target population includes subjects who are not hospitalized with COVID-19.

[0041] Any of the methods described above or herein may be reorganized as (i) antigen-binding molecules or antibodies (and antigen-binding fragments) for use in methods for treating and / or preventing SARS-CoV-2 infection and / or COVID-19, and / or for treating, preventing and reducing the severity or progression of SARS-CoV-2 infection and / or COVID-19, or the symptoms thereof; or (ii) the use of antigen-binding molecules or antibodies (and antigen-binding fragments) in the manufacture of agents for treating and / or preventing SARS-CoV-2 infection and / or COVID-19, and / or for treating, preventing and reducing the severity or progression of SARS-CoV-2 infection and / or COVID-19, or the symptoms thereof. In particular, this disclosure includes the use of antigen-binding molecules that bind to the surface protein of SARS-CoV-2, including anti-SARS-CoV-2 spike glycoprotein antibodies or antigen-binding fragments thereof, as considered 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. This disclosure also includes the use of antigen-binding molecules that bind to the surface protein of SARS-CoV-2, including anti-SARS-CoV-2 spike glycoprotein antibodies or antigen-binding fragments thereof, as considered herein, in the manufacture of agents 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. Where described herein, if a method is considered with reference to a combination of two anti-SARS-CoV-2 spike protein antibodies, such combination includes the use of a first such antibody or its antigen-binding fragment in the manufacture of a drug for use in combination with a second such antibody or its antigen-binding fragment (or a third or fourth such antibody or its antigen-binding fragment), and the use of a second such antibody or its antigen-binding fragment (or a third or fourth such antibody or its antigen-binding fragment) in the manufacture of a drug for use in combination with a first such antibody.

[0042] In various embodiments, any combination of features or components of the embodiments discussed above or herein may be used, and such combinations are included within the scope of this disclosure. Any particular value discussed above or herein may be combined with other relevant values ​​discussed above or herein to enumerate ranges in which those values ​​represent upper and lower limits, and such ranges are included within the scope of this disclosure.

[0043] Other embodiments will become apparent from a detailed examination of the embodiments for carrying out the invention, which will be described later. [Brief explanation of the drawing]

[0044] [Figure 1A] This diagram illustrates the outline of a study design to evaluate the prophylactic efficacy of anti-SARS-CoV-2 spike glycoprotein antibodies in a rhesus monkey model of SARS-CoV-2 infection (Figure 1A). [Figure 1B] Figure 1B outlines the study design to evaluate the effects of anti-SARS-CoV-2 spike glycoprotein antibody prophylaxis on viral genomic RNA (gRNA) and subgenomic RNA (sgRNA) in nasopharyngeal swabs and bronchoalveolar lavage (BAL) fluids. [Figure 2A] This diagram illustrates the outline of a study design to evaluate the prophylactic and therapeutic efficacy of anti-SARS-CoV-2 spike glycoprotein antibodies in a rhesus monkey model of SARS-CoV-2 infection (Figure 2A). [Figure 2B] Figure 2B illustrates the outline of a study design to evaluate the effects of anti-SARS-CoV-2 spike glycoprotein antibody prophylaxis on viral gRNA and sgRNA in nasopharyngeal and oral swabs. [Figure 2C] Figure 2C outlines the study design to evaluate the effects of anti-SARS-CoV-2 spike glycoprotein antibody treatment on viral gRNA and sgRNA in nasopharyngeal and oral swabs. [Figure 2D]A summary of the study design for evaluating representative histopathological images (Figure 2D) of the lungs of treated and placebo-controlled animals is illustrated. [Figure 3A] Figures 2A-2D illustrate the results of RNA sequence analysis of viral RNA from the studies shown. Figure 3A shows the frequency of all amino acid changes identified in the spike protein across all viral sequences; each dot represents the frequency of the corresponding amino acid change in a particular viral sample, and the samples are grouped based on the treatment regimen: isotype control (placebo), and therapeutic antibody administered before (prevention) or after (treatment) viral inoculation. [Figure 3B] Figures 2A-2D illustrate the results of RNA sequence analysis of viral RNA from the studies shown. Figure 3B shows detailed genomic information regarding 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 are shown as the percentage of the viral population with amino acid changes in the administered virus, or as a range of frequency percentages (minimum to maximum) in the viral populations isolated from placebo, prophylactic, and therapeutic groups. [Figure 4A] This diagram illustrates the outline of a study design to evaluate the therapeutic and prophylactic efficacy of anti-SARS-CoV-2 spike glycoprotein antibodies in a golden Syrian hamster model of SARS-CoV-2 infection (Figure 4A). [Figure 4B] A summary of the study design to evaluate the effects of anti-SARS-CoV-2 spike glycoprotein antibody therapy or prophylaxis on weight loss (Figure 4B) is illustrated. [Figure 4C] A schematic diagram illustrates a study design to evaluate the effects of anti-SARS-CoV-2 spike glycoprotein antibody therapy on gRNA and sgRNA levels in the lungs. [Figure 5] This is a schematic diagram of the research design discussed in Example 2. [Figure 6] The CONSORT diagram illustrating the screening, randomization, and treatment of subjects in the study discussed in Example 2 is shown. [Figure 7]The relationship between baseline serum antibody status and baseline viral load in the placebo group of the study discussed in Example 2 is illustrated. [Figure 8] The time course of viral load in the placebo group, based on baseline serum antibody status in the study discussed in Example 2, is illustrated. [Figure 9] In the study discussed in Example 2, the proportion of patients in the placebo group who had ≥1 COVID-19 related medical intervention visit (MAV) by day 29 is illustrated. [Figure 10A] In the study discussed in Example 2, the daily change in the time-weighted average (TWA) of viral load (log10 copies / mL) from baseline due to REGEN-COV treatment (forest plot) is illustrated. [Figure 10B] In the study discussed in Example 2, the daily change in the time-weighted average (TWA) of viral load (log10 copies / mL) from baseline due to REGEN-COV treatment (forest plot) is illustrated. [Figure 11] In the study discussed in Example 2, the daily change in TWA (total viral load) from baseline in terms of viral load (log10 copies / mL) due to REGEN-COV treatment is illustrated (graph). The change in mean viral load (log10 copies / mL) from baseline at each visit up to day 7 is shown for the entire population (a modified complete analysis set, excluding patients who tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by qualitative reverse transcriptase polymerase chain reaction at baseline) and for groups defined by baseline antibody status and baseline viral load. The bars in Panel C indicate the standard error. The lower limit of detection (dashed line) is 714 copies / mL (2.85 log10 copies / mL). IV: Intravenous; SE: Standard error. [Figure 12] The time to sustained negative RT-qPCR by baseline viral load category in the study discussed in Example 2 is illustrated. [Figure 13]The percentage of patients with high viral load at each hospital visit in the study discussed in Example 2 is illustrated. [Figure 14A] The proportion of patients with Covid-19-related MAV in the study discussed in Example 2 is illustrated. [Figure 14B] The proportion of patients with Covid-19-related MAV in the study discussed in Example 2 is illustrated. [Figure 14C] The proportion of patients with Covid-19-related MAV in the study discussed in Example 2 is illustrated. [Figure 15A] The viral load up to day 29 in patients with and without 1 or more COVID-19-related MAV episodes in the study discussed in Example 2 is illustrated. [Figure 15B] The viral load up to day 29 in patients with and without 1 or more COVID-19-related MAV episodes in the study discussed in Example 2 is illustrated. [Figure 15C] The viral load up to day 29 in patients with and without 1 or more COVID-19-related MAV episodes in the study discussed in Example 2 is illustrated. [Figure 16] Seronegative patients (n=217) had significantly higher viral loads at the time of randomization compared to patients who had already developed antibodies against SARS-CoV-2 (seronegative). [Figure 17] The figure illustrates that among hospitalized COVID-19 patients receiving low-flow oxygen supplementation, serologically positive patients had a lower cumulative incidence of death or mechanical ventilation compared to serologically negative patients. [Figure 18] The clinical outcomes of Cohort 1 based on serostatus and viral load are illustrated. Patients who were seronegative at baseline or had a high viral load at baseline had poorer clinical outcomes. [Figure 19] This diagram illustrates a seamless Phase 1 / 2 / 3 study design for hospitalized patients with COVID-19. [Figure 20]The number of seronegative patients, seropositive patients, or patients with ambiguous results or missing data ("other") in a full analysis set (FAS) or modified full analysis set (mFAS) with a viral load of >10⁶ or >10⁷ is illustrated. [Figure 21] The average viral load is plotted for seronegative patients (circles), seropositive patients (squares), and other patients (ambiguous results or missing data; triangles). TWA (Time Weighted Average) is shown; CI (Confidence Interval) is shown. [Figure 22] The average viral load in patients treated intravenously with placebo (round), 1.2g of mAb10933 + 1.2g of mAb10987 (total 2.4g, square), or 4g of mAb10933 + 4g of mAb10987 (total 8g, triangle) is illustrated. [Figure 23] The graph illustrates the change in mean viral load from baseline in patients treated intravenously with placebo (circles), 1.2 g of mAb10933 + 1.2 g of mAb10987 (total 2.4 g, squares), or 4 g of mAb10933 + 4 g of mAb10987 (total 8 g, triangles). The graph separates patients by viral load: >10⁴ copies / ml, >10⁵ copies / ml, >10⁶ copies / ml, and >10⁷ copies / ml. [Figure 24] The graph illustrates the mean viral load over time in patients treated intravenously with placebo (circles), 1.2 g of mAb10933 + 1.2 g of mAb10987 (total 2.4 g, squares), or 4 g of mAb10933 + 4 g of mAb10987 (total 8 g, triangles). The graph separates patients by baseline viral load: >10⁴ copies / ml, >10⁵ copies / ml, >10⁶ copies / ml, and >10⁷ copies / ml. [Figure 25]The graphs illustrate the mean viral load over time in sero-negative or sero-positive patients treated intravenously with placebo (circles), 1.2 g of mAb10933 + 1.2 g of mAb10987 (total 2.4 g, squares), or 4 g of mAb10933 + 4 g of mAb10987 (total 8 g, triangles). The graphs separate patients by serostatus and clinical trial: 2066 (inpatient study, Example 1) and 2067 (outpatient study, Example 2). [Figure 26] The graphs illustrate the change in mean viral load from baseline in patients treated intravenously with placebo (circles), 1.2 g of mAb10933 + 1.2 g of mAb10987 (total 2.4 g, squares), or 4 g of mAb10933 + 4 g of mAb10987 (total 8 g, triangles). The graphs are segmented by serostatus and clinical trial: 2066 (inpatient study, Example 1) and 2067 (outpatient study, Example 2). [Figure 27] The graph illustrates the change in mean viral load over time in patients treated intravenously with placebo (circle), 1.2 g of mAb10933 + 1.2 g of mAb10987 (total 2.4 g, square), or 4 g of mAb10933 + 4 g of mAb10987 (total 8 g, triangle). The graph separates patients by baseline viral load and clinical trial: 2066 (inpatient study, Example 1) and 2067 (outpatient study, Example 2). [Figure 28] The graphs illustrate the change in mean viral load from baseline in patients treated intravenously with placebo (circles), 1.2 g of mAb10933 + 1.2 g of mAb10987 (total 2.4 g, squares), or 4 g of mAb10933 + 4 g of mAb10987 (total 8 g, triangles). The graphs are separated by baseline viral load and clinical trial: 2066 (inpatient study, Example 1) and 2067 (outpatient study, Example 2). [Figure 29]The neutralization percentage of pseudotyped VSV expressing the B.1.1.7 SARS-CoV-2 variant (also known as the "UK variant") is shown for mAb10933 (REGN10933) alone, mAb10987 (REGN10987) alone, and the combination of mAb10933 + mAb10987 (REGN10933 + REGN10987). The antibodies neutralize the virus both alone and in combination. [Figure 30] The weekly viral loads of individual symptomatic subjects (filled in) and asymptomatic subjects (outlined) in two treatment groups, placebo and mAb10933+mAb10987 (collectively known as REGEN-COV®), are illustrated. As assessed by viral load measurement, infections in the REGEN-COV® group did not last more than one week, while approximately 40% of infections in the placebo group lasted for 3-4 weeks. [Figure 31] A schematic diagram of the Phase 3 trial in non-hospitalized patients treated with REGEN-COV or placebo is shown. [Figure 32] The revised Phase 3 cohort enrollment, which includes doses of 2400 mg and 1200 mg, is illustrated. [Figure 33] The clinical efficacy of REGEN-COV is illustrated, comparing the therapeutic effects in intravenous treatment groups of placebo, 2400 mg, and 1200 mg. Treatment significantly reduced COVID-19-related hospitalizations or all-cause mortality and symptom duration, with similar therapeutic effects at both dose levels (the point estimate for the 2400 mg dose was more reliable due to its larger event size). [Figure 34] Balanced baseline demographics are illustrated for a phase 3 cohort 1mFAS (patients ≥18 years of age with baseline SARS-CoV-2 PCR positivity and a severe COVID-19 risk factor ≥1) of outpatients treated with 8000 mg REGEN-COV, 2400 mg REGEN-COV, 1200 mg REGEN-COV, or placebo (PBO). Phase 3 patients had higher baseline viral loads and higher baseline seronegativity than high-risk patients in phases 1 / 2. [Figure 35] The Kaplan-Meier curves illustrating the time to COVID-19-related hospitalization or all-cause mortality up to day 29 after administration of 1200 mg mAb10933 + 1200 mg mAb10987 (intravenous) in subjects with a severe COVID-19 risk factor of ≥1 are shown. The risk of COVID-19 hospitalization or all-cause mortality was reduced by 71% compared to placebo in the overall modified complete analysis set (mFAS) population. [Figure 36] The Kaplan-Meier curves illustrating the time to COVID-19-related hospitalization or all-cause mortality up to day 29 after administration of 600 mg mAb10933 + 600 mg mAb10987 (intravenous) in subjects with a severe COVID-19 risk factor of ≥1 are shown. The risk of COVID-19 hospitalization or all-cause mortality was reduced by 71% compared to placebo in the overall modified complete analysis set (mFAS) population. [Figure 37] The number of COVID-19-related hospitalizations or all-cause deaths up to day 29 after administration of 1200 mg mAb10933 + 1200 mg mAb10987 (intravenous) or 600 mg mAb10933 + 600 mg mAb10987 (intravenous) in subjects with a severe COVID-19 risk factor of ≥1 is illustrated. The results were consistent between the two treatment groups. [Figure 38] The Kaplan-Meier curves illustrating the time to resolution of COVID-19-matched symptoms among patients with a severe COVID-19 risk factor of ≥1 are shown. HR: Hazard Ratio. The median time to resolution was 14 days in the placebo group and 10 days in each of the 1.2g and 2.4g treatment groups. [Figure 39] This diagram illustrates the time to symptom resolution in outpatients with a severe COVID-19 risk factor of ≥1. Improvement in symptom resolution was consistent between the modified complete analysis set (mFAS) population and the baseline high viral load or sero-negative population. [Figure 40]This figure illustrates serious adverse events (SAEs) and events of special interest (SAEIs) in outpatients in Phase 3 Cohort 1 treated intravenously with 1200 mg of REGEN-COV, 2400 mg of REGEN-COV, 8000 mg of REGEN-COV, or placebo (PBO). Safety across all treatment groups was acceptable, and no serious safety concerns were identified. In particular, SAEs and AESIs occurred more frequently in the placebo group compared to any REGEN-COV treatment group, no safety imbalances were observed between different REGEN-COV dose groups, no safety signals were observed in safety tests (chemistry, hematology), more patients experienced treatment-induced adverse events (TEAEs) with fatal outcomes in the placebo group compared to any REGEN-COV treatment group, and very few patients experienced infusion-related reactions (IRRs), AESIs, and hypersensitivity reactions in the REGEN-COV dose groups. [Figure 41] This figure illustrates serious adverse events (SAEs) occurring in >1 patient in any treatment group in Phase 3 Cohort 1 outpatients treated intravenously with 1200 mg REGEN-COV, 2400 mg REGEN-COV, 8000 mg REGEN-COV, or placebo (PBO). SAEs occurred more frequently in the placebo group compared to any REGEN-COV dose group, and the more frequently reported events were consistent with COVID-19 and related complications, while the lower frequency of events in the REGEN-COV dose groups was consistent with treatment efficacy. [Figure 42] This figure illustrates adverse events of particular interest (AESIs) (e.g., infusion-related reactions and hypersensitivity reactions) occurring in >1 patient in any treatment group in Phase 3 Cohort 1 outpatients treated intravenously with 1200 mg REGEN-COV, 2400 mg REGEN-COV, 8000 mg REGEN-COV, or placebo (PBO). The rates of infusion-related reactions or hypersensitivity reactions were low across all dose groups. [Figure 43]This diagram illustrates the change from baseline in viral load (log10 copies / mL) at day 7 after treatment with mAb10933 and mAb10987 in outpatients with one or more risk factors for severe COVID-19. [Figure 44] This diagram illustrates the change from baseline in viral load (log10 copies / mL) at day 7 after treatment with mAb10933 and mAb10987 in outpatients with one or more risk factors for severe COVID-19. N: number of subjects, SD: standard deviation, D7: day 7, mFAS: modified complete analysis set, PA6: protocol correction 6, modifying the clinical trial protocol by removing the 8g dose and introducing the 1.2g dose. [Figure 45] The demographic and baseline characteristics of seronegative IV patients (seronegative mFAS) are illustrated. The group was well-balanced. [Figure 46] The demographics and baseline characteristics of seronegative subcutaneous patients (seronegative mFAS) are illustrated. The group was well-balanced. [Figure 47] This graph illustrates the least squares mean change from baseline viral load in patients treated with mAb10933 + mAb10987 either intravenously (IV) or subcutaneously (SC) over time. [Figure 48] The changes from baseline viral load in the 2067 (Example 2; outpatient) Phase 1 / 2 and Phase 3 trials, and the 20145 (Example 7; dose-range exploration) trial, among seronegative patients, are illustrated. The changes from baseline viral load were comparable across studies. [Figure 49] The safety data from the clinical trial described in Example 7 are illustrated. All treatment groups were well tolerated, and no safety signals were identified. [Figure 50] Adverse events that occurred during treatment among patients treated subcutaneously in the clinical trial described in Example 7 are illustrated. All doses were well tolerated, and few adverse events occurred during treatment. Of the observed events, none were serious. [Figure 51]A comparison between the clinical trial described in Example 2 ("2067 analysis set") and the clinical trial described in Example 7 ("20145 analysis set") is illustrated. The 2067 data are presented both before and after correction, with the dosage group changed from 2400 mg and 8000 mg to 1200 mg and 2400 mg (original Ph3 and corrected Ph3, respectively). Analysis of the change in viral load (log10 copies / mL) from baseline to day 7 showed similar viral load reductions before and after the correction change and across all doses. [Figure 52] The mean viral loads of patients with hospitalization / death outcomes and those without hospitalization / death outcomes are illustrated. Before PA6, viral loads are shown for patients treated with placebo (PBO), 2.4g of REGEN-COV, or 8.0g of REGEN-COV. From PA6 onward, viral loads are shown for patients treated with PBO, 1.2g of REGEN-COV, or 2.4g of REGEN-COV. [Figure 53] Spaghetti plots of viral loads (placebo, 1.2g REGEN-COV, and 2.4g REGEN-COV) for individual patients with hospitalization / death outcomes and those without hospitalization / death outcomes are shown. [Figure 54] Spaghetti plots of viral loads (placebo, 2.4g REGEN-COV, and 8.0g REGEN-COV) for individual patients with hospitalization / death outcomes and those without hospitalization / death outcomes are shown. [Figure 55] Box plots of baseline and 7-day post-treatment viral load (placebo, 1.2g REGEN-COV, and 2.4g REGEN-COV) for patients with hospitalization / death outcomes and those without hospitalization / death outcomes are shown. [Figure 56] Box plots of baseline and 7-day post-treatment viral loads (placebo, 2.4g REGEN-COV, and 8.0g REGEN-COV) for patients with hospitalization / death outcomes and those without hospitalization / death outcomes are shown. [Figure 57] An outline of the clinical trial described in Example 7 is shown in the diagram. [Figure 58]The changes in viral load at day 7 post-treatment are illustrated in all patients, seronegative patients, and seropositive patients, separated into those with and without COVID-19-related events. Patients with events in the placebo group had higher baseline viral loads and cleared the virus more slowly, while seropositive patients with events also had high baseline viral loads, slower clearance, and may have had an ineffective antibody response. [Figure 59] The hierarchy for hypothesis testing in the Phase 3 prevention trial described in Example 4, and the therapeutic effects of each endpoint, are illustrated. REGEN-COV prevented infection, modified disease progression, and reduced viral load. [Figure 60] The symptomatic infection endpoint in the Phase 3 prevention trial described in Example 4 is illustrated. REGEN-COV significantly reduced symptomatic COVID-19 under all three definitions. [Figure 61] The cumulative incidence of symptomatic infections in the Phase 3 prophylaxis trial described in Example 4 is shown. REGEN-COV prevented the onset of symptomatic infections that began one day after administration. [Figure 62] The weekly incidence of symptomatic infections in the Phase 3 prevention trial described in Example 4 is illustrated. REGEN-COV reduced the risk of symptomatic infections by 81% overall, 72% in week 1, and 93% in weeks 2-4. [Figure 63] The figure illustrates that the number of weeks of symptomatic infection was significantly reduced by REGEN-COV in the Phase 3 prophylaxis trial described in Example 4. [Figure 64] The figure illustrates that the number of weeks of symptomatic infection was significantly reduced by REGEN-COV in the Phase 3 prophylaxis trial described in Example 4. [Figure 65] The figure illustrates that the overall number of weeks of infection was significantly reduced by REGEN-COV in the Phase 3 prevention trial described in Example 4. [Figure 66]The hierarchy of hypothesis testing in the Phase 3 preemptive therapy described in Example 4 is illustrated. REGEN-COV significantly prevented the progression of asymptomatic infection and reduced the viral load. The therapeutic effect intensified after the first three days. [Figure 67] The mean viral load over time in asymptomatic patients in the Phase 3 preemptive therapy trial described in Example 4 (2069) is shown, compared to symptomatic patients in the corrected Phase 3 trial described in Example 2 (2067). Early treatment with REGEN-COV resulted in greater viral load reduction over time. [Figure 68] The indices for a single 1200 mg dose and the mean serum concentrations of mAb10933 and mAb10987 over time in the safety cohort in the Phase 3 preemptive therapy trial described in Example 4 are shown in the figure. [Figure 69] The Phase 3 trial of Example 4 illustrates that REGEN-COV has an acceptable and well-tolerated safety profile without serious or severe safety concerns. [Figure 70] In the Phase 3 trial of Example 4, adverse events that occurred during treatment in ≥2% of any treatment group are illustrated. [Figure 71] This diagram illustrates that serious adverse events are rare in patients treated with REGEN-COV, and that there have been no serious COVID-related adverse events. [Figure 72] This graph illustrates the cumulative incidence of symptomatic infections by study day in a clinical trial evaluating REGEN-COV's ability to prevent symptoms of COVID-19. Subcutaneous administration of REGEN-COV reduced the risk of symptomatic SARS-CoV-2 infection by 81.4%. [Figure 73]This graph illustrates the cumulative incidence of symptomatic infections by study day in a clinical trial evaluating the ability of REGEN-COV to prevent symptoms of COVID-19. Treatment with REGEN-COV 1200 mg subcutaneously (SC) resulted in a 31.5% relative risk reduction in progression from asymptomatic to symptomatic infection during the efficacy evaluation period (29 / 100 [29.0%] vs. 44 / 104 [42.3%] compared to placebo; p=0.0380), with the effect being more pronounced after 3 days post-administration of REGEN-COV (76.4% relative risk reduction). [Figure 74] The mean viral load over time for patients who were PCR-positive and seronegative at baseline in the clinical trial described in Example 7 is shown. [Figure 75] The mean total REGEN-COV concentrations in serum after a single intravenous (IV) and subcutaneous (SC) administration in outpatient PCR-positive patients enrolled in the clinical trial described in Example 7 are shown in the figure. [Figure 76] This diagram illustrates 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 77A illustrates the clinical efficacy of REGEN-COV at a 1200 mg IV dose against hospitalization or all-cause mortality. Treatment significantly reduced hospitalization or all-cause mortality. [Figure 77B] Figure 77B illustrates the clinical efficacy of REGEN-COV at a 2400 mg IV dose against hospitalization or all-cause mortality. Treatment significantly reduced hospitalization or all-cause mortality. [Figure 77C] Figure 77C illustrates the clinical efficacy of REGEN-COV at 1200 mg IV and 2400 mg IV doses in relation to the time to symptom resolution. Treatment reduced the median time to symptom resolution by 4 days. [Figure 78] This diagram illustrates the demographic and baseline medical characteristics of patients assigned to different treatment groups in a clinical trial designed to study REGEN-COV treatment in non-hospitalized patients. [Figure 79]The efficacy of different treatment groups across each of the Phase 3 clinical trial endpoints in non-hospitalized adult patients with COVID-19 is illustrated. [Figure 80] A summary of serious and particularly noteworthy adverse events in patients treated intravenously with 1200 mg of REGEN-COV, 2400 mg of REGEN-COV, 8000 mg of REGEN-COV, or placebo is illustrated. [Figure 81] A schematic diagram of the study design for evaluating treatment with REGEN-COV in non-hospitalized adult patients with COVID-19 is shown. [Figure 82] The time course of viral load in the placebo group, based on baseline serum antibody status, is illustrated. [Figure 83A] Figure 83A illustrates a forest plot showing COVID-19-related hospitalizations or all-cause mortality up to day 29 in non-hospitalized adults with one or more severe COVID-19 risk factors. [Figure 83B] Figure 83B classifies the data according to protocol-defined risk factors. [Figure 83C] Figure 83C classifies the data by combinations of other risk factors. [Figure 84A] Figure 84A illustrates the proportion of patients treated with a single intravenous dose of 1200 mg of REGEN-COV who experienced COVID-19-related hospitalization or all-cause death between days 4 and 29. [Figure 84B] Figure 84B illustrates the proportion of patients treated with a single intravenous dose of 2400 mg of REGEN-COV who experienced COVID-19-related hospitalization or all-cause death between days 4 and 29. [Figure 85] This diagram illustrates the time to symptom resolution in outpatients with one or more severe COVID-19 risk factors who were treated intravenously with 1200 mg of REGEN-COV or 2400 mg of REGEN-COV. [Figure 86]Figure 86A illustrates the viral load over time in outpatients with one or more severe COVID-19 risk factors who were treated intravenously with either 1200 mg of REGEN-COV or 2400 mg of REGEN-COV. Both doses significantly reduced viral load compared to placebo. Figure 86B illustrates the viral load over time in these patients, classified by their baseline serum antibody status (seronegative vs. seronegative). [Figure 86C] Figure 86C illustrates the viral load over time in these patients, categorized by baseline viral load category (>10⁴ copies / mL, >10⁵ copies / mL, >10⁶ copies / mL, and >10⁷ copies / mL). [Figure 87] This diagram illustrates the change from baseline in viral load (log10 copies / mL) at day 7 in outpatients with one or more severe COVID-19 risk factors who were treated intravenously with 1200 mg or 2400 mg of REGEN-COV. [Figure 88] Figure 88A illustrates the viral load over time in outpatients with one or more severe COVID-19 risk factors who were treated intravenously with either 2400 mg of REGEN-COV or 8000 mg of REGEN-COV. Both doses significantly reduced viral load compared to placebo. Figure 88B illustrates the viral load over time in these patients, classified by their baseline serum antibody status (seronegative vs. seronegative). [Figure 88C] Figure 88C illustrates the viral load over time in these patients, categorized by baseline viral load category (>10⁴ copies / mL, >10⁵ copies / mL, >10⁶ copies / mL, and >10⁷ copies / mL). [Figure 89] The sequence of primary and secondary endpoints in the major hierarchical analysis trials is illustrated. [Figure 90] This diagram illustrates the protocol-defined risk factors for severe COVID-19 in a clinical trial evaluating REGEN-COV in non-hospitalized patients. [Figure 91]The demographic and baseline medical characteristics of patients who received 8000 mg of REGEN-COV or placebo are illustrated. [Figure 92] The proportion of patients in the placebo group with at least one COVID-19-related hospitalization or all-cause death, based on baseline viral load categories, is illustrated. [Figure 93] The viral load in the placebo group (with or without hospitalization / death, and baseline serum antibody status) is illustrated. [Figure 94] The percentage of patients with one or more COVID-19-related hospitalizations and / or all-cause deaths is illustrated. [Figure 95] This diagram illustrates the percentage of patients who, after treatment with REGEN-COV, required one or more medical interventions or experienced all-cause mortality. [Figure 96] This diagram illustrates the outcomes of outpatients who were hospitalized during a clinical trial in patients with one or more severe COVID-19 risk factors. [Figure 97] This shows the proportion of patients treated with 1200 mg of REGEN-COV, 2400 mg of REGEN-COV, or placebo who experienced one or more COVID-19-related hospitalizations, emergency room visits, or all-cause deaths. [Figure 98] The proportion of patients treated with 8000 mg of REGEN-COV or placebo who experienced one or more COVID-19-related hospitalizations and / or all-cause deaths is illustrated. [Figure 99] The graph illustrates the proportion of patients treated with 8000 mg of REGEN-COV or placebo who experienced one or more hospital visits requiring COVID-19-related medical intervention or all-cause death. [Figure 100] This diagram illustrates treatment-related adverse events that resulted in death in patients treated with 1200 mg of REGEN-COV, 2400 mg of REGEN-COV, 8000 mg of REGEN-COV, or placebo. [Figure 101]This diagram illustrates a summary of serious and particularly noteworthy adverse events that occurred during treatment in patients treated with 1200 mg of REGEN-COV, 2400 mg of REGEN-COV, 8000 mg of REGEN-COV, or placebo. [Figure 102] This section illustrates adverse events of particular interest in patients treated with 1200 mg REGEN-COV, 2400 mg REGEN-COV, 8000 mg REGEN-COV, or placebo who required medical intervention in a healthcare setting. [Figure 103] The mean pharmacokinetic parameters of serum mAb10933 and mAb10987 in patients treated with 1200 mg of REGEN-COV, 2400 mg of REGEN-COV, 8000 mg of REGEN-COV, or placebo are shown. [Modes for carrying out the invention]

[0045] Before describing the present invention, please understand that the present invention is not limited to such methods and conditions, as the specific methods and experimental conditions described may vary. Also, please understand that the terms used herein are for the purpose of describing only specific embodiments and are not intended to limit the scope of the present invention, as it is limited only by the appended claims.

[0046] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this invention pertains. Where used herein, the term “about” means that, when used in reference to a particular enumerated number, that value may vary by no more than 1% from the enumerated value. For example, where used herein, the expression “about 100” includes 99 and 101 and all values ​​in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0047] Any methods and materials similar to or equivalent to those described herein may be used in carrying out or testing the present invention, but preferred methods and materials will be described below. All patents, applications and non-patent publications referenced herein are incorporated herein by reference in their entirety.

[0048] Methods for preventing and treating SARS-CoV-2 infection and COVID-19 The present invention provides a method for preventing and treating SARS-CoV-2 infection and COVID-19 in subjects requiring such treatment, by administering an antigen-binding molecule that binds to the surface protein of SARS-CoV-2, comprising an anti-SARS-CoV-2 spike glycoprotein antibody or an antigen-binding fragment thereof, as discussed herein. In some cases, subjects are hospitalized COVID-19 patients. In some cases, subjects are outpatients (i.e., day care patients) who have tested 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, subjects are human COVID-19 patients who (a) require low-flow oxygen supplementation, (b) require high-load oxygen therapy but are not receiving mechanical ventilation, or (c) require mechanical ventilation. In some cases, subjects are non-hospitalized symptomatic COVID-19 humans. In some cases, the subjects are uninfected individuals, such as uninfected individuals in groups at high risk of exposure (e.g., healthcare workers or first responders), or uninfected individuals who have been exposed in close contact with an infected person (e.g., a cohabitant or family member with COVID-19). In some cases, the subjects are individuals at high risk of complications from COVID-19 or those who are more likely to be infected with SARS-CoV-2, such as the elderly, immunocompromised individuals, and individuals who often do not respond well to vaccines. In some embodiments, the present invention provides methods for treating, preventing, and reducing the severity or progression of SARS-CoV-2 infection and / or COVID-19.

[0049] The present invention also includes the use of antigen-binding molecules that bind to the surface protein of SARS-CoV-2, including anti-SARS-CoV-2 spike glycoprotein antibodies or antigen-binding fragments thereof, as considered 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. The present invention also includes the use of antigen-binding molecules that bind to the surface protein of SARS-CoV-2, including anti-SARS-CoV-2 spike glycoprotein antibodies or antigen-binding fragments thereof, as considered herein, in the manufacture of agents 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. Where described herein, if a method is considered with reference to a combination of two anti-SARS-CoV-2 spike protein antibodies, such a combination includes the use of a first such antibody or its antigen-binding fragment in the manufacture of a drug for use in combination with a second such antibody or its antigen-binding fragment, and the use of a second such antibody or its antigen-binding fragment in the manufacture of a drug for use in combination with a first such antibody.

[0050] As used herein, a therapeutic or prophylactic agent that “prevents” a disorder or condition (e.g., an anti-SARS-CoV-2 spike glycoprotein antibody) refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in a treated sample compared to an untreated control sample, or delays the onset of the disorder or condition compared to an untreated control sample. As used herein, the term “treats” includes, once established, the recovery or elimination of a condition. In either case, prevention or treatment may be identified in a diagnosis made by a physician or other healthcare provider, and in the intended outcome of the administration of a therapeutic or prophylactic agent.

[0051] Generally, the treatment or prevention of the diseases or conditions described herein is achieved by administering one or more anti-SARS-CoV-2 spike glycoprotein antibodies or their antigen-binding fragments in an effective dose. The effective dose of a drug refers to the amount effective in the dosage and duration required to achieve the desired therapeutic or preventive outcome. The therapeutic effective dose of a drug in this disclosure may vary depending on factors such as the individual's disease state, age, sex, and weight, as well as the drug's ability to induce the desired response in the individual. The preventive effective dose refers to the amount effective in the dosage and duration required to achieve the desired preventive outcome.

[0052] In some embodiments, anti-SARS-CoV-2 spike glycoprotein antibodies or their antigen-binding fragments may be used to treat, prevent, or reduce SARS-CoV-2 infection or the progression of COVID-19. In some cases, anti-SARS-CoV-2 spike glycoprotein antibodies or their antigen-binding fragments block the interaction between the spike protein receptor-binding domain (RBD) and angiotensin-converting enzyme 2 (ACE2), resulting in a reduction in the infectivity of host cells. By blocking viral entry, SARS-CoV-2 RNA replication and corresponding viral shedding in affected tissues are reduced. Therefore, in some embodiments, anti-SARS-CoV-2 spike glycoprotein antibodies or their antigen-binding fragments reduce viral shedding in the upper respiratory tract. In some embodiments, viral shedding is measured in samples collected from the patient's upper respiratory tract 7 to 29 days after the start of administration (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 days after the start of administration). In some cases, the reduction from baseline in SARS-CoV-2 viral shedding is determined by RT-qPCR of nasopharyngeal swab samples, nasal cavity samples, or saliva samples.

[0053] In some cases, anti-SARS-CoV-2 spike glycoprotein antibodies or their antigen-binding fragments 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 (a rating of clinical status from death [1] to non-hospitalization [7]) used to assess the change in clinical status. The use of an ordinal scale incorporating multiple clinical outcomes of interest (e.g., death, mechanical ventilation, etc.) ordered by clinical importance is an appropriate scale for evaluating efficacy in trials of severe and / or critically ill patients with COVID-19. In some cases, administration of anti-SARS-CoV-2 spike glycoprotein antibodies or their antigen-binding fragments improves the clinical status of patients by at least 1 or 2 points. In some cases, administration of anti-SARS-CoV-2 spike glycoprotein antibodies or their antigen-binding fragments leads to a reduction in mortality and / or oxygen therapy use, and / or an increase in the number of days without ventilation in such patients. As discussed above, improvement in clinical status can be assessed using the following ordinal scales: [1] Death; [2] Hospitalization requiring invasive mechanical ventilation or ECMO, [3] Hospitalization requiring non-invasive ventilation or high-flow oxygen devices, [4] Hospitalization requiring oxygen supplementation [5] Hospitalization requiring ongoing medical care (COVID-19 related or not) but not requiring oxygen supplementation, [6] Hospitalizations that do not require oxygen supplementation and no longer require ongoing medical treatment. [7] Do not hospitalize.

[0054] In some cases, after administration of an anti-SARS-CoV-2 spike glycoprotein antibody or its antigen-binding fragment, subjects may experience fewer than five COVID-19-related medical visits, telemedicine visits, hospitalizations, and / or intensive care unit (ICU) admissions. In some cases, fewer than five (e.g., fewer than five, four, three, two, or one) COVID-19-related medical visits, telemedicine visits, hospitalizations, and / or intensive care unit (ICU) admissions may be indicated by subjects within a period of 7–42 (e.g., 21–42 days) after administration of the first dose of the anti-SARS-CoV-2 spike glycoprotein antibody or its antigen-binding fragment. In some embodiments, fewer than five COVID-19-related visits may be indicated by subjects within a period of 29 days after administration of the first dose. In some cases, subjects may experience fewer than four COVID-19-related medical visits, telemedicine visits, hospitalizations, and / or intensive care unit (ICU) admissions. In some cases, eligibility refers to fewer than three visits, telemedicine visits, hospitalizations, and / or intensive care unit (ICU) admissions requiring COVID-19-related medical interventions. In some cases, eligibility refers to fewer than two visits, telemedicine visits, hospitalizations, and / or intensive care unit (ICU) admissions requiring COVID-19-related medical interventions. In some cases, eligibility refers to one or fewer visits, telemedicine visits, hospitalizations, and / or intensive care unit (ICU) admissions requiring COVID-19-related medical interventions.

[0055] In some cases, after administration of an anti-SARS-CoV-2 spike glycoprotein antibody or its antigen-binding fragment, subjects will test negative for SARS-CoV-2 within 2 days to 3 weeks after the first dose of the therapeutic composition. In some cases, a negative result for SARS-CoV-2 testing is determined by RT-qPCR of nasopharyngeal swab samples, nasal cavity samples, or saliva samples.

[0056] In any of the embodiments described above or discussed herein (for example, a combination of prophylactic or therapeutic administration of mAb10933 and mAb10987), the outcome of administration of an anti-SARS-CoV-2 spike glycoprotein antibody or antibody may be any one or more of the following: (a) Time-weighted average viral shedding from baseline (log) as measured by RT-qPCR of nasopharyngeal (NP) swabs. 10 Reduction of copies / mL, (b) Time-weighted average viral shedding from baseline (log) as measured by RT-qPCR of nasal swabs 10 Reduction of copies / mL, (c) Time-weighted average viral shedding from baseline (log) as measured by RT-qPCR of saliva samples. 10 Reduction of copies / mL, (d) Improvement of at least 1 point on a 7-point ordinal scale relative to baseline in clinical condition. (e) Compared to the control group, a reduction in visits requiring COVID-19-related medical intervention (visits requiring COVID-19-related medical intervention are defined as follows: the primary reason for the visit is COVID-19, hospitalization, emergency room (ER) visit, emergency treatment visit, clinic visit, or telemedicine visit), (f) No subsequent positive RT-qPCR compared to the control, reduced time to negative RT-qPCR of NP swab, (g) Reduction in the incidence of hospitalization or the length of hospital stay compared to the control group. (h) Reduction in the incidence of ICU admission or the number of days spent in the ICU compared to the control group. (i) Reduction in the incidence of mechanical ventilation or the duration of mechanical ventilation compared to the control group. (j) Reduction in the duration of COVID-19 symptoms compared to the control, (k) Compared to the control, no subsequent positive RT-qPCR in any tested sample (nasopharyngeal swab, nasal swab, saliva), reduction in time to negative RT-qPCR in all tested samples, (l) Reduction in the incidence of subsequent development of signs or symptoms of SARS-CoV-2 infection (in a strict or broad sense), (m) Time-weighted average reduction of daily viral load (for example, a reduction of 0.4 or more log10 copies / mL by day 7, a reduction of 0.5 or more log10 copies / mL by day 7, or a reduction of 0.6 or more log10 copies / mL by day 7, or a reduction of 0.5 or more log10 copies / mL by day 11, a reduction of 0.6 or more log10 copies / m by day 11, or a reduction of 0.7 or more log10 copies / m by day 11, and (n) Reduction of time-weighted average viral load (log10 copies / mL) from baseline.

[0057] In some embodiments, administration of anti-SARS-CoV-2 spike glycoprotein antibodies may have a greater effect on subjects without a sufficient amount of pre-existing antibodies against SARS-CoV-2 in their blood ("seronegative" subjects) than on subjects with a sufficient amount of pre-existing antibodies against SARS-CoV-2 in their blood ("seronegative" subjects). In the embodiments provided herein, serological status (i.e., seronegative, seronegative, or undetermined) was determined by assessing the presence of serum anti-SARS-CoV-2 antibodies: anti-spike[S1]IgA (Euroimmun IgA test), anti-spike[S1]IgG (Euroimmun IgG test), and anti-nucleocapsid IgG (Abbot IgG test). Study participants were divided for analysis as seronegative (if all available tests were negative), seronegative (if any of the tests were positive), or seronegative (missing or indeterminate result). A test was classified as negative if the antibody level in the sample was below the lower limit of quantification for the test. As described herein, the methods described herein may have differential effects in seronegative subjects compared to equivalent seropositive subjects (e.g., greater reduction in viral load, faster time to symptom relief, fewer hospital visits requiring post-administration medical intervention).

[0058] 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 to the surface protein of SARS-CoV-2. In some embodiments, the antigen-binding molecule is an anti-SARS-CoV-2 spike glycoprotein antibody or an antigen-binding fragment thereof.

[0059] Tables 1 and 2 below show the variable regions, CDRs, and amino acid and nucleotide sequences of the heavy and light chains of exemplary antibodies that bind to the SARS-CoV-2 spike protein. Additional amino acid and nucleotide sequences of the heavy and light chains of exemplary antibodies and antigen-binding fragments that bind to the SARS-CoV-2 spike protein and are useful in the methods described herein are found in their entirety in U.S. Patent No. 10,787,501, which is incorporated herein by reference.

[0060] [Table 1]

[0061] [Table 2]

[0062] In various embodiments, the anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment for use in the methods or uses discussed herein is an antibody or antigen-binding fragment containing any one or more of six CDRs (HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) from the antibodies listed in Table 1. In some cases, the anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment contains a CDR of a heavy chain variable region (HCVR) and a light chain variable region pair containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 2 / 10, 22 / 30, 42 / 50, and 73 / 81. Methods and techniques for identifying CDRs within HCVR amino acid sequences and LCVR amino acid sequences are well known in the art and can be used to identify CDRs within specific HCVR amino acid sequences and / or LCVR amino acid sequences disclosed herein. Exemplary rules that can be used to identify CDR boundaries include, for example, the Kabat definition, the Chothia definition, and the AbM definition. Generally, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. 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 are also available for identifying CDR sequences within antibodies.

[0063] In some embodiments, the anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment comprises an HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 domain, each containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 4-6-8-12-14-16, 24-26-28-32-34-36, 44-46-48-52-34-54, and 75-77-79-83-85-87.

[0064] In some embodiments, the anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment comprises an HCVR / LCVR amino acid sequence pair, which includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 2 / 10, 22 / 30, 42 / 50, and 73 / 81.

[0065] In some embodiments, the anti-SARS-CoV-2 spike glycoprotein antibody comprises a heavy chain (HC) and a light chain (LC) pair containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 18 / 20, 38 / 40, 56 / 58, and 89 / 91.

[0066] In some embodiments, anti-SARS-CoV-2 spike glycoprotein antibodies bind to an epitope within the SARS-CoV-2 spike protein receptor-binding domain (RBD) (amino acids 1-1273 of NCBI acceptance number (MN908947.3), SEQ ID NO: 59). In some cases, the antibody (e.g., mAb10989) binds to residues 467-513 of the RBD (DISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVL) (SEQ ID NO: 60). In some cases, the antibody (e.g., mAb10987) binds to residues 432-452 of the RBD (CVIAWNSNNLDSKVGGNYNYL) (SEQ ID NO: 61). In some cases, the antibody (e.g., mAb10933) binds to residues 467-510 of RBD (DISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRV) (SEQ ID NO: 62).

[0067] In some embodiments, the anti-SARS-CoV-2 spike glycoprotein antibody is mAb10933. In some embodiments, the anti-SARS-CoV-2 spike glycoprotein antibody is mAb10987. In some embodiments, the anti-SARS-CoV-2 spike glycoprotein antibody is mAb10989. In various embodiments, the anti-SARS-CoV-2 spike glycoprotein antibody is an antibody comprising the CDR, HCVR, and LCVR of mAb10933, or the heavy and light chains (e.g., the amino acid sequences shown in Table 1). In various embodiments, the anti-SARS-CoV-2 spike glycoprotein antibody is an antibody comprising the CDR, HCVR, and LCVR, or the heavy and light chains (e.g., the amino acid sequences shown in Table 1) of mAb10987. In various embodiments, the anti-SARS-CoV-2 spike glycoprotein antibody is an antibody comprising the CDR, HCVR, and LCVR of mAb10989, or the heavy and light chains (e.g., the amino acid sequences shown in Table 1). The 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 and nucleic acid sequence provided in Table 1 and Table 2, respectively). Similarly, mAb10987 and REGN10987 are equivalent, mAb10989 and REGN10989 are equivalent, and mAb10985 and REGN10985 are equivalent. Furthermore, mAb10933 may be referred to as casirivimab, and mAb10987 may be referred to as imudevimab. The combination of casirivimab and imdevimab is known as REGEN-COV.

[0068] In some embodiments, the methods and uses considered herein include a composition comprising a first antigen-binding molecule (e.g., an antibody) bound to a first epitope on the SARS-CoV-2 surface protein and a second antigen-binding molecule (e.g., an antibody) bound to a second epitope on the SARS-CoV-2 surface protein, wherein the first and second epitopes are structurally non-overlapping. In some embodiments, the methods and uses considered herein include a combination of two or more anti-SARS-CoV-2 spike glycoprotein antibodies or their antigen-binding fragments. In some cases, the two antibodies or antigen-binding fragments used in the combination bind to structurally non-overlapping epitopes of the RBD. In some embodiments, the combination includes mAb10987 and mAb10933. In some embodiments, the combination includes mAb10987 and mAb10989. In some embodiments, the combination includes mAb10933, mAb10987, and mAb10985. In various embodiments, the combination includes a first anti-SARS-CoV-2 spike glycoprotein antibody which is an antibody containing the CDR, HCVR, and LCVR of mAb10933, or the heavy and light chains (e.g., the amino acid sequence shown in Table 1); a second anti-SARS-CoV-2 spike glycoprotein antibody which is an antibody containing the CDR, HCVR, and LCVR, or the heavy and light chains (e.g., the amino acid sequence shown in Table 1); and optionally a third anti-SARS-CoV-2 spike glycoprotein antibody which is an antibody containing the CDR, HCVR, and LCVR, or the heavy and light chains (e.g., the amino acid sequence shown in Table 1) of mAb10985. In various embodiments, the combination includes a first anti-SARS-CoV-2 spike glycoprotein antibody which is an antibody containing the CDR, HCVR, and LCVR of mAb10989, or the heavy and light chains (e.g., the amino acid sequence shown in Table 1), and a second anti-SARS-CoV-2 spike glycoprotein antibody which is an antibody containing the CDR, HCVR, and LCVR, or the heavy and light chains of mAb10987 (e.g., the amino acid sequence shown in Table 1).In some embodiments, combinations of antigen-binding molecules (antibodies such as mAb10987 and mAb10933, mAb10987 and mAb10989, or mAb10987, mAb10933, and mAb10985) can reduce the frequency of escape variants (e.g., SARS-CoV-2 viruses with one or more mutations in the S protein, for example, to reduce therapeutic efficacy by decreasing antibody binding to the S protein). Escape variants were identified after two passages in cell cultures of recombinant VSV encoding the SARS-CoV-2 spike protein in the presence of mAb10933 (casiribimab) or mAb10987 (imudevimab) individually, but not after two passages in the presence of casiribimab and imudevimab together. This combination of antibodies is also effective against mutant SARS-CoV-2 viruses. For example, the combination of mAb10933 and mAb10987 was evaluated for its ability to neutralize pseudotype VSV expressing the SARS-CoV-2 variant known as B.1.1.7, also called the "UK variant." This variant spreads rapidly and may have different effects from wild-type SARS-CoV-2, including more severe symptoms than wild-type virus, as well as potential resistance to vaccines and / or therapeutics. It is classified in part by the following mutations in the spike protein: deletions of HV69-70, Y144 deletion, N501Y, A570D, P681H, T716I, S982A, and D1118H. Casiribimab and imdevimab, in combination, were shown to effectively neutralize the virus (Figure 29). In fact, casirivimab and imdevimab, individually and together, retained neutralizing activity against pseudoviruses expressing all spike protein substitutions found in the B.1.1.7 strain (UK origin), as well as against pseudoviruses expressing only N501Y found in B.1.1.7 and other circulating strains.Casiribimab and imdevimab together retain neutralizing activity against pseudoviruses expressing all spike protein substitutions, or the individual substitutions K417N, E484K, or N501Y found in the B.1.1351 strain (originating from South Africa), and against K417T+E484K found in the P.1 strain (originating from Brazil). However, casirivimab alone exhibits reduced activity against pseudoviruses expressing K417N or E484K, as shown above, while imdevimab did not. The E484K substitution is also found in the B.1.526 strain (originating from New York).

[0069] [Table 3]

[0070] [Table 4] a We tested a pseudovirus expressing the entire mutant spike protein. The following changes from the wild-type spike protein were observed in the mutant: del69-70, del145, N501Y, A570D, D614G, P681H, T716I, S982A, D1118H. b We tested pseudoviruses expressing the entire mutant spike protein. The following changes from the wild-type spike protein were observed in the mutants: D80Y, D215Y, del241-243, K417N, E484K, N501Y, D614G, A701V. c No change: Sensitivity reduced by more than 2 times. d All isolates from the New York lineage possess the E484K replacement (as of February 2021).

[0071] Certain mutants showed reduced sensitivity to casirivimab alone and included those with the spike protein amino acid substitutions K417E (>182x), K417N (>7x), K417R (>61x), Y453F (>438x), L455F (>80x), E484K (>25x), F486V (>438x), and Q493K (>438x). Mutants showing reduced sensitivity to imudevimab alone included those with the substitutions K444N (>755x), K444Q (>548x), K444T (>1,033x), and V445A (>548x). Casiribimab and imudevimab together showed reduced sensitivity to mutants with the K444T (>6x) and V445A (>5x) substitutions. In a neutralization assay using VSV pseudotypes with 39 different spike protein variants identified in circulating SARS-CoV-2 variants, variants with reduced susceptibility to casirivimab alone included those with the Q409E (4x), G476S (5x), and S494P (5x) substitutions, while variants with reduced susceptibility to imudevimab included the N439K (463x) substitution. Further substitutions that reduced activity against casirivimab alone, as tested in a pseudoviral assay, included E484Q (9x) and Q493E (446x). Together, casirivimab and imudemab 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 including, for example, HV69-70 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 showed only one mutant (G446V) occurring in ≥15% of the allele fraction, which was detected in 3 out of 66 subjects with nucleotide sequencing data at a single time point (two at baseline for subjects from placebo and the 2,400 mg casirivimab and imudevimab groups, and one at day 25 for subjects from the 8,000 mg casirivimab and imudevimab groups). The G446V mutant had a 135-fold reduced sensitivity to imudevimab compared to the wild type in the VSV pseudoparticle neutralization assay, but retained sensitivity to casirivimab alone and to casirivimab and imudevimab together.

[0072] In some embodiments, the methods and uses discussed herein include a composition comprising a first antigen-binding molecule (e.g., an antibody) bound to a first epitope on the surface protein of SARS-CoV-2, and a second antigen-binding molecule (e.g., an antibody) bound to a second epitope on the surface protein of SARS-CoV-2, wherein the first and second antigen-binding molecules can be simultaneously bound to the surface protein of SARS-CoV-2.

[0073] In certain embodiments, one, two, three, four or more antibodies, or their antigen-binding fragments, can be administered in combination (for example, simultaneously or sequentially). Exemplary combinations include mAb10933 and mAb10987, mAb10989 and mAb10987, mAb10933 and mAb10989, mAb10933 and mAb10987 and mAb10985.

[0074] As used herein, "antibody that binds to the SARS-CoV-2 spike protein" or "anti-SARS-CoV-2 spike glycoprotein antibody", or "anti-SARS-CoV-2 spike protein antibody" includes antibodies and antigen-binding fragments thereof that bind to soluble fragments of the SARS-CoV-2 spike protein and can also bind to epitopes within the receptor-binding domain (RBD) of the spike protein. For use in the context of the methods of the present disclosure, other antibodies that can be used alone, or with each other, or in combination with one or more antibodies disclosed herein 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).

[0075] 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 particular antigen (e.g., the SARS-CoV-2 spike protein). The term "antibody" includes immunoglobulin molecules comprising four polypeptide chains interconnected by disulfide bonds, two heavy (H) chains and two light (L) chains, and multimers thereof (e.g., IgM). Each heavy chain includes a heavy-chain variable region (abbreviated herein as HCVR or V H and a heavy-chain constant region. The heavy-chain constant region includes three domains, C H 1, C H 2, and C H 3. Each light chain includes a light-chain variable region (abbreviated herein as LCVR or V L and a light-chain constant region. The light-chain constant region includes one domain (C L 1). The V H region and the V LThe region can be further subdivided into a highly variable region called the Complementarity Determination Region (CDR), which contains more conserved regions called the framework region (FR). H and V L It consists of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments of the present invention, the FRs of the anti-SARS-CoV-2 spike protein antibody (or its antigen-binding moiety) may be identical to the human germline sequence or may be naturally or artificially modified. The amino acid consensus sequence may be defined based on a parallel analysis of two or more CDRs.

[0076] As used herein, the term “antibody” also includes the antigen-binding fragment of a complete antibody molecule. “Antigen-binding portion” of an antibody, “antigen-binding fragment” of an antibody, and similar terms, as used herein, include natural, enzymatically available, synthetic, or genetically engineered polypeptides or glycoproteins that specifically bind to an antigen to form a complex. Antigen-binding fragments of antibodies may originate from complete antibody molecules using any suitable standard technique, such as protein digestion techniques or recombinant genetic engineering techniques, which may involve the manipulation and expression of the DNA-coding antibody variable domain and optionally the constant domain. Such DNA is known and / or readily available, for example, from commercially available sources, DNA libraries (e.g., including phage antibody libraries), or can be synthesized. DNA can be sequenced and manipulated chemically or by molecular biological techniques to, for example, position one or more variable domains and / or constant domains into a suitable configuration, or to introduce codons, create cysteine ​​residues, modify, add, or delete amino acids.

[0077] Non-limiting examples of antigen-binding fragments include (i) Fab fragments, (ii) F(ab')2 fragments, (iii) Fd fragments, (iv) Fv fragments, (v) single-chain Fv(scFv) molecules, (vi) dAb fragments, and (vii) minimal recognition units consisting of amino acid residues that mimic the hypervariable region of an antibody (e.g., isolated complementarity-determining regions (CDRs) such as the CDR3 peptide), or restricted FR3-CDR3-FR4 peptides. Domain-specific antibodies, single-domain antibodies, domain-deletion antibodies, chimeric antibodies, CDR-implanted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and other manipulated molecules such as shark variable IgNAR domains are also included within the expression "antigen-binding fragment" as used herein.

[0078] The antigen-binding fragment of an antibody typically contains at least one variable domain. The variable domain can be of any size or amino acid composition and generally contains at least one CDR adjacent to or in-frame with one or more framework sequences. H Domain is V L In antigen-binding fragments associated with the domain, V H Domain and V L The domains may be positioned relative to each other in any preferred arrangement. For example, the variable region is a dimer, V H -V H , V H -V L , or V L -V L It may contain dimers. Alternatively, the antigen-binding fragment of the antibody may be a monomer V H Domain or V L You may include a domain name.

[0079] In certain embodiments, the antigen-binding fragment of the antibody may include at least one variable domain covalently bound to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that may be found within the antigen-binding fragment of the antibody of the present invention include (i)V H -C H 1. (ii)V H -C H 2, (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 -C H 1-C H 2. (xii)V L -C H 1-C H 2-C H 3. (xiii)V L -C H 2-C H 3, and (xiv)V L -C LThese include any of the exemplary configurations listed above for the variable domain and the constant domain, in which the variable domain and the constant domain may be directly linked to each other or linked by a complete or partial hinge region or linker region. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that result in flexible or semi-flexible linkage between adjacent variable domains and / or constant domains in a single polypeptide molecule. Furthermore, the antigen-binding fragment of the antibody of the present invention may be linked to each other and / or one or more monomers V H Or V L In non-covalent bonds with the domain (e.g., via disulfide bonds), the domain may contain a homodimer or heterodimer (or other polymer) among the variable domain configurations and constant domain configurations listed above.

[0080] Similar to complete antibody molecules, antibody-binding fragments can be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies typically comprise at least two distinct variable domains, each capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody form, including the exemplary bispecific antibody forms disclosed herein, can be adapted for use in association with the antibody antigen-binding fragments of the present invention using conventional techniques available in the art.

[0081] In certain embodiments of the present invention, the anti-SARS-CoV-2 spike protein antibody of the present invention is a human antibody. As used in the present invention, 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 present invention may include, for example, amino acid residues in the CDR, particularly CDR3, that are not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-directed mutagenesis in vitro or by somatic mutation in vivo). However, as used herein, the term “human antibody” is not intended to include antibodies in which a CDR sequence derived from the germline of another mammalian species (e.g., mouse) has been transplanted into a human framework sequence.

[0082] In some embodiments, the antibodies of the present invention may be recombinant human antibodies. The term "recombinant human antibody," as used herein, is intended to include all human antibodies prepared, expressed, produced, or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into host cells (as described later), antibodies isolated from recombinant combinatorial human antibody libraries (as described later), antibodies isolated from animals transgenic to human immunoglobulin genes (e.g., mice) (e.g., Taylor et al., Nucl Acids Res 20:6287-6295 (1992)), or antibodies prepared, expressed, produced, or isolated by any other means involving splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or in vivo somatic mutagenesis when animals transgenic to human Ig sequences are used), and therefore the V of the recombinant antibody H and V L The amino acid sequence of the region is human germline V H and V LThese sequences are derived from and related to other sequences, but they are sequences that cannot naturally exist within the human antibody germline repertoire in vivo.

[0083] Human antibodies can exist in two forms related to hinge heterogeneity. In the first form, the immunoglobulin molecule contains a stable quadruple-chain construct of approximately 150-160 kDa, where the dimers are held together by interchain heavy-chain disulfide bonds. In the second form, the dimers are not linked by interchain disulfide bonds, and a molecule of approximately 75-80 kDa is formed, consisting of covalently bonded light and heavy chains (half-antibodies). These forms are considered extremely difficult to separate, even after affinity purification.

[0084] The frequency of occurrence of the second form in various intact IgG isotypes is due to, but not limited to, structural differences related to the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the occurrence of the second form to the level typically observed using the human IgG1 hinge (Angal et al. Molecular Immunology 30:105 1993). This invention relates to the hinge region, C H 2 regions, or C H This includes antibodies having one or more mutations in three regions, which may be desirable, for example, to improve the yield of a desired antibody morphology during production.

[0085] The antibodies of the present invention may be isolated antibodies. “Isolated antibodies,” as used herein, mean antibodies identified, isolated and / or recovered from at least one component of their natural environment. For example, antibodies isolated or removed from at least one component of an organism, or from tissues or cells in which antibodies are naturally present or naturally produced, are “isolated antibodies” for the purposes of the present invention. Isolated antibodies also include antibodies in situ within recombinant cells. Isolated antibodies are antibodies subjected to at least one purification or isolation step. According to certain embodiments, isolated antibodies may substantially contain no other cellular material and / or chemical substances.

[0086] The present invention comprises neutralizing and / or blocking an anti-SARS-CoV-2 spike protein antibody. As used herein, “neutralizing” or “blocking” antibody is intended to mean an antibody that inhibits the ability of SARS-CoV-S to bind to a receptor such as ACE2, which inhibits the activity of the SARS-CoV-2 spike protein to any detectable extent, for example, by being cleaved by a protease such as TMPRSS2, or mediating viral entry into or replication in host cells.

[0087] The anti-SARS-CoV-2 spike protein antibodies disclosed herein may contain one or more amino acid substitutions, insertions, and / or deletions in the framework and / or CDR region of the heavy and light chain variable domains compared to the corresponding germline sequence from which the antibody is derived. Such mutations can be readily identified by comparing the amino acid sequences disclosed herein with germline sequences available, for example, from public antibody sequence databases. The present invention comprises antibodies and antigen-binding fragments derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids in one or more framework regions and / or CDR regions are mutated to corresponding residues in the germline sequence from which the antibody is derived, or to corresponding residues in another human germline sequence, or to conserved amino acid substitutions of corresponding germline residues (such sequence changes are collectively referred to herein as “germline mutations”). Those skilled in the art can readily produce many antibodies and antibody-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, V H and / or V LAll framework and / or CDR residues within the domain are mutated back to residues found in the original germline sequence from which the antibody originated. In other embodiments, only specific residues are mutated back to the original germline sequence, for example, the mutated residue is found in the first eight amino acids of FR1 or in the last eight amino acids of FR4, or the mutated residue is found only in CDR1, CDR2, or CDR3. In other embodiments, one or more of the framework and / or CDR residues are mutated to corresponding residues in a different germline sequence (i.e., a germline sequence different from the germline sequence from which the antibody originally originated). Furthermore, the antibody of the present invention may contain any combination of two or more germline mutations within the framework and / or CDR region, for example, certain individual residues are mutated to corresponding residues in a particular germline sequence, while other specific residues different from the original germline sequence are maintained or mutated to corresponding residues in a different germline sequence. Once obtained, antibodies and antibody-conjugated fragments containing one or more germline mutations can be easily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, improved or enhanced (in some cases) biological properties of antagonists or agonists, or decreased immunogenicity. Antibodies and antibody-conjugated fragments obtained by this general method are included within the scope of the present invention.

[0088] The present invention also includes anti-SARS-CoV-2 spike protein antibodies comprising a variant of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein having one or more conservative substitutions. For example, the present invention includes anti-SARS-CoV-2 spike protein antibodies comprising an HCVR, LCVR, and / or CDR amino acid sequence having a conservative amino acid substitution associated with any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein, such as 10 or fewer, 8 or fewer, 6 or fewer, or 4 or fewer.

[0089] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule, known as a paratope. A single antigen may have two or more epitopes. Therefore, different antibodies may bind to different regions on an antigen and have different biological effects. Epitopes can be conformational or linear. Conformational epitopes are produced by spatially juxtaposed amino acids from different segments of a linear polypeptide chain. Linear epitopes are produced by adjacent amino acid residues in a polypeptide chain. In certain circumstances, epitopes may include saccharide, phosphoryl, or sulfonyl groups on an antigen.

[0090] The terms “substantial identity” or “substantially identical,” when referring to a nucleic acid or fragment thereof, indicate that, when optimally aligned with appropriate nucleotide insertions or deletions with another nucleic acid (or its complementary strand), it has at least about 95%, more preferably at least about 96%, 97%, 98%, or 99% nucleotide sequence identity as measured by any well-known algorithm of sequence identity, such as FASTA, BLAST, or Gap, as discussed below. A nucleic acid molecule having substantial identity with a reference nucleic acid molecule may, in certain cases, encode a polypeptide having the same or substantially similar amino acid sequence as the polypeptide encoded by the reference nucleic acid molecule.

[0091] When applied to polypeptides, the term “substantial similarity” or “substantially identical” means that two peptide sequences share at least 95% sequence identity, and more preferably at least 98% or 99%, when optimally aligned using predefined gap weights by programmed GAP or BESTFIT, etc. Preferably, the non-identical residue positions differ in their conserved amino acid substitutions. A “conservative amino acid substitution” is one in which an amino acid residue is replaced by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). Generally, conservative amino acid substitutions do not substantially alter the functional properties of the protein. If the conservative substitutions of two or more amino acid sequences are different from each other, the sequence identity percentage or degree of similarity can be adjusted upward to compensate for the conservative nature of the substitutions. Means for making this adjustment are well known to those skilled in the art. See, for example, Pearson, WR, Methods Mol Biol 24:307-331 (1994), incorporated herein by reference. Examples of amino acids having side chains with similar chemical properties include: (1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; (2) aliphatic hydroxyl side chains: serine and threonine; (3) amide-containing side chains: asparagine and glutamine; (4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; (5) basic side chains: lysine, arginine, and histidine; (6) acidic side chains: aspartic acid and glutamic acid; and (7) sulfur-containing side chains: cysteine ​​and methionine. Preferred conserved amino acid substituents are valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamic acid-aspartic acid, and asparagine-glutamine. Alternatively, a conservative permutation 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 herein by reference. A "moderately conservative" permutation is any change that has a non-negative value in the PAM250 log-likelihood matrix.

[0092] Sequence similarity to polypeptides, also known as sequence identity, is typically measured using sequence analysis software. Protein analysis software matches similar sequences using similarity measurements assigned to various substitutions, deletions, and other modifications, including conserved amino acid substitutions. For example, GCG software includes programs such as Gap and Bestfit, which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species, or between wild-type proteins and their mutant proteins. See, for example, GCG version 6.1. Polypeptide sequences can also be compared using FASTA, a program in GCG version 6.1 with default or recommended parameters. FASTA (e.g., FASTA2 and FASTA3) provides the best overlap region alignment and sequence identity percentage between the query sequence and the search sequence (see, for example, Pearson, WR, Methods Mol Biol 132:185-219 (2000), incorporated herein by reference). Another preferred algorithm for comparing the sequences of the present invention with a database containing numerous sequences from different biological origins is the computer program BLAST, particularly BLASTP or TBLASTN, which uses default parameters. See, for example, Altschul et al., J Mol Biol 215:403-410 (1990) and Altschul et al., Nucleic Acids Res 25:3389-402 (1997), which are incorporated herein by reference, respectively.

[0093] specific binding When used herein, terms such as "specifically bind" refer to an antigen-specific binding protein or antigen-specific binding domain having a dissociation constant (K) of 50 nM or less. D) is characterized by forming a complex with a specific antigen that does not bind to other unrelated antigens under normal test conditions. An "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 and surface plasmon resonance. For example, an antigen-specific binding protein or antigen-specific binding domain used in the context of the present invention, when measured by a surface plasmon resonance assay, has a K content of 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. D The molecule contains a specific antigen (for example, SARS-CoV-2 spike protein, SARS-CoV-2 spike protein RBD, or a specific epitope of SARS-CoV-2 spike protein RBD) or a part thereof.

[0094] As used herein, the term "surface plasmon resonance" refers to an optical phenomenon that enables real-time analysis of interactions by detecting changes in protein concentration within a biosensor matrix, for example, using the BIAcore® system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ).

[0095] "K D When used herein, the term "K" refers to the equilibrium dissociation constant of a particular protein-protein interaction (e.g., antibody-antigen interaction). Unless otherwise indicated, the K disclosed herein refers to the equilibrium dissociation constant of a particular protein-protein interaction. D The value was determined by a surface plasmon resonance assay at 25°C. D It refers to a value.

[0096] Antibodies containing heavy chain constant region mutants According to a particular embodiment of the present invention, an anti-SARS-CoV-2 spike protein antibody is provided, for example, comprising an Fc domain containing one or more mutations that enhance or decrease antibody binding to the FcRn receptor at acidic pH compared to neutral pH. For example, the present invention provides an antibody comprising the Fc domain C H 2 or C H The antibody contains an anti-SARS-CoV-2 spike protein antibody with mutations in three regions, which increase the affinity of the Fc domain to FcRn in an acidic environment (e.g., in endosomes with a pH in the range of approximately 5.5 to 6.0). Such mutations may result in an increased serum half-life of the antibody when administered to animals. Non-restrictive examples of such Fc modifications include, for example, modifications at positions 250 (e.g., E or Q), 250 and 428 (e.g., L or F), 252 (e.g., L / Y / F / W or T), 254 (e.g., S or T), and 256 (e.g., S / R / Q / E / D or T), or modifications at positions 428 and / or 433 (e.g., H / L / R / S / P / Q or K), and / or 434 (e.g., A, W, H, F, or Y [N434A, N434W, N434H, N434F, or N434Y]), or 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 / or 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 (e.g., 252Y, 254T, and 256E) modifications, 250Q and 428L modifications (e.g., T250Q and M428L), and 307 and / or 308 modifications (e.g., 308F or 308P). In yet another embodiment, the modifications include 265A (e.g., D265A) and / or 297A (e.g., N297A) modifications.

[0097] For example, the present invention includes 250Q and 248L (e.g., T250Q and M248L), 252Y, 254T, and 256E (e.g., M252Y, S254T, and T256E), 428L and 434S (e.g., M428L and N434S), 257I and 311I (e.g., P257I and Q311I), and 257I and 434H (e.g., P257I and N434H). The present invention comprises an anti-SARS-CoV-2 spike protein antibody comprising an Fc domain containing one or more pairs or groups of mutations selected from the group consisting of 376V and 434H (e.g., D376V and N434H), 307A, 380A, and 434A (e.g., T307A, E380A, and N434A), and 433K and 434F (e.g., H433K and N434F). All possible combinations of the aforementioned Fc domain mutations and other mutations within the antibody variable domain disclosed herein are considered within the scope of the present invention.

[0098] In various embodiments, anti-SARS-CoV-2 spike protein antibodies include a heavy chain constant region that combines sequences derived from two or more immunoglobulin isotypes. For example, the chimeric heavy chain constant region may be human IgG1, human IgG2, or human IgG4 C. H C originating from 2 regions H 2. Part or all of the sequence, and C derived from human IgG1, human IgG2, or human IgG4. H 3. The chimeric heavy chain constant region may include part or all of the sequence. The chimeric heavy chain constant region may also include a chimeric hinge region. For example, the chimeric hinge may include an "upper hinge" sequence derived from the human IgG1 hinge region, human IgG2 hinge region, or human IgG4 hinge region, combined with a "lower hinge" sequence derived from the human IgG1 hinge region, human IgG2 hinge region, or human IgG4 hinge region. A specific example of a chimeric heavy chain constant region that may be included in any of the antibodies described herein is, from the N-terminus to the C-terminus, [IgG4 C H It includes [1]-[IgG4 upper hinge]-[IgG2 lower hinge]-[IgG4 CH2]-[IgG4 CH3]. Another example of a chimeric heavy chain constant region that may be contained in any of the antibodies described herein is [IgG1 C] from the N-terminus to the C-terminus.H The structure includes [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 present invention are described in International Publication No. 2014 / 121087 (8550-WO). Chimeric heavy chain constant regions having these common structural configurations and their variants may have modified Fc receptor binding, which affects Fc effector function.

[0099] In various embodiments, the anti-SARS-CoV-2 spike protein antibody comprises a heavy chain constant region including a hinge domain, where 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, and the positions are numbered by EU numbering. Optionally, the heavy chain constant region comprises a hinge domain, a CH2 domain, and a CH3 domain from the N-terminus to the C-terminus. Optionally, the heavy chain constant region comprises a CH1 domain, a hinge domain, a CH2 domain, and a CH3 domain from the N-terminus to the C-terminus. Optionally, if present, the CH1 region, if present, the remainder of the hinge region, the CH2 region, and the CH3 region are of the same human isotype. Optionally, if present, the CH1 region, if present, the remainder of the hinge region, the CH2 region, and the CH3 region are human IgG1. Optionally, if present, the CH1 region, the remainder of the hinge region, the CH2 region, and the CH3 region are human IgG2. Optionally, if present, the CH1 region, the remainder of the hinge region, 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 can be included in any of the antibodies of the present invention are described in International Publication No. 2016 / 161010 (10140WO01).

[0100] Epitope mapping and related techniques The present invention includes an anti-SARS-CoV-2 spike protein antibody that interacts with one or more amino acids found within the SARS-CoV-2 spike protein (e.g., within the spike protein RBD). The epitope to which the antibody binds may consist of a single continuous sequence of three or more amino acids located within the spike protein RBD (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more). Alternatively, the epitope may consist of a plurality of discontinuous amino acids (or amino acid sequences) located within the spike protein RBD.

[0101] Various techniques known to those skilled 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, the routine cross-blocking assay described in Antibodies, Harlow and Lane (Cold Spring Harbor Press, Cold Spring Harb., NY), alanine scanning mutation 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 employed (Tomer, Protein Science 9:487-496 (2000)). Another method that can be used to identify the amino acids within the polypeptide with which the antibody interacts is hydrogen / deuterium exchange detected by mass spectrometry. Generally speaking, hydrogen / deuterium exchange methods involve deuterizing the protein of interest and then conjugating the antibody to the deuterium-labeled protein. Next, the protein / antibody complex is transferred to water to induce hydrogen-deuterium exchange at all residues except those protected by the antibody (which remain deuterium-labeled). After antibody dissociation, the target protein is subjected to protease cleavage and mass spectrometry to identify the deuterium-labeled residues corresponding to the specific amino acids with which the antibody interacts. See, for example, Ehring, Analytical Biochemistry 267(2):252-259 (1999) and Engen and Smith, Anal. Chem. 73:256A-265A (2001).

[0102] The present invention further comprises an anti-SARS-CoV-2 spike protein antibody that binds to the same epitope as any of the specific exemplary antibodies described herein (e.g., mAb10933, mAb10987, or mAb10989). Similarly, the present invention also comprises an anti-SARS-CoV-2 spike protein antibody that competes with any of the specific exemplary antibodies described herein (e.g., mAb10933, mAb10987, or mAb10989) for binding to the SARS-CoV-2 spike protein.

[0103] By using methods readily known in the art and commonly illustrated herein, it can be easily determined whether an antibody binds to the same epitope as a reference anti-SARS-CoV-2 spike protein antibody, or whether it competes with the reference anti-SARS-CoV-2 spike protein antibody 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 considered herein, the reference antibody is conjugated to the SARS-CoV-2 spike protein. Next, the ability of the test antibody to bind to the SARS-CoV-2 spike protein is evaluated. If the test antibody can bind to the SARS-CoV-2 spike protein after saturated binding with the reference anti-SARS-CoV-2 spike protein antibody, it can be concluded that the test antibody binds to a different epitope than the reference anti-SARS-CoV-2 spike protein antibody. On the other hand, if the test antibody is unable to bind to the SARS-CoV-2 spike protein after saturated binding with the reference anti-SARS-CoV-2 spike protein antibody, the test antibody may bind to the same epitope as the one bound by the reference anti-SARS-CoV-2 spike protein antibody discussed herein. Further conventional experiments (e.g., peptide mutation and binding analysis) can then be performed to determine whether the observed deletion of the test antibody's binding is indeed due to binding to the same epitope as the reference antibody, or whether steric barrier (or another phenomenon) is the cause of the observed deletion. These 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 a particular embodiment of the present invention, for example, if one antibody in 1, 5, 10, 20, or 100-fold excess inhibits the binding of the other antibody by at least 50%, but preferably 75%, 90%, and even 99%, as measured by a competitive binding assay, then the two antibodies bind to the same (or overlapping) epitopes (see, for example, Junghans et al., Cancer Res. 50:1495-1502 (1990)).Alternatively, if essentially all amino acid mutations in an antigen that reduce or eliminate the binding of one antibody also reduce or eliminate the binding of the other antibody, then the two antibodies are considered to bind to the same epitope. If only a subset of amino acid mutations that reduce or eliminate the binding of one antibody reduces or eliminates the binding of the other antibody, then the two antibodies are considered to have a “duplicate epitope.”

[0104] Preparation of human antibodies Methods for producing monoclonal antibodies, including fully human monoclonal antibodies, are known in the art. Any such known method may be used in the context of the present invention to produce human antibodies that specifically bind to the SARS-CoV-2 spike protein.

[0105] To generate fully human monoclonal antibodies, high-affinity chimeric antibodies against the SARS-CoV-2 spike protein, possessing a human variable region and a mouse constant region, are first isolated using, for example, VELOCIMMUNE™ technology or any other known method. The antibodies are then characterized and selected for desirable features, including affinity, selectivity, and epitopes. If necessary, the mouse constant region is replaced with a desired human constant region, e.g., wild-type or modified IgG1 or IgG4, to generate fully human anti-SARS-CoV-2 spike protein antibodies. The selected constant region may vary depending on the specific application, but high-affinity antigen-binding and target-specific features reside in the variable region. In certain cases, fully human anti-SARS-CoV-2 spike protein antibodies are isolated directly from antigen-positive B cells.

[0106] biological equivalent The anti-SARS-CoV-2 spike protein antibodies and antibody fragments of the present invention include proteins having amino acid sequences that are different from those of the antibodies described but retain the ability to bind to the SARS-CoV-2 spike protein. Such mutant antibodies and antibody fragments include the addition, deletion, or substitution of one or more amino acids compared to the parent sequence, but exhibit biological activity that is essentially equivalent to the biological activity of the described antibody. Similarly, the anti-SARS-CoV-2 spike protein antibody-coding DNA sequences of the present invention include sequences encoding anti-SARS-CoV-2 spike protein antibodies or antibody fragments that are essentially biologically equivalent to the anti-SARS-CoV-2 spike protein antibodies or antibody fragments of the present invention, but include the addition, deletion, or substitution of one or more nucleotides compared to the disclosed sequence.

[0107] For example, two antibodies are considered bioequivalent if, when administered at the same molar dose under similar experimental conditions, whether as a single dose or multiple doses, they do not show significant differences in absorption rate and degree, and are therefore considered pharmaceutical equivalents or substitutes. Some antibodies are equivalent in their absorption rate but not in their absorption rate, and if such a difference in absorption rate is intentional and reflected in the labeling, they may be considered bioequivalent. In such cases, they are considered equivalents or substitutes and are not essential, for example, for achieving effective drug concentrations in the body for long-term use, and are not medically significant for the particular drug product being studied.

[0108] In one embodiment, two antibodies are bioequivalent if there is no clinically significant difference in their safety, purity, and potency.

[0109] In one embodiment, two antibodies are bioequivalent if a patient can switch between a reference product and a bioproduct once or more without an expected increase in the risk of adverse effects, including clinically significant changes in immunogenicity or attenuation of efficacy, compared to continuous therapy without such switching.

[0110] In one embodiment, two antibodies are biologically equivalent if they both act by a common mechanism of action for the conditions of use, to the extent that such a mechanism is known.

[0111] Bioequivalence can be demonstrated by in vivo and in vitro methods. Measures of bioequivalence include, for example, (a) in vivo studies in humans or other mammals in which the concentration of an antibody or its metabolite is measured as a function of time in blood, plasma, serum, or other biological fluids; (b) reasonably predictive in vitro studies that correlate with human in vivo bioavailability data; (c) in vivo studies in humans or other mammals in which the appropriate acute pharmacological effect of an antibody (or its target) is measured as a function of time; and (d) well-controlled clinical trials to establish the safety, efficacy, or bioavailability or bioequivalence of an antibody.

[0112] Biologically equivalent mutants of the anti-SARS-CoV-2 spike protein antibody of the present invention can be constructed, for example, by causing various substitutions of residues or sequences, or by deleting terminal or internal residues or sequences that are not required for biological activity. For example, cysteine ​​residues that are not essential for biological activity can be deleted or substituted with other amino acids to prevent the formation of unnecessary or inaccurate intramolecular disulfide crosslinks during regeneration. In other contexts, biologically equivalent antibodies may include anti-SARS-CoV-2 spike protein antibody mutants that include amino acid changes that modify the glycosylation characteristics of the antibody, such as mutations that eliminate or remove glycosylation.

[0113] In some embodiments, the antibodies disclosed herein lack fucose in their constant region glycosylation. Methods for measuring fucose in antibody compositions are described in the Art, for example, in U.S. Patent No. 8,409,838 (Regeneron Pharmaceuticals), incorporated herein by reference. In some embodiments, fucose is undetectable in compositions comprising a population of antibody molecules. In some embodiments, fucose-lacking antibodies have enhanced ADCC activity.

[0114] In some embodiments, fucose-deficient antibodies can be produced using cell lines that lack their ability to fucosylate proteins, i.e., have reduced or eliminated ability to fucosylate proteins. Glycan fucosylation requires the synthesis of GDP-fucose via either a de novo or salvage pathway, both of which involve the sequential functioning of several enzymes that lead to the addition of a fucose molecule to the first N-acetylglucosamine (GlcNAc) moiety at the reducing end of the glycan. The two main enzymes in the de novo pathway involved in GDP-fucose production are GDP-D-mannose-4,6-dehydratase (GMD) and GDP-keto-6-deoxymannose-3,5-epimerase,4-reductase (FX). In the absence of fucose, these two de novo pathway enzymes (GMD and FX) convert mannose and / or glucose to GDP-fucose, which is then transported to the Golgi complex, where nine fucosyltransferases (FUT1-9) act in coordination with the fucosylation of the first GlcNAc molecule of the glycan. However, in the presence of fucose, salvage pathway enzymes, fucose kinases, and GDP-fucose pyrophosphorylas convert fucose to GDP-fucose.

[0115] Cell lines lacking their ability to fucosylate proteins have been described in the art. In some embodiments, the cell lines lacking their ability to fucosylate proteins are mammalian cell lines (e.g., CHO cell lines, e.g., CHO K1, DXB-11 CHO, Veggie-CHO) that include mutations or gene modifications in one or more of the endogenous FUT1-9 genes resulting in the absence of one or more functional fucosyltransferases. In some embodiments, the mammalian cell lines include mutations in the endogenous FUT8 gene (e.g., FUT8 knockout cell lines in which the FUT8 gene is disrupted, resulting in the absence of functional α1,6-fucosyltransferase in the cell line, as described in U.S. Patent No. 7,214,775 (Kyowa Hakko Kogyo Co., Ltd.) and U.S. Patent No. 7,737,725 (Kyowa Hakko Kirin Co., Ltd.) (incorporated herein by reference)). In some embodiments, the mammalian cell line includes a mutation or gene modification in the endogenous GMD gene that results in a lack of functional GMD in the cell line (e.g., a GMD knockout cell line in which the GMD gene is disrupted, as described in U.S. Patent No. 7,737,725 (Kyowa Hakko Kirin Co., Ltd) (incorporated herein by reference)). In some embodiments, the mammalian cell line includes a mutation or gene modification in the endogenous Fx gene that results 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 is disrupted (e.g., see U.S. Patent No. 7,737,725 (Kyowa Hakko Kirin Co., Ltd) (incorporated herein by reference)). In some embodiments, the mammalian cell line includes a mutation in the endogenous Fx mutation that confers a temperature-sensitive phenotype (e.g., as described in U.S. Patent No. 8,409,838 (Regeneron Pharmaceuticals) (incorporated herein by reference).In some embodiments, the mammalian cell lines lacking the ability to fucosylate proteins are cell lines selected based on their resistance to certain lectins, such as Lens culinaris lectin. See, for example, U.S. Patent No. 8,409,838 (Regeneron Pharmaceuticals), incorporated herein by reference.

[0116] Therapeutic formulations and administration The anti-SARS-CoV-2 spike protein antibody or antigen-binding fragment used in the methods and uses of the present invention may be formulated for administration in a pharmaceutical composition using one or more pharmaceutically acceptable carriers, excipients, or diluents. The pharmaceutical composition is formulated with a suitable carrier, excipient, and other agents that provide improved mobility, delivery, resistance, etc. Many suitable formulations can be found in the prescription collection known to all pharmacists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids (cationic or anionic) containing vesicles (LIPOFECTIN®, Life Technologies, Carlsbad, CA, etc.), DNA complexes, anhydrous absorbent pastes, oil-in-water emulsions and water-in-oil emulsions, emulsion carbowaxes (polyethylene glycol of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowaxes. See also Powell et al. "Compendium of excipients for parenteral formulations," PDA, J Pharm Sci Technol 52:238-311 (1998).

[0117] 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. A combination that can be found in an antibody cocktail called REGN-COV2 or REGEN-COV, mAb10933 and mAb10987 are produced by recombinant DNA technology in Chinese hamster ovary (CHO) cell suspension culture and may have molecular weights of approximately 145.23 kDa and 144.14 kDa, respectively. The antibodies described herein (e.g., mAb10933 and mAb10987) may be individually or co-formulated. For example, co-formulated compositions can be used to simplify administration (e.g., intravenously or subcutaneously), while individual formulations offer greater flexibility in administration. In certain embodiments, the two antibodies in a composition referred to as REGEN-COV (mAb10933 and mAb10987) may be co-formulated, or the two antibodies may be formulated individually and combined before administration.

[0118] In some embodiments, mAb10933 and mAb10987 injections are sterile, preservative-free, clear to slightly milky white, colorless to pale yellow solutions with a pH of 6.0. In some embodiments, each of mAb10933 and mAb10987 is 120 mg / mL Antibody, 10 mM histidine, 8% (w / v) sucrose, and 0.1% (w / v) polysorbate 80, It can be formulated at pH 6.0. Two intensities are available for each antibody: 300 mg in 2.5 mL, and 1332 mg in 11.1 mL. In some embodiments, mAb10933 and mAb10987 are available as vials containing 300 mg of antibody (e.g., in 2.5 mL of solution) or 1332 mg of antibody (e.g., in 11.1 mL of solution), respectively. Exemplary contents of each vial are shown below. 300mg vial ●mAb10933: Each 2.5 mL solution contains 300 mg of mAb10933, L-histidine (1.9 mg), L-histidine monohydrochloride monohydrate (2.7 mg), polysorbate 80 (2.5 mg), sucrose (200 mg), and sterile water for injection, USP. The pH is 6.0. ●mAb10987: Each 2.5 mL solution contains 300 mg of mAb10987, L-histidine (1.9 mg), L-histidine monohydrochloride monohydrate (2.7 mg), polysorbate 80 (2.5 mg), sucrose (200 mg), and water for injection, USP. The pH is 6.0. 1332mg vial ●mAb10933: Each 11.1 mL solution contains 1332 mg of mAb10933, L-histidine (8.3 mg), L-histidine monohydrochloride monohydrate (12.1 mg), polysorbate 80 (11.1 mg), sucrose (888 mg), and water for injection, USP. The pH is 6.0. ●mAb10987: Each 11.1 mL solution contains 1332 mg of mAb10987, L-histidine (8.3 mg), L-histidine monohydrochloride monohydrate (12.1 mg), polysorbate 80 (11.1 mg), sucrose (888 mg), and water for injection, USP. The pH is 6.0.

[0119] The dose of antibody administered to a patient may vary depending on the patient's age and size, condition, and route of administration. Preferred doses are typically calculated according to body weight or body surface area. When the antibody of the present invention is used to treat adult patients, it may be advantageous to administer the antibody intravenously as a single dose, usually 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. The frequency and duration of treatment can be adjusted according to the severity of the condition. Effective doses and schedules for administering anti-SARS-CoV-2 spike protein antibodies can be determined experimentally; for example, patient progression can be monitored by periodic evaluations, and the dose can be adjusted accordingly. Furthermore, interspecies scaling of doses can be performed using methods well known in the art (e.g., Mordenti et al., Pharmaceut Res 8:1351 (1991)).

[0120] Various delivery systems are known and can be used to administer the pharmaceutical compositions of the present invention, including, for example, liposome encapsulation, microparticles, microcapsules, recombinant cells capable of expressing the antibodies or other therapeutic proteins of the present invention, and receptor-mediated endocytosis (see, for example, Wu et al., J Biol Chem 262:4429-4432 (1987)). The antibodies and other therapeutic active ingredients of the present invention can also be delivered by gene therapy techniques. Delivery methods include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compositions can be administered by any convenient route, for example, by injection or bolus injection, by absorption through the epithelial or mucocutaneous linings (e.g., oral mucosa, rectum, and intestinal mucosa), and can be administered together with other bioactive agents. Administration may be systemic or topical.

[0121] Pharmaceutical compositions can be delivered subcutaneously or intravenously using standard needles and syringes. In addition, with respect to subcutaneous delivery, pen-type delivery devices facilitate the application of the pharmaceutical compositions of the present invention. Such pen-type delivery devices may be reusable or disposable. Reusable pen-type delivery devices generally utilize replaceable cartridges containing the pharmaceutical composition. Once all of the pharmaceutical composition in the cartridge has been administered and the cartridge is empty, the empty cartridge can be easily discarded and easily replaced with a new cartridge containing the pharmaceutical composition. The pen-type delivery device can then be reused. In disposable pen-type delivery devices, there are no replaceable cartridges. Rather, disposable pen-type delivery devices are pre-filled with the pharmaceutical composition held in a reservoir within the device. Once the pharmaceutical composition is emptied from the reservoir, the entire device is discarded.

[0122] Numerous reusable pen-type and auto-injector delivery devices have applications for subcutaneous delivery of the pharmaceutical compositions discussed herein. Examples include AUTOPEN® (Owen Mumford, Inc., Woodstock, UK), DISETRONIC® pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25® pen, HUMALOG® pen, HUMALIN 70 / 30® pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN® I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR® (Novo Nordisk, Copenhagen, Denmark), BD® pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN®, OPTIPEN PRO®, and OPTIPEN Examples of disposable pen-type delivery devices for subcutaneous delivery of the pharmaceutical compositions of the present invention include, but are not limited to, STARLET (trademark) and OPTICLIK (trademark) (sanofi-aventis, Frankfurt, Germany). Examples of, but are not limited to, STARLET (trademark) and OPTICLIK (trademark) (sanofi-aventis), FLEXPEN (trademark) (Novo Nordisk), KWIKPEN (trademark) (Eli Lilly), SURECLICK (trademark) auto-injector (Amgen, Thousand Oaks, CA), PENLET (trademark) (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA (trademark) pen (Abbott Labs, Abbott Park, IL).

[0123] In certain circumstances, pharmaceutical compositions can be delivered via a sustained-release system. In one embodiment, a pump can be used (see Langer, Sefton, CRC Crit.Ref.Biomed.Eng.14:201 (1987) above). In another embodiment, a polymer material can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida). In yet another embodiment, the sustained-release system can be placed near the target of the composition, thereby requiring only a fraction of the systemic dose (see, for example, Goodson, 1984, in Medical Applications of Controlled Release, vol.2, pp.115-138 above). Other sustained-release systems are discussed in the review by Langer, Science 249:1527-1533 (1990).

[0124] Injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injection, intravenous infusion, etc. These injectable preparations may be prepared by publicly known methods. For example, an injectable preparation may be prepared by dissolving, suspending, or emulsifying the antibody or a salt thereof in a sterile aqueous or oily medium conventionally used for injection. Examples of aqueous media for injection include physiological saline, glucose, and isotonic solutions containing other adjuvants.

[0125] Combination therapy In some cases, anti-SARS-CoV-2 spike protein antibodies may be administered together with further therapeutic agents. In some embodiments, the further therapeutic agents are antiviral drugs or vaccines. In some embodiments, the further therapeutic agents are selected from the group consisting of anti-inflammatory agents, antimalarial agents, antibodies or antigen-binding fragments thereof that specifically bind to TMPRSS2, and antibodies or antigen-binding fragments thereof that specifically bind to the SARS-CoV-2 spike protein. In some cases, the antimalarial agent is chloroquine or hydroxychloroquine. In some cases, the anti-inflammatory agent is an antibody such as sarilumab, tocilizumab, or gymcirumab. In some embodiments, the further therapeutic agent is a secondary antibody or antigen-binding fragment containing the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences of Table 1.

[0126] Further therapeutic agents may be administered to or used in a subject prior to the administration of the anti-SARS-CoV-2 spike protein antibody of the present invention. For example, if the first component is administered / used one week, 72 hours, 60 hours, 48 ​​hours, 36 hours, 24 hours, 12 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, 10 minutes, 5 minutes, or less than 1 minute prior to the administration / use of the second component, the first component may be considered administered / used "before" the second component. In other embodiments, further therapeutic agents may be administered to or used in a subject after the administration of the anti-SARS-CoV-2 spike protein antibody of the present invention. For example, if the first component is administered / used 1 minute, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, and 72 hours after the administration / use of the second component, the first component may be considered administered / used "after" the second component. In yet other embodiments, further therapeutic agents may be administered or used to a subject concurrently with the administration of the anti-SARS-CoV-2 spike protein antibody of the present invention. "Concurrent" administration for the purposes of the present invention includes, for example, the administration of the anti-SARS-CoV-2 spike protein antibody and the additional therapeutic active ingredient to a subject in a single dosage form, or in separate dosage forms administered to the subject within approximately 30 minutes of each other. When administered in separate dosage forms, each dosage form may be administered via the same route (for example, both the anti-SARS-CoV-2 spike protein and the additional therapeutic active ingredient may be administered intravenously, subcutaneously, etc.). In any event, administration of this component in a single dose, in different dosage forms via the same route, or in different dosage forms via different routes shall all be considered “concurrent administration” for the purposes of this disclosure. For the purposes of this disclosure, administration of anti-SARS-CoV-2 spike protein antibody “before,” “concurrently with,” or “after” the administration of further therapeutic agents shall be considered administration of anti-SARS-CoV-2 spike protein antibody “in combination with” further therapeutic agents.

[0127] Dosage The amount of the active ingredient that can be administered to the target (e.g., an anti-SARS-CoV-2 spike protein antibody, or other therapeutic agents given in combination with an anti-SARS-CoV-2 spike protein antibody) is generally a therapeutically effective dose, as discussed elsewhere in this specification.

[0128] The effective dosage for treatment is approximately 0.05mg to approximately 20g. For example, approximately 0.05mg, approximately 0.1mg, approximately 1.0mg, approximately 1.5mg, approximately 2.0mg, approximately 10mg, approximately 20mg, approximately 30mg, approximately 40mg, approximately 50mg, approximately 60mg, approximately 70mg, approximately 80mg, approximately 90mg, approximately 100mg, approximately 110mg, approximately 120mg, approximately 130mg, approximately 140mg, approximately 150mg, approximately 160mg, approximately 170mg, approximately 180mg, approximately 190mg, approximately 200mg, approximately 210mg, approximately 220mg, approximately 230mg, approximately 240mg, approximately 250mg, approximately 260mg, approximately 27mg. 0mg, approximately 280mg, approximately 290mg, approximately 300mg, approximately 310mg, approximately 320mg, approximately 330mg, approximately 340mg, approximately 350mg, approximately 360mg, approximately 370mg, approximately 380mg, approximately 390mg, approximately 400mg, approximately 410mg, approximately 420mg, approximately 430mg, approximately 440mg, approximately 450mg, approximately 460mg, approximately 470mg, approximately 480mg, approximately 490mg, approximately 500mg, approximately 510mg, approximately 520mg, approximately 530mg, approximately 540mg, approximately 550mg, approximately 560mg, approximately 570mg, approximately 580mg, approximately 590mg, approximately 600mg, approximately 610mg, approximately 620mg, approximately 6 30mg, approximately 640mg, approximately 650mg, approximately 660mg, approximately 670mg, approximately 680mg, approximately 690mg, approximately 700mg, approximately 710mg, approximately 720mg, approximately 730mg, approximately 740mg, approximately 750mg, approximately 760mg, approximately 770mg, approximately 780mg, approximately 790mg, approximately 800mg, approximately 810mg, approximately 820mg, approximately 830mg, approximately 840mg, approximately 850mg, approximately 860mg, approximately 870mg, approximately 880mg, approximately 890mg, approximately 900mg, approximately 910mg, approximately 920mg, approximately 930mg, approximately 940mg, approximately 950mg, approximately 960mg, approximately 970mg, approximately 980mg Approximately 990mg, approximately 1g, approximately 1.1g, approximately 1.2g, approximately 1.3g, approximately 1.4g, 1.5g, approximately 1.6g, approximately 1.7g, approximately 1.8g, approximately 1.9g, approximately 2g, approximately 2.1g, approximately 2.2g, approximately 2.3g, approximately 2.4g, approximately 2.5g, approximately 2.6g, approximately 2.7g, approximately 2.8g, approximately 2.9g, approximately 3g Approximately 3.1g, 3.2g, 3.3g, 3.4g, 3.5g, 3.6g, 3.7g, 3.8g, 3.9g, 4g, 4.1g, 4.2g, 4.3g, 4.4g, 4.5g, 4.6g, 4.7g, 4.8g, 4.9g, 5g, 5.1g, and 5g.2g, about 5.3g, about 5.4g, about 5.5g, about 5.6g, about 5.7g, about 5.8g, about 5.9g, about 6g, about 6.1g, about 6.2g, about 6.3g, about 6.4g, about 6.5g, about 6.6g, about 6 .7g, about 6.8g, about, 6.9g, about 7g, about 7.1g, about 7.2g, about 7.3g, about 7.4g, about 7.5g, about 7.6g, about 7.7g, about 7.8g, about 7.9g, about 8g, about 8.1g, about 8 The effective therapeutic dose may be 0.2g, approximately 8.3g, approximately 8.4g, approximately 8.5g, approximately 8.6g, approximately 8.7g, approximately 8.8g, approximately 8.9g, approximately 9g, approximately 9.1g, approximately 9.2g, approximately 9.3g, approximately 9.4g, approximately 9.5g, approximately 9.6g, approximately 9.7g, approximately 9.8g, approximately 9.9g, approximately 10g, approximately 11g, approximately 12g, approximately 13g, approximately 14g, approximately 15g, approximately 16g, approximately 17g, approximately 18g, approximately 19g, or approximately 20g of each antibody. In some cases, the effective therapeutic dose is 0.1g to 3.5g. In some cases, the effective therapeutic dose is 0.5g to 2g. In some cases, the effective therapeutic dose is 0.8g to 1.6g. In some cases, the effective therapeutic dose is 1.0g to 1.4g. In some cases, the effective therapeutic dose is 1g to 7g. In other cases, the effective therapeutic dose is 3g to 5g. In other cases, the effective therapeutic dose is 3.5g to 4.5g. In any of these embodiments discussed above, the dose may represent the dose of a single antibody, or alternatively, the total dose of a combination of antibodies. For example, two different anti-SARS-CoV-2 spike glycoprotein antibodies can be co-administered, with the dose of each antibody representing half of the total dose administered.

[0129] 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 cases, the total dose is 100 mg to 5000 mg. In some embodiments, the total dose 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 dose 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, or 2400 mg. In some cases, the total dose may be 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 1000mg, 1050mg, 1100mg, 1150mg, 1200mg, 1250mg, 1300mg, 1350mg, 1400mg, 1450mg, 1500mg, 1550mg, 1600mg The doses are mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, or 3000 mg. In some embodiments, the total dose is 2400 mg, and each of mAb10933 and mAb10987 is administered intravenously in doses of 1200 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 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 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 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.

[0130] The amount of anti-SARS-CoV-2 spike protein antibody or other therapeutic agent contained in each dose can be expressed in milligrams of antibody per kilogram of the patient's body weight (i.e., mg / kg). For example, anti-SARS-CoV-2 spike protein antibody is available in doses ranging from approximately 0.0001 to approximately 200 mg / kg of the patient's 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). g / kg, 9.5mg / kg, 10.0mg / kg, 10.5mg / kg, 11.0mg / kg, 11.5mg / kg, 12.0mg / kg, 12.5mg / kg, 13.0mg / kg, 13.5mg / kg, 14.0mg / kg, 14.5mg / kg , 15.0mg / kg, 15.5mg / kg, 16.0mg / kg, 16.5mg / kg, 17.0mg / kg, 17.5mg / kg, 18.0mg / kg, 18.5mg / kg, 19.0mg / kg, 19.5mg / kg, 20.0mg / kg, 20 .5mg / kg, 21.0mg / kg, 21.5mg / kg, 22.0mg / kg, 22.5mg / kg, 23.0mg / kg, 23.5mg / kg, 24.0mg / kg, 24.5mg / kg, 25.0mg / kg, 25.5mg / kg, 26.0 mg / kg, 26.5mg / kg, 27.0mg / kg, 27.5mg / kg, 28.0mg / kg, 28.5mg / kg, 29.0mg / kg, 29.5mg / kg, 30.0mg / kg, 30.5mg / kg, 31.0mg / kg, 31.5mg / kg, 32.0mg / kg, 32.5mg / kg, 33.0mg / kg, 33.5mg / kg, 34.0mg / kg, 34.5mg / kg, 35.0mg / kg, 35.5mg / kg, 36.0mg / kg, 36.5mg / kg, 37.0mg / kg, 37.5mg / kg, 38.0mg / kg, 38.5mg / kg, 39.0mg / kg, 39.5mg / kg, 40.0mg / kg, 40.5mg / kg, 41.0mg / kg, 41.5mg / kg, 42.0mg / kg, 42.5mg / kg, 43.0mg / kg、43.5mg / kg、44.0mg / kg、44.5mg / kg、45.0mg / kg、45.5mg / kg、46.0mg / kg、46.5mg / kg、47.0mg / kg、47.5mg / kg、48.0mg / kg、48.5mg / kg、49.0mg / kg、49.5mg / kg、50.0mg / kg、50.5mg / kg、51.0mg / kg、51.5mg / kg、52.0mg / kg、52.5mg / kg、53.0mg / kg、53.5mg / kg、54.0mg / kg、54.5mg / kg、55.0mg / kg、55.5mg / kg、56.0mg / kg、56.5mg / kg、57.0mg / kg、57.5mg / kg、58.0mg / kg、58.5mg / kg、59.0mg / kg、59.5mg / kg、60.0mg / kg、60.5mg / kg、61.0mg / kg、61.5mg / kg、62.0mg / kg、62.5mg / kg、63.0mg / kg、63.5mg / kg、64.0mg / kg、64.5mg / kg、65.0mg / kg、65.5mg / kg、66.0mg / kg、66.5mg / kg、67.0mg / kg、67.5mg / kg、68.0mg / kg、68.5mg / kg、69.0mg / kg、69.5mg / kg、70.0mg / kg、70.5mg / kg、71.0mg / kg、71.5mg / kg、72.0mg / kg、72.5mg / kg、73.0mg / kg、73.5mg / kg、74.0mg / kg、74.5mg / kg、75.0mg / kg、75.5mg / kg、76.0mg / kg、76.5mg / kg、77.0mg / kg、77.5mg / kg、78.0mg / kg、78.5mg / kg、79.0mg / kg、79.5mg / kg、80.0mg / kg、80.5mg / kg、81.0mg / kg、81.5mg / kg、82.0mg / kg、82.5mg / kg、83.0mg / kg、83.5mg / kg、84.0mg / kg、84.5mg / kg、85.0mg / kg、85.5mg / kg、86.0mg / kg、86.5mg / kg、87.0mg / kg、87.5mg / kg、88.0mg / kg、88.5mg / kg、89.0mg / kg、89.5mg / kg、90.0mg / kg、90.5mg / kg、91.0mg / kg、91.5mg / kg、92.0mg / kg、92.5mg / kg、93.0mg / kg、93.5mg / kg、94.0mg / kg、94.5mg / kg、95.0mg / kg、95.5mg / kg、96.0mg / kg、96.5mg / kg、97.0mg / kg、97.5mg / kg、98.0mg / kg、98.5mg / kg、99.0mg / kg、99.5mg / kg、100.0mg / kg、100.5mg / kg、101.0mg / kg、101.5mg / kg、102.0mg / kg、102.5mg / kg、103.0mg / kg、103.5mg / kg、104.0mg / kg、104.5mg / kg、105.0mg / kg、105.5mg / kg,106.0mg / kg、106.5mg / kg、107.0mg / kg、107.5mg / kg、108.0mg / kg、108.5mg / kg、109.0mg / kg、109.5mg / kg、110.0mg / kg、110.5mg / kg、111.0mg / kg、111.5mg / kg、112.0mg / kg、112.5mg / kg、113.0mg / kg、113.5mg / kg、114.0mg / kg、114.5mg / kg、115.0mg / kg、115.5mg / kg、116.0mg / kg、116.5mg / kg、117.0mg / kg、117.5mg / kg、118.0mg / kg、118.5mg / kg、119.0mg / kg、119.5mg / kg、120.0mg / kg、120.5mg / kg、121.0mg / kg、121.5mg / kg、122.0mg / kg、122.5mg / kg、123.0mg / kg、123.5mg / kg、124.0mg / kg、124.5mg / kg、125.0mg / kg、125.5mg / kg、126.0mg / kg、126.5mg / kg、127.0mg / kg、127.5mg / kg、128.0mg / kg、128.5mg / kg、129.0mg / kg、129.5mg / kg、130.0mg / kg、130.5mg / kg、131.0mg / kg、131.5mg / kg、132.0mg / kg、132.5mg / kg、133.0mg / kg、133.5mg / kg、134.0mg / kg、134.5mg / kg、135.0mg / kg、135.5mg / kg、136.0mg / kg、136.5mg / kg、137.0mg / kg、137.5mg / kg、138.0mg / kg、138.5mg / kg、139.0mg / kg、139.5mg / kg、140.0mg / kg、140.5mg / kg、141.0mg / kg、141.5mg / kg、142.0mg / kg、142.5mg / kg、143.0mg / kg、143.5mg / kg、144.0mg / kg、144.5mg / kg、145.0mg / kg、145.5mg / kg、146.0mg / kg、146.5mg / kg、147.0mg / kg、147.5mg / kg、148.0mg / kg、148.5mg / kg、149.0mg / kg、149.5mg / kg、150.0mg / kg、150.5mg / kg、151.0mg / kg、151.5mg / kg、152.0mg / kg、152.5mg / kg、153.0mg / kg、153.5mg / kg、154.0mg / kg、154.5mg / kg、155.0mg / kg、155.5mg / kg、156.0mg / kg、156.5mg / kg、157.0mg / kg、157.5mg / kg、158.0mg / kg、158.5mg / kg、159.0mg / kg、159.5mg / kg、160.0mg / kg、160.5mg / kg、161.0mg / kg、161.5mg / kg、162.0mg / kg、162.5mg / kg、163.0mg / kg、163.5mg / kg、164.0mg / kg、164.5mg / kg、165.0mg / kg、165.5mg / kg、166.0mg / kg、166.5mg / kg、167.0mg / kg、167.5mg / kg、168.0mg / kg、168.5mg / kg、169.0mg / kg、169.5mg / kg、170.0mg / kg、170.5mg / kg、171.0mg / kg、171.5mg / kg、172.0mg / kg、172.5mg / kg、173.0mg / kg、173.5mg / kg、174.0mg / kg、174.5mg / kg、175.0mg / kg、175.5mg / kg、176.0mg / kg、176.5mg / kg、177.0mg / kg、177.5mg / kg、178.0mg / kg、178.5mg / kg、179.0mg / kg、179.5mg / kg、180.0mg / kg、180.5mg / kg、181.0mg / kg、181.5mg / kg、182.0mg / kg、182.5mg / kg、183.0mg / kg、183.5mg / kg、184.0mg / kg、184.It can be administered to a patient at 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).

[0131] Dosing regimen According to certain embodiments of the present invention, multiple doses of an active ingredient (e.g., an anti-SARS-CoV-2 spike protein antibody) can be administered to a subject over a defined period of time. The method according to this aspect of the present invention includes continuously administering multiple doses of the active ingredient of the present invention to a subject. As used in the present invention, "continuously administering" means that each dose of the active ingredient is administered to the subject on different days separated by different time points, e.g., a predetermined interval (e.g., several hours, several days, several weeks, or several months). The present invention includes methods that include continuously administering to a patient a single initial dose of the active ingredient, followed by one or more secondary doses of the active ingredient, and optionally followed by one or more tertiary doses of the active ingredient.

[0132] The terms “initial dose,” “secondary dose,” and “tertiary dose” refer to the temporal sequence of administration of the active ingredient, e.g., the anti-SARS-CoV-2 spike protein antibody of the present invention, or the combination therapy of the present invention, e.g., two different anti-SARS-CoV-2 spike protein antibodies. Therefore, the “initial dose” is the dose administered at the start of the treatment regimen (also called the “baseline dose”). The “secondary dose” is the dose administered after the initial dose, and the “tertiary dose” is the dose administered after the secondary dose. The initial, secondary, and tertiary doses may all contain the same amount of the active ingredient, e.g., the anti-SARS-CoV-2 spike protein antibody, but may generally differ from each other in terms of administration frequency. However, in certain embodiments, the amounts of anti-SARS-CoV-2 spike protein antibody contained in the initial, secondary, and / or tertiary doses may differ from each other during the course of treatment (e.g., adjusted up or down as needed). In certain embodiments, two or more doses (e.g., two, three, four, or five) are administered as a “loading dose” at the start of the treatment regimen, followed by subsequent doses (e.g., “maintenance doses”) administered at a lower frequency.

[0133] In certain exemplary embodiments of the present invention, each secondary and / or tertiary dose is 1 to 26 of the preceding dose (e.g., 1, 1 1 / 2, 2, 2 1 / 2, 3, 3 1 / 2, 4, 4 1 / 2, 5, 5 1 / 2, 6, 6 1 / 2, 7, 7 1 / 2, 8, 8 1 / 2, 9, 9 1 / 2, 10, 10 1 / 2, 11, 11 1 / 2, 12, 12 1 / 2) Administered 2, 13, 13 1 / 2, 14, 14 1 / 2, 15, 15 1 / 2, 16, 16 1 / 2, 17, 17 1 / 2, 18, 18 1 / 2, 19, 19 1 / 2, 20, 20 1 / 2, 21, 21 1 / 2, 22, 22 1 / 2, 23, 23 1 / 2, 24, 24 1 / 2, 25, 25 1 / 2, 26, 26 1 / 2 or more weeks later. The phrase "immediately preceding dose," as used herein, means the dose of the active ingredient, e.g., anti-SARS-CoV-2 spike protein antibody, administered to the patient in a series of doses without an intervention dose, sequentially before the administration of the immediate following dose.

[0134] Methods according to this aspect of the present invention may involve administering to a patient any number of secondary and / or tertiary doses of the active ingredient of the present invention, for example, an anti-SARS-CoV-2 spike protein antibody. For example, in one particular embodiment, only a single secondary dose is administered to the patient. In other embodiments, two or more secondary doses (e.g., two, three, four, five, six, seven, eight or more) are administered to the patient. Similarly, in one particular embodiment, only a single tertiary dose is administered to the patient. In other embodiments, two or more tertiary doses (e.g., two, three, four, five, six, seven, eight or more) are administered to the patient.

[0135] In embodiments involving multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1-2 weeks or 1-2 months after the most recent dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 2-12 weeks after the most recent dose. In certain embodiments of the present invention, the frequency at which secondary and / or tertiary doses are administered to the patient may vary over the course of the treatment regimen. The administration frequency may also be adjusted by the physician during the course of treatment according to the individual patient's needs after clinical examinations.

[0136] The present invention includes a dosing regimen in which 2 to 6 loading doses are administered to a patient 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 2 or more maintenance doses administered to the patient at a less frequent frequency. For example, according to this aspect of the present invention, if the loading dose is administered at a frequency of once a month, the maintenance dose may be administered to the patient at a frequency of 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 the treatment of a prophylactic or therapeutic course. In some embodiments, the dose is administered to treat high-risk adult or pediatric patients with diagnosed mild to moderate coronavirus disease (COVID-19).

[0137] In some embodiments, the dosage for adult and pediatric patients (those aged 12 years and older weighing at least 40 kg) is: ○ 600 mg mAb10933 (casiribimab) and 600 mg mAb10987 (imdevimab) (see Table 4A) may be administered together as a single intravenous infusion via pump or gravity, or as a single subcutaneous injection, or as two subcutaneous injections, or ○These are 1,200 mg of casirivimab and 1,200 mg of imdevimab (see Table 4B), administered together as a single intravenous infusion via pump or gravity. Exemplary preparation instructions for mAb10933 + mAb10987 (casirivimab and imdevimab, respectively) are as follows: 1. Remove the casirivimab and imdevimab vials from refrigerated storage and allow them to equilibrate at room temperature for approximately 20 minutes before preparation. Do not expose them to direct heat. Do not shake the vials. 2. Before administration, visually inspect the casirivimab and imdevimab vials for particulate matter and discoloration. If any of these are observed, the solution must be discarded and a fresh solution prepared. The solution in each vial should be clear to slightly milky white, and colorless to pale yellow. Obtain a pre-filled V-injection bag containing 3.50 mL, 100 mL, 150 mL, or 250 mL of 0.9% sodium chloride injection solution. When administering a dose of 4,600 mg / 600 mg, ○Using two separate syringes, withdraw 5 mL of casirivimab and 5 mL of imudevimab from each vial (see Table 4A), and inject the entire 10 mL into a pre-filled infusion bag containing 0.9% sodium chloride injection (see Table 4A). Discard any product remaining in the vials. or When administering the alternative 1,200 mg / 1,200 mg dose, ○Using two separate syringes, withdraw 10 mL of casirivimab and 10 mL of imudevimab from each vial (see Table 4B), and inject all 20 mL into a pre-filled infusion bag containing 0.9% sodium chloride injection solution (see Table 4B). Discard any remaining product in the vials. 5. Turn the infusion bag inverted by hand about 10 times. Do not shake. 6. This product does not contain preservatives; therefore, the diluted injection solution should be administered immediately. ● If immediate administration is not possible, do not store catiribimab diluted with imudevimab infusion solution in a refrigerator at 2°C to 8°C (36°F to 46°F) for more than 36 hours, or at room temperature of 25°C (77°F) or below for more than 4 hours. If refrigeration is necessary, allow the infusion solution to equilibrate to room temperature for approximately 30 minutes before administration.

[0138] An example of a dosage instruction is as follows: 1. Gather the materials recommended for injection. a. Polyvinyl chloride (PVC), polyethylene (PE) lined PVC, or polyurethane (PU) injection set b. In-line or add-on 0.2 micrometer polyethersulfone (PES) filter 2. Attach the infusion set to the IV bag. 3. Prime the injection set. 4. Administer as an IV infusion for at least 60 minutes via a pump or gravity through an intravenous line equipped with a sterile in-line or add-on 0.2-micrometer polyethersulfone (PES) filter (see Table 4A or Table 4B). 5. The prepared infusion solution should not be administered simultaneously with any other medications. The compatibility of mAb10933 and mAb10987 injections with medications other than IV solution and 0.9% sodium chloride injection is unknown. 6. After the injection is complete, rinse with 0.9% sodium chloride injection solution. 7. Dispose of any unused products. 8. Clinically monitor the patient during administration and observe the patient for at least 1 hour after the infusion is complete.

[0139]

Table 5

[0140]

Table 6

[0141] Kit The present invention further provides a manufactured article or kit comprising a packaging material, a container, and a medicament contained within the container, the medicament comprising at least one anti-SARS-CoV-2 spike glycoprotein antibody, and the packaging material comprising a label or package insert indicating the indication and instructions for use. In one embodiment, the kit may comprise two anti-SARS-CoV-2 spike glycoprotein antibodies, and the two antibodies may be contained in separate containers.

Example

[0142] The following examples are provided to give a complete disclosure and explanation of how the methods and compositions of the present invention are prepared and used, and are not intended to limit the scope of what the inventors consider to be the present invention. Although efforts have been made to ensure accuracy with respect to the numerical values ​​used (e.g., quantity, temperature, etc.), some degree of experimental error and deviation should be taken into consideration. Unless otherwise indicated, parts are parts by weight, molecular weight is the average molecular weight, temperature is in degrees Celsius, and pressure is atmospheric pressure or near atmospheric pressure.

[0143] Example 1. Clinical evaluation of anti-SARS-CoV-2 spike glycoprotein 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 tolerability of mAb10933 + mAb10987 in hospitalized adult patients with COVID-19. The safety, tolerability, and efficacy of mAb10989 will also be evaluated in the phase 1 portion of the study to enable further investigation in other clinical settings.

[0144] Research Objectives: The primary and secondary objectives of each phase of the research are described below.

[0145] Primary purpose: 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 SARS-CoV-2 viral shedding. Part B ● To evaluate the safety and tolerability of mAb10989 compared to placebo. ● To evaluate the virological efficacy of mAb10989 compared to placebo in reducing SARS-CoV-2 viral shedding. Phase 2 ● To evaluate the virological efficacy of mAb10933 + mAb10987 compared to placebo in reducing SARS-CoV-2 viral shedding. ● To evaluate the clinical efficacy of mAb10933 + mAb10987 compared to placebo in improving clinical condition. Phase 3 The primary objective of Phase 3 is The purpose is to evaluate and confirm the clinical efficacy of mAb10933 + mAb10987 compared to placebo in improving clinical condition.

[0146] Secondary purpose: Phase 1 Part A ● To evaluate additional indicators of virological efficacy of mAb10933 + mAb10987 compared to placebo. ● To evaluate the clinical efficacy of mAb10933 + mAb10987 compared to placebo in improving clinical outcomes. ● To characterize the pharmacokinetic (PK) profiles of mAb10933 and mAb10987 in serum. ●To evaluate the immunogenicity of mAb10933 and mAb10987 Part B ● To evaluate additional indicators of virological efficacy of mAb10989 compared to placebo. ● To evaluate the clinical efficacy of mAb10989 compared to placebo in improving clinical outcomes. ● To compare quantitative reverse transcription polymerase chain reaction (RT-qPCR) results obtained from different sample types (intranasal cavity, nasal cavity, and saliva). ● To characterize the PK profile of mAb10989 in serum ● To evaluate the immunogenicity of mAb10989 Phase 2 ● To evaluate additional indicators of virological efficacy of mAb10933 + mAb10987 compared to placebo. ● To evaluate additional indicators of clinical efficacy of mAb10933 + mAb10987 compared to placebo. ● To evaluate the safety and tolerability of mAb10933 + mAb10987 compared to placebo. ● To measure the concentrations of mAb10933 and mAb10987 in serum over time. ●To evaluate the immunogenicity of mAb10933 and mAb10987 Phase 3 ● To evaluate the clinical efficacy of mAb10933 + mAb10987 compared to placebo. ● To evaluate the safety and tolerability of mAb10933 + mAb10987 compared to placebo. ● To measure the concentrations of mAb10933 and mAb10987 in serum over time. ●To evaluate the immunogenicity of mAb10933 and mAb10987

[0147] Study Design: This study was an adaptive phase 1 / 2 / 3 randomized, double-blind, placebo-controlled master protocol to evaluate the efficacy, safety, and tolerability of mAb10933 + mAb10987 in hospitalized adult patients with COVID-19. The safety, tolerability, and efficacy of mAb10989 were also evaluated in the phase 1 portion of the study to allow for further investigation in other clinical settings. Eligible patients hospitalized within ≤72 hours of screening were enrolled in one of four cohorts based on disease severity at randomization. Phase 2 was initiated after authorization by the independent data monitoring committee (IDMC) for the phase 1 indicator safety group and enrolled concurrently with phase 1 thereafter. As phase 2 progressed, phase 1 continued until enrollment was complete, but phase 2 enrollment did not require completion of phase 1 enrollment.

[0148] Study period: Phase 1 of the study lasted up to 170 days. Phase 2 of the study lasted up to 58 days. Phase 3 of the study lasted up to 58 days.

[0149] Study population: To evaluate the spectral potential differential therapeutic effects in hospitalized COVID-19 patients, the study was conducted and analyzed in four cohorts of hospitalized adult patients with COVID-19: Cohort 1A (patients with COVID-19 symptoms but not requiring oxygen supplementation), Cohort 1 (patients receiving low-flow oxygen supplementation), Cohort 2 (patients requiring high-intensity oxygen therapy but not receiving mechanical ventilation), and Cohort 3 (patients requiring mechanical ventilation).

[0150] Cohort-eligible patients were enrolled in one of four cohorts based on disease severity at randomization: Cohort 1A (patients with COVID-19 symptoms but not requiring oxygen supplementation), Cohort 1 (O2 saturation >93% with low-flow oxygen via nasal cannula, simple face mask, or other similar device), and Cohort 2 (high-intensity oxygen therapy). * They are receiving treatment, but not mechanical ventilation. * High-intensity oxygen therapy is defined as the use of a non-rebreathing mask with an oxygen flow rate of at least 10 L / min, the use of a high-flow device with at least 50% FiO2, or the use of non-invasive ventilation to treat hypoxemia, and Cohort 3 (receiving mechanical ventilation).

[0151] Sampling size - The Phase 1 portion of the study included up to 100 patients from Cohort 1 only: Part A of mAb10933 + mAb10987: approximately 20 patients per group, totaling 60 patients across three treatment arms; and Part B of mAb10989: approximately 20 patients per group, totaling 40 patients across two treatment arms. The Phase 2 portion of the study included approximately 1560 patients: Cohort 1A: approximately 130 patients per group, totaling 390 patients across three treatment arms; Cohort 1: approximately 130 patients per group, totaling 390 patients across three treatment arms; Cohort 2: approximately 130 patients per group, totaling 390 patients across three treatment arms; and Cohort 3: approximately 130 patients per group, totaling 390 patients across three treatment arms. The Phase 3 sample size is estimated to be approximately 1,350 people (150 patients per group across three treatment groups in each of the three cohorts). The final determination of the Phase 3 sample size and patient population may change and will be made after a full review of the Phase 2 data.

[0152] Selection Criteria: Patients must meet the following criteria to be eligible for inclusion in the study. 1. Provide informed consent (signed by the research patient or their legal representative); 2. Adult male or female ≥ 18 years of age at randomization (or the legal age of majority in the country); 3. Having a SARS-CoV-2 positive molecular diagnostic test (by SARS-CoV-2 RT-PCR or other molecular diagnostic assay validated using appropriate samples such as NP, nasal cavity, oropharyngeal [OP], or saliva) ≤ 72 hours prior to randomization, and having no alternative explanation for the current clinical condition. Past records of positive results from tests performed ≤ 72 hours prior to randomization are acceptable; 4. Having symptoms consistent with COVID-19 that developed ≤ 10 days prior to randomization; and 5. At the time of randomization, patients who have been hospitalized for COVID-19 illness within the past 72 hours due to at least one of the following criteria – patients meeting two or more of these criteria will be classified into the most severely affected category: a. Cohort 1A: Patients exhibiting symptoms of COVID-19 but not requiring oxygen supplementation. b. Cohort 1: Maintaining O2 saturation >93% with low-flow oxygen via nasal cannula, simple face mask, or other similar device. c. Cohort 2: High-intensity oxygen therapy without mechanical ventilation. High intensity is defined as receiving oxygen supplementation delivered by one of the following devices: - Non-rebreathing mask (SpO2 ≤ 96%, however (Receiving an oxygen flow rate of at least 10 L / min) - High-flow devices with at least 50% FiO2 (e.g., AIRVO® or Optiflow®) - Non-invasive ventilation devices, including continuous positive airway pressure (CPAP) for treating hypoxemia (excluding isolated use for sleep-disordered breathing). d. Cohort 3: Receiving mechanical ventilation.

[0153] Exclusion Criteria: Patients who meet any of the following criteria will be excluded from the study. 1. Phase 1 only: Patients maintaining O2 saturation > 94% in room air; 2. In the opinion of the principal investigator, the likelihood of survival >48 hours from screening is low; 3. Receiving extracorporeal membrane oxygenation (ECMO); 4. Having a first stroke or paroxysmal disorder during hospitalization; 5. Initiate renal replacement therapy due to COVID-19; 6. Having circulatory shock requiring vasoconstrictors at the time of randomization (patients requiring vasoconstrictors for reasons other than sedation-related hypotension or circulatory shock may be eligible in this study); 7. Patients who have received convalescent plasma or IVIG in the past five months, or who are scheduled to receive it during the study period for any indication; 8. Participation in any clinical research trial, including any double-blind study evaluating the investigational drug, within 30 days prior to the screening visit and within 5 half-lives of the investigational drug (use of remdesivir, hydroxychloroquine, or other treatments used for the treatment of COVID-19 in connection with local standard treatment, open-label studies, or rescue use protocols (excluding COVID-19 convalescent plasma or IVIG) is permitted); 9. Any physical examination findings, medical history, and / or concomitant medications that, in the opinion of the principal investigator, could complicate the outcome of the study or pose an additional risk to the patient by participation in the study; 10. Known allergies or hypersensitivity to the components of the research drug; 11. Pregnant or breastfeeding women or 12. Women of childbearing potential (WOCBP) * Sexually active men who do not wish to practice highly effective contraception during continuous sexual activity, or before the initial dose / before the start of the first treatment, during the study, and for at least six months after the last dose. Highly effective contraceptive methods for women include: ● Stable use of combined (estrogen and progestogen-containing) hormonal contraceptives (oral, vaginal, transdermal) or progestogen-only hormonal contraceptives (oral, injectable, implantable) associated with ovulation inhibition for two or more menstrual cycles that began prior to screening. ● Intrauterine devices (IUDs) ● Intrauterine hormone-releasing system (IUS) ● Bilateral tubal ligation ● A partner who has undergone vasectomy† and / or ●Sexual abstinence‡, § Male study participants with a WOCBP partner required condom use unless they had undergone vasectomy† or were practicing sexual abstinence‡,§. * WOCBP was defined as women of reproductive age who are not permanently infertile and who have not experienced menopause since menarche. The postmenopausal state is defined as the absence of menstruation for 12 months without alternative medical causes. The high follicle stimulating hormone (FSH) levels in the postmenopausal range can be used to confirm the postmenopausal state in women not using hormonal contraceptives or hormone replacement therapy. However, one FSH measurement is insufficient to determine the occurrence of the postmenopausal state if there has been no amenorrhea for 12 months. The above definition follows the guidance of the Clinical Trial Facilitation Group (CTFG). Pregnancy testing and contraception are not required for women with a recorded hysterectomy or tubal ligation. Permanent contraceptive methods include hysterectomy, bilateral salpingectomy, bilateral oophorectomy, etc. †Male partners or male study participants who have had a vasectomy must have a medical evaluation of surgical success. ‡Sexual abstinence is considered a very effective method only when defined as refraining from heterosexual intercourse for the entire duration of the risks associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the patient's preferred normal lifestyle. §Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable contraceptive methods. Female and male condoms should not be used together.

[0154] Investigative treatment: In Phase 1, Part A, patients received a single intravenous (IV) dose of co-administered mAb10933+mAb10987 combination therapy 2.4g (1.2g mAb10933 + 1.2g mAb10987), a single IV dose of co-administered mAb10933+mAb10987 combination therapy 8.0g (4.0g mAb10933 + 4.0g mAb10987), or a single IV dose of placebo. In Phase I, Part B, patients received a single IV dose of mAb10989 monotherapy 1.2g, or a single IV dose of placebo. In Phase 2, patients received either a single IV dose of 2.4 g of co-administered mAb10933+mAb10987 combination therapy (1.2 g of mAb10933 + 1.2 g of mAb10987), a single IV dose of 8.0 g of co-administered mAb10933+mAb10987 combination therapy (4.0 g of mAb10933 + 4.0 g of mAb10987), or a single IV dose of placebo. The treatment group for Phase 3 will be determined after a review of the Phase 2 data.

[0155] Endpoints: Primary, secondary, and exploratory endpoints are specified for each phase, as defined below.

[0156] Primary endpoint Phase 1 (Cohort 1 only) The Phase 1 primary endpoints (Parts A and B) were as follows: ●Percentage of patients who experienced a serious adverse event (SAE) during treatment up to day 169 ●Percentage of patients experiencing infusion-related reactions (grade ≥ 2) up to day 4 ●Percentage of patients experiencing hypersensitivity reactions (grade ≥ 2) up to day 29 ●Baseline viral shedding (log) from day 1 to day 22, as measured by quantitative reverse transcription polymerase chain reaction (RT-qPCR) in nasopharyngeal (NP) swab samples. 10 Time-weighted average change from (copies / mL) (calculated for each patient using the trapezoidal method, where the time-weighted average of the change from baseline viral shedding from day 1 to day 22 is calculated as the area under the curve obtained by dividing the change from baseline at each time point by the time interval of the observation period). Phase 2 The primary endpoints for Phase 2 in each cohort were as follows: Cohort 1A and Cohort 1 ●Baseline viral shedding (log) from day 1 to day 22, as measured by RT-qPCR in nasopharyngeal (NP) swabs. 10 Time-weighted average change from (copies / mL) ● Percentage of patients who showed at least a 1-point improvement in their clinical condition from day 1 (randomization) to day 8, using a 7-point ordinal scale. Cohort 2 and Cohort 3 ●Baseline viral shedding (log) from day 1 to day 22, as measured by RT-qPCR in NP swabs. 10 Time-weighted average change from (copies / mL) ● Percentage of patients who showed at least a 1-point improvement in their clinical condition from day 1 (randomization) to day 22, using a 7-point ordinal scale. Phase 3 The primary endpoints for Phase 3 in each cohort are as follows: Cohort 1A and Cohort 1 ● Percentage of patients who showed at least a 1-point improvement in their clinical condition from day 1 (randomization) to day 8, using a 7-point ordinal scale. Cohort 2 and Cohort 3 ● Percentage of patients who showed at least a 1-point improvement in their clinical condition from day 1 (randomization) to day 22, using a 7-point ordinal scale. The patient population (Cohort 1A, Cohort 1, Cohort 2, and / or Cohort 3) and the Phase 3 primary clinical efficacy endpoint will be finalized after a review of the Phase 2 data.

[0157] Secondary endpoint Phase 1 (Cohort 1 only) The secondary endpoints for Phase 1 were as follows: ●Baseline viral shedding (log) from day 1 to day 22, measured by RT-qPCR in saliva samples. 10Time-weighted average change from (copies / mL) ●Baseline viral shedding (log) from day 1 to day 22, measured by RT-qPCR in nasal cavity samples. 10 Time-weighted average change from (copies / mL) ●Time to negative RT-qPCR result in any tested sample (NP swab, saliva, or nasal swab) for which no positive RT-qPCR result was obtained afterward. ● Changes from baseline in SARS-CoV-2 virus shedding at each hospital visit up to day 29, as measured by RT-qPCR in NP swabs. ● Changes from baseline in SARS-CoV-2 virus shedding at each visit up to day 29, as measured by RT-qPCR in saliva samples. ● Changes from baseline in SARS-CoV-2 virus shedding at each visit up to day 29, as measured by RT-qPCR in nasal swabs. ● Correlation and agreement between RT-qPCR results over time between different sample types (NP, nasal cavity, and saliva). ●Time-weighted mean change from baseline in viral shedding (log10 copies / mL) from day 1 to post-baseline study days (e.g., days 5, 7, 15, and 29), and the percentage of patients with at least a 1-point improvement in clinical status from day 1 (randomization) to day 8, using a 7-point ordinal scale. ● Percentage of patients who showed at least a 2-point improvement in their clinical condition from day 1 (randomization) to day 8, using a 7-point ordinal scale. ●Percentage of patients who showed at least a 1-point improvement in their clinical condition from day 1 (at randomization) to day 29 or discharge, using a 7-point ordinal scale. ●Percentage of patients who showed at least a 2-point improvement in their clinical status from day 1 (at randomization) to day 29 or discharge, using a 7-point ordinal scale. ● Time until oxygen supplementation is no longer needed by day 29 ● Maximum number of days of oxygen supplementation use: up to 29 days ●Percentage of patients who initiate high-intensity oxygen therapy by the 29th day or before discharge. ● Number of days of high-intensity oxygen therapy up to a maximum of 29 days ●Percentage of patients who initiate mechanical ventilation by the 29th day or before discharge ● Number of days of mechanical ventilation up to a maximum of 29 days ● Number of days without using the ventilation system up to a maximum of 29 days ● Maximum number of days of hospitalization up to 29 days ●Percentage of patients who were readmitted after discharge until the end of the trial. ● Percentage of patients admitted to the intensive care unit (ICU) for up to 29 days ● Number of days spent in the ICU up to a maximum of 29 days ● All-cause deaths up to day 29 ● All-cause mortality until the end of the study ●Overall survival ●Percentage of patients who developed SAEs during treatment 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. Phase 2 The secondary endpoints for Phase 2 were as follows: Cohort 1A and Cohort 1 only ● Percentage of patients who showed at least a 2-point improvement in their clinical condition from day 1 (randomization) to day 8, using a 7-point ordinal scale. Cohorts 2 and 3 only ● Percentage of patients who showed at least a 2-point improvement in their clinical condition from day 1 (randomization) to day 22, using a 7-point ordinal scale. Cohort 1A, Cohort 1, Cohort 2, and Cohort 3 ●Time until no positive RT-qPCR is found in the NP swab, and until a negative RT-qPCR is found. ● Changes from baseline in viral shedding at each visit up to day 29, as measured by RT-qPCR in NP swabs. ●Viral shedding (log) from day 1 to the post-baseline study day (e.g., days 5, 7, 15, and 29) 10 Time-weighted average change from baseline in copies / mL ●Percentage of patients who showed at least a 1-point improvement in their clinical condition from day 1 (at randomization) to day 29 or discharge, using a 7-point ordinal scale. ●Percentage of patients who showed at least a 2-point improvement in their clinical status from day 1 (at randomization) to day 29 or discharge, using a 7-point ordinal scale. ●Time until oxygen supplementation is no longer needed by day 29 (Cohorts 1, 2, and 3 only) ● Maximum number of days of oxygen supplementation use: up to 29 days ●Percentage of patients who initiate high-intensity oxygen therapy by the 29th day. ● Number of days of high-intensity oxygen therapy up to a maximum of 29 days ●Percentage of patients who initiate mechanical ventilation by the 29th day or before discharge ● Number of days of mechanical ventilation up to a maximum of 29 days ● Number of days without using the ventilation system up to a maximum of 29 days ● Maximum number of days of hospitalization up to 29 days ●Percentage of patients who were readmitted after discharge until the end of the trial. ● Percentage of patients who were admitted to the ICU for up to 29 days ● Number of days spent in the ICU up to a maximum of 29 days ● All-cause deaths up to day 29 ● All-cause mortality until the end of the study ●Overall survival ●Percentage of patients who developed SAEs during treatment up to day 29 ●Percentage of patients who developed SAEs during treatment up to day 57 ●Percentage of patients experiencing infusion-related reactions (grade ≥ 2) up to day 4 ●Percentage of patients experiencing hypersensitivity reactions (grade ≥ 2) up to day 29 ● Concentrations of mAb10933 and mAb10987 in serum over time ● Immunogenicity of mAb10933 and mAb10987 as measured by ADA Phase 3 The patient population (Cohort 1A, Cohort 1, Cohort 2, and / or Cohort 3) and the Phase 3 secondary clinical efficacy endpoint will be finalized after review of the Phase 2 data. Other possible secondary endpoints in Phase 3 included: ●Percentage of patients who developed SAEs during treatment up to day 57 ●Percentage of patients experiencing infusion-related reactions (grade ≥ 2) up to day 4 ●Percentage of patients experiencing hypersensitivity reactions (grade ≥ 2) up to day 29 ● Concentrations of mAb10933 and mAb10987 in serum over time ● Immunogenicity of mAb10933 and mAb10987 as measured by ADA

[0158] exploratory endpoints Exploratory endpoints include: ●Percentage of patients with treatment failure who have mutations in the gene encoding the SARS-CoV-2 protein by day 29 ● Changes and percentage changes in neutrophil-lymphocyte ratio (NLR) at each visit up to day 29 ● Changes and rate of change of D-dimers at each visit up to day 29 ● Changes and rate of change in ferritin levels at each visit up to day 29 ● Changes and rate of change of C-reactive protein (CRP) at each visit up to day 29 ●Changes and percentage changes in lactate dehydrogenase (LDH) at each visit up to day 29

[0159] Procedure and evaluation: Efficacy - Nasopharyngeal (all phases), saliva (Phase 1 only), and / or nasal swab (Phase 1 only) for SARS-CoV-2 RT-PCR, as well as clinical and oxygen status; Safety - Serious adverse events and adverse events of particular interest were recorded. Secretions were collected from patients using nasal swabs, saliva samples, and (Phase 1) nasopharyngeal samples to determine the presence or absence of SARS-CoV-2 virus and to measure viral shedding. Samples were used for RT-qPCR analysis. Samples may be further used for exploratory viral RNA sequencing (nasopharyngeal, nasal swab, saliva) and / or viral culture (nasopharyngeal, nasal swab).

[0160] Statistical plan: Phase 1 – The sample size is 60 patients in Part A of Phase 1 and 40 patients in Part B. The sample size allows for a preliminary estimate of the incidence of SAEs, AESIs, and Grade 3 or 4 TEAEs in the treatment group compared to placebo. The primary efficacy endpoint for Phase 1 was viral shedding (log) in NP swab samples from day 1 to day 22. 10 This was the time-weighted mean change from baseline in copies / mL. The standard deviation was 2.1 log. 10 Assuming copies / mL, the sample size of 20 patients per group in Phase 1 was 1.91 log between the treatment group and the placebo group using a two-sample t-test with two-sided significance of α=0.05. 10 It should have at least 80% detection power to detect differences in copies / mL. Phase 2 - Phase 2 sample size is determined by the viral shedding (log) in NP swab samples from day 1 to day 22. 10 Based on time-weighted mean change from baseline in copies / mL. Dropout rate was approximately 23% (including missing data at baseline) and standard deviation was 2.1 log. 10 Assuming copies / mL, the sample size of 130 patients per group across three treatment groups within each of the three cohorts (i.e., 100 patients per group with available data) is 0.84 log between each treatment group and the placebo group using a two-sample t-test with two-sided significance of α=0.05.10 The detection power should be at least 80% to detect differences in copies / mL. The standard deviation should be 3.8 log. 10 Assuming copies / mL, the difference detectable with 80% power is 1.51 log 10 It's probably copies / mL. For the clinical endpoint of the proportion of patients with at least one point improvement in clinical status from baseline to day 22, the minimum detectable difference (MDD) (based on equal proportions of chi-squared tests) between the treatment group and placebo, with a sample size of 100 per group (130 per group assuming an approximately 23% dropout rate), is as follows: ●In cohorts 1A and 1, the MDD rate was 13.7%, assuming a placebo response rate of 51% (i.e., anti-SARS-CoV-2 S protein mAb 64.7% vs. placebo 51%). The assumed response rate in the placebo group is similar to the rate observed for remdesivir. In cohorts 2 and 3, the MDD rate was 13.3%, assuming a placebo response rate of 57.1% (i.e., anti-SARS-CoV-2 S protein mAb 70.4% vs. placebo 57.1%). The assumed response rate in the placebo group was similar to that observed in the sarilumab COVID-19 Phase 2 / 3 study (6R88-COV-2040), and the progression population was similar to that of cohorts 2 and 3 in this study. Phase 3 – The study will continue to seamlessly enroll additional patients in the Phase 3 portion of the study until a decision on the primary endpoint and final sample size for Phase 3 is made based on the complete Phase 2 data analysis. The initial sample size of a total of 1350 patients is an estimate for the Phase 3 portion of the study (150 patients per group across three treatment groups in three cohorts). For example, for Cohort 3, a sample size of 450 patients (150 patients per group) provides 90% power by using a chi-squared test to detect a 15.9% treatment difference in the proportion of patients surviving at day 22 and patients not receiving mechanical ventilation, assuming a rate of 68.2% in the placebo group.

[0161] Results – An analysis of the 1st / 2nd / 3rd clinical trials of the antibody cocktail, casirivimab and imdevimab (mAb10933 and mAb10987, respectively) in hospitalized COVID-19 patients requiring low-flow oxygen (see Figure 19) was prospectively designed to focus on these patients, as evidence (Example 2) suggested that patients who had not yet initiated their own immune response to SARS-CoV-2 (i.e., those without antibodies at baseline; seronegative) were at higher risk. In addition, among the subjects treated with placebo, patients who had initiated an immune response at baseline (seronegative patients) had much lower viral levels at baseline and achieved a viral load below the lower level of quantification (LLQ) more quickly, even without treatment, compared with patients who had not initiated an immune response at baseline (seronegative patients). See Figure 16. In addition, among hospitalized patients with COVID-19 receiving low-flow oxygen supplementation, seronegative patients had a lower cumulative incidence of death or mechanical ventilation compared with seronegative patients. See Figure 17. Clinical outcomes in Cohort 1 were poor in patients who were sero-negative at baseline or had a high viral load at baseline. See Figure 18. The primary clinical objective of this initial analysis was to determine whether there was sufficient efficacy in these patients (i.e., futility analysis) to ensure the continuation of the trial. Since sero-negative patients treated with the antibody cocktail had a lower risk of death or mechanical ventilation (hazard ratio (HR): 0.78; 80% CI: 0.51–1.2), the results passed the futility analysis (p<0.3 one-sided). Benefit was derived from results initiated one week after treatment, where the risk of death or mechanical ventilation was reduced by approximately half with antibody cocktail treatment, based on post-hoc analysis.

[0162] Cohort 1 was analyzed for seronegativity in both the full analysis set (FAS; randomized and administered patients) and the modified full analysis set (mFAS; patients who tested positive for SARS-CoV-2 by nasopharyngeal qualitative testing at baseline). Seronegativity was similar in both the FAS and mFAS groups. See Figure 20. Seronegativity patients (n=217) had significantly higher viral loads than patients who had already developed their own antibodies against SARS-CoV-2 (seropositive) at randomization. See Figure 16. As hypothesized, the antibody cocktail had a strong antiviral effect compared to placebo in patients who had not initiated their own immune response (seronegativity at baseline), patients treated with the antibody cocktail reduced their virus more smoothly than patients treated with placebo, and the cocktail reduced viral load more rapidly compared to all baseline viral load thresholds. See Figures 21–24. In seronegative patients, the antibody cocktail reduced the time-weighted mean daily viral load by -0.54 log10 copies / mL by day 7 and by -0.63 log10 copies / mL by day 11 (nominal p=0.002 at the combined dose). At day 5, the relative reduction compared to placebo was -1.1 log10 copies (nominal p=0.002 at the combined dose). In seropositive patients (n=270), the clinical and virological benefits of the antibody cocktail were limited (clinical endpoint HR: 0.98; time-weighted mean viral load reduction of -0.20 log10 copies / mL by day 7 at the combined dose). Treatment with the cocktail resulted in similar viral load reductions in inpatients and outpatients, with the most significant difference observed between patients treated with the cocktail and those receiving placebo in seronegative patients, which is consistent with the data from Example 2 (Figures 25-28).

[0163] Clinical and virological analyses included data from hospitalized patients receiving low-flow oxygen (defined as maintaining >93% oxygen saturation via a nasal cannula, simple face mask, or similar device), which included 217 sero-negative and 270 sero-positive patients at the time of their participation in the study, although sero-negative patients comprised less than half of the study population based on the placebo rate, which accounted for approximately two-thirds of deaths in the absence of antibody cocktail treatment. Patients were randomized to receive either an antibody cocktail (either a high dose of 8,000 mg or a low dose of 2,400 mg) or a placebo in addition to standard therapy, with 67% receiving remdesivir and 74% receiving systemic corticosteroids. Similar clinical and virological efficacy was observed for both the high-dose and low-dose antibody cocktails.

[0164] Both antibody cocktail doses were well tolerated. In the overall study population, the incidence of serious adverse events was 21% in the high-dose group, 20% in the low-dose group, and 24% in the placebo group. Infusion reactions were more common in the high-dose antibody cocktail (high-dose 2.7%, low-dose 0.9%, placebo 1.4%), and there were two discontinuations due to infusion-related reactions, both of which occurred in the high-dose group.

[0165] Example 2. Clinical evaluation of anti-SARS-CoV-2 spike glycoprotein antibodies in outpatients 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 tolerability of mAb10933 + mAb10987 combination therapy (which may be collectively referred to as REGN-COV2 or REGN-COV) or alternatively mAb10989 monotherapy in adult outpatients (i.e., day patients) with COVID-19 or asymptomatic SARS-CoV-2 infection.

[0166] Research Objectives: The primary and secondary objectives of each phase of the research are described below.

[0167] Exemplary Uses: Exemplary uses that may be permitted based on the results (including intermediate results) from this embodiment are as follows: This exemplary use applies to intravenous infusion of REGEN-COV, with mAb10933 and mAb10987 administered together. REGEN-COV should be administered as soon as possible after a SARS-CoV-2 positive virus test and within 7 days of symptom onset in adults and children aged 12 years or older weighing at least 40 kg who are at risk of progressing to severe COVID-19 and / or hospitalization. COVID-19 illness can range from very mild (including some unreported symptoms) to severe, including illness that results in death. While the information available to date suggests that most COVID-19 illnesses are mild, severe illness can occur and some other medical conditions may be exacerbated. For example, people of all ages with severe persistent (chronic) medical conditions such as heart disease, lung disease, and diabetes, as well as other conditions including obesity, appear to be at higher risk of hospitalization with COVID-19. Older age, with or without other conditions, also increases the risk of hospitalization with COVID-19. This exemplary approval is for the use of REGEN-COV to treat mild to moderate coronavirus disease 2019 (COVID-19) in adult and pediatric patients aged 12 years or older, weighing at least 40 kg, and who have a positive direct SARS-CoV-2 virus test result indicating a high risk of progressing to severe COVID-19 and / or hospitalization.

[0168] The following medical conditions or other factors apply to adults and Pediatric patients (12-17 years old and weighing at least 40 kg) This could increase the risk of developing severe COVID-19. ○Elderly (for example, age ≥ 65 years old) ○ Obese or overweight (for example, BMI > 25 kg / m²) 2If you are an adult or between 12 and 17 years old, you have a BMI of ≥85th percentile for your age and sex based on the CDC growth charts (https: / / www.cdc.gov / growthcharts / clinical_charts.htm). ○Pregnancy ○Chronic kidney disease ○Diabetes ○ Immunosuppressive diseases or immunosuppressive treatments ○ Cardiovascular disease (including congenital heart disease) or hypertension ○ Chronic lung diseases (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 give rise to medical complications (e.g., genetic or metabolic syndromes and severe congenital abnormalities) ○Dependent on medical technology (e.g., tracheostomy, gastrostomy, or positive pressure ventilation (unrelated to COVID-19))

[0169] Other medical conditions or factors (e.g., race or ethnicity) also increase the risk of individual patients progressing to severe COVID-19, and approval of REGEN-COV under the EUA is not limited to the conditions listed above. For additional information on medical conditions and factors associated with an increased risk of progressing to severe COVID-19, please refer to the CDC website: www.cdc.gov / coronavirus / 2019-ncov / need-extra-precautions / people-with-medical-conditions.html. Healthcare providers should consider the benefit-risk of each individual patient.

[0170] Restrictions on authorized use: ●In this exemplary use, REGEN-COV should not be used in the following patients: -Patients hospitalized due to COVID-19, or -Patients who require oxygen therapy due to COVID-19, or - Patients receiving long-term oxygen therapy due to underlying non-COVID-19 related comorbidities who require an increase in baseline oxygen flow rate due to COVID-19. However, an alternative approved use is conceivable for the use of REGEN-COV in patients who may be hospitalized due to COVID-19, and / or who require oxygen therapy due to COVID-19, and / or who require increased baseline oxygen flow due to COVID-19 in patients receiving long-term oxygen therapy due to underlying non-COVID-19 related comorbidities.

[0171] Primary purpose: 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 SARS-CoV-2 viral shedding. Part B ● To evaluate the safety and tolerability of mAb10989 compared to placebo. ● To evaluate the virological efficacy of mAb10989 compared to placebo in reducing SARS-CoV-2 viral shedding. Phase 2 To evaluate the virological efficacy of mAb10933+mAb10987 and mAb10989 compared to placebo in reducing SARS-CoV-2 viral shedding. Phase 3 To evaluate the clinical efficacy of mAb10933 + mAb10987 and mAb10989 compared to placebo.

[0172] Secondary purpose: Phase 1 Part A ● To evaluate additional indicators of virological efficacy of mAb10933 + mAb10987 compared to placebo. ● To evaluate the clinical efficacy of mAb10933 + mAb10987 compared to placebo. ● To compare quantitative reverse transcription polymerase chain reaction (RT-qPCR) results obtained from different sample types (intranasal [NP], nasal cavity, and saliva). ● To characterize the pharmacokinetic (PK) profiles of mAb10933 and mAb10987 in serum. ●To evaluate the immunogenicity of mAb10933 and mAb10987 Part B ● To evaluate additional indicators of virological efficacy of mAb10933 + mAb10987 compared to placebo. ● To evaluate the clinical efficacy of mAb10989 compared to placebo. ● To compare RT-qPCR results obtained from different sample types (NP, nasal cavity, and saliva) ● To characterize the PK profile of mAb10989 in serum ● To evaluate the immunogenicity of mAb10989 Phase 2 ● To evaluate additional indicators of virological efficacy of mAb10933 + mAb10987 compared to placebo. ● To evaluate the clinical efficacy of mAb10933 + mAb10987 and mAb10989 compared to placebo. ● To evaluate the safety and tolerability of mAb10933 + mAb10987 and mAb10989 compared to placebo. ● To characterize the concentrations of mAb10933, mAb10987, and mAb10989 in serum. ●To evaluate the immunogenicity of mAb10933, mAb10987, and mAb10989 Phase 3 ● To evaluate the virological efficacy of mAb10933+mAb10987 and mAb10989 compared to placebo in reducing SARS-CoV-2 viral shedding. ● To evaluate the safety and tolerability of mAb10933 + mAb10987 and mAb10989 compared to placebo. ● To characterize the concentrations of mAb10933, mAb10987, and mAb10989 in serum. ●To evaluate the immunogenicity of mAb10933, mAb10987, and mAb10989

[0173] Study Design: This is an adaptive phase 1 / 2 / 3 randomized, double-blind, placebo-controlled master protocol to evaluate the efficacy, safety, and tolerability of mAb10933 + mAb10987 combination therapy and mAb10989 monotherapy in adult outpatients (i.e., day patients) with COVID-19 or asymptomatic SARS-CoV-2 infection. To be eligible, adult patients must have laboratory-confirmed symptoms of SARS-CoV-2 and COVID-19 but must not have been hospitalized or be currently hospitalized. In phase 1, only patients with COVID-19 were enrolled. In phase 2, symptomatic and asymptomatic patients were enrolled in separate cohorts. Phase 1 In Phase 1 Part A, randomization was limited to low-dose mAb10933+mAb10987, high-dose mAb10933+mAb10987, and placebo. In Part B, randomization was limited to mAb10989 and placebo. On day 1, eligible patients in Part A were randomized to receive a single intravenous (IV) dose of either mAb10933+mAb10987 (low-dose), mAb10933+mAb10987 (high-dose), mAb10989, or placebo. Patients were then isolated 48 hours after administration, during which time they were closely monitored for serious adverse events (SAEs) and adverse events of particular interest (AESIs). On day 3, after completing the day's assessment, patients could return home if medically appropriate. After completing the assessment on day 7, all patients were discharged home if medically appropriate. Throughout the study, safety information (SAEs and AESIs) was collected as it concerned visits requiring any medical intervention related to COVID-19. Nasopharyngeal (NP) swabs, nasal swabs, and saliva samples were collected to assess viral shedding. The study concluded on day 29 with a final in-person assessment of patients, including NP swab, nasal swab, and / or saliva sample collection (where feasible), as well as blood sampling for PK, anti-drug antibodies (ADA), and exploratory analysis. Phase 2 On day 1, eligible patients were randomized in a 1:1:1:1 ratio to receive either a single dose of mAb10933+mAb10987 (low dose), mAb10933+mAb10987 (high dose), mAb10989, or placebo. After administration of the study drug, patients were observed for 2 hours and discharged home if no SAE or AESI was observed. Nasopharyngeal swabs were collected at intervals of the first two weeks and twice weekly thereafter. Blood samples were collected periodically. Information on SAEs, AESIs, and the need for COVID-19-related medical interventions that occurred during treatment was recorded throughout the study. On day 29, patients underwent a final evaluation including nasopharyngeal swab collection and blood sampling for PK, ADA, and exploratory analysis.

[0174] Study period: The trial period was 30 days for each patient.

[0175] Study population: This study enrolled non-hospitalized adult patients who tested positive for SARS-CoV-2.

[0176] Sampling size – In Phase 1, up to 100 patients were enrolled until randomization. In Phase 2, approximately 1300 patients were enrolled until randomization. It was estimated that 704 patients (176 patients per group) would be needed for Phase 3.

[0177] Selection Criteria: Patients must meet the following criteria to be eligible for inclusion in the study. 1. Male or female ≥ 18 years of age (or the legal age of majority in the country) at the time of randomization; 2. Having a SARS-CoV-2 positive molecular diagnostic test (by SARS-CoV-2 RT-PCR or other molecular diagnostic assay validated using an appropriate sample such as NP, nasal cavity, oropharyngeal [OP], or saliva) ≤ 72 hours prior to randomization. Past records of positive results from tests performed ≤ 72 hours prior to randomization are acceptable; 3. Meets one of the following two criteria. a. Symptomatic cohort (all phases): Patients with symptoms consistent with COVID-19, determined by the principal investigator to have had onset ≤ 7 days prior to randomization. or b. Asymptomatic cohort (Phase 2): All of the following conditions must be met. ● No symptoms consistent with COVID-19 occurring at any point in time <2 months prior to randomization (as determined by the principal investigator) ● No positive SARS-CoV-2 test results from samples collected >7 days prior to randomization. ● No known contact (for any period) with individuals who have confirmed COVID-19 or a confirmed positive SARS-CoV-2 test within 14 days prior to randomization. 4. Maintain an O2 saturation level of ≥93% in indoor air; 5. We are willing and willing to provide informed consent signed by the research patient or their legal representative; and 6. The patient is willing and able to comply with research procedures, including providing samples for viral shedding tests after discharge.

[0178] Exclusion Criteria: Patients who meet any of the following criteria will be excluded from the study. 1. Patients who were hospitalized due to COVID-19 before randomization or who are hospitalized at the time of randomization (hospitalized patients); 2. Within three months prior to the screening visit or within five half-lives of the investigational drug (whichever is longer), the patient has participated in or is currently participating in a clinical study evaluating COVID-19 convalescent plasma, monoclonal antibodies against SARS-CoV-2, or intravenous immunoglobulin (IVIG); 3. Prior, current, or planned future use of COVID-19 convalescent plasma, mAbs for SARS-CoV-2, intravenous immunoglobulin (IVIG) (any indication), systemic corticosteroids (any indication), or any treatment approved under Emergency Use Authorization (EUA) within the past 30 days prior to the screening visit or within 5 half-lives of the investigational drug (whichever is longer); 4. Having a known allergy or hypersensitivity to any component of the drug being studied; 5. Has been discharged from the hospital, or is scheduled to be discharged and enter an isolation facility; 6. Pregnant or breastfeeding women or 7. Women of childbearing potential (WOCBP) * Sexually active men who do not wish to practice highly effective contraception during continuous sexual activity, or before the initial dose / before the start of the first treatment, during the study, and for at least six months after the last dose. Signs and symptoms of hypersensitivity, including infusion-related reactions, may include fever, chills, nausea, headache, bronchospasm, hypotension, angioedema, pharyngeal irritation, and rash (including urticaria, itching, myalgia, and dizziness). Highly effective contraceptive methods for women include: ● Stable use of combined (estrogen and progestogen-containing) hormonal contraceptives (oral, vaginal, transdermal) or progestogen-only hormonal contraceptives (oral, injectable, implantable) associated with ovulation inhibition for two or more menstrual cycles that began prior to screening. ● Intrauterine contraceptive device (IUD), ● Intrauterine hormone-releasing system (IUS) ● Bilateral tubal ligation, ● Partner who has undergone vasectomy † , and / or ●Sexual abstinence ‡、§ . Male study participants with a WOCBP partner underwent vasectomy. † or sexual abstinence ‡、§ Unless you practice [unclear / unclear], you will need to use a condom. * WOCBP is defined as a woman of childbearing potential from menarche to menopause, unless permanently infertile. Postmenopausal status is defined as the absence of menstruation for 12 months without an alternative medical cause. A high follicle-stimulating hormone (FSH) level range in postmenopausal women can be used to confirm the postmenopausal status in women not using hormonal contraceptives or hormone replacement therapy. However, if there is no amenorrhea for 12 months, a single FSH measurement is insufficient to determine the onset of postmenopausal status. The above definitions follow the guidance of the Clinical Trials Advancement Group (CTFG). Pregnancy tests and contraception are not required for women who have had a hysterectomy or tubal ligation. Permanent contraception methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. †Partners who have undergone vasectomy or participants in vasectomy studies must have received a medical evaluation of the success of the surgery. ‡Sexual abstinence is considered a highly effective method only if it is defined as refraining from heterosexual intercourse for the entire duration of the risk associated with the research drug. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the patient's preferred normal lifestyle.

[0179] Research treatments: Co-administered mAb10933+mAb10987 combination therapy, 2.4g (1.2g each of mAb10933 and mAb10987) IV single dose, co-administered mAb10933+mAb10987 combination therapy, 8.0g (4.0g each of mAb10933 and mAb10987) IV single dose, mAb10989 monotherapy, 1.2gm IV single dose, or placebo IV single dose.

[0180] Endpoints: Primary, secondary, and exploratory endpoints were specified for each phase, as defined below.

[0181] Primary endpoint Phase 1 The primary endpoint for Phase 1 was as follows: Parts A and B ●Percentage of patients experiencing serious adverse events (SAEs) during treatment up to day 29 ●Percentage of patients experiencing infusion-related reactions (grade ≥ 2) up to day 4 ●Percentage of patients experiencing hypersensitivity reactions (grade ≥ 2) up to day 29 ●Viral shedding (log) from day 1 to day 22 was measured in nasopharyngeal (NP) swab samples by quantitative reverse transcription quantitative polymerase chain reaction (RT-qPCR). 10 Time-weighted average change from baseline in copies / mL. Phase 2 The primary endpoint of Phase 2 was viral shedding (log) from day 1 to day 22, as measured by RT-qPCR in NP swab samples. 10 This was the time-weighted average change from baseline in copies / mL. Phase 3 The primary endpoint for Phase 3 was the proportion of patients who had visited the hospital requiring ≥1 COVID-19-related medical intervention by day 29.

[0182] Secondary endpoint Phase 1 Virology ●Viral shedding (log) from day 1 to day 22, as measured by RT-qPCR in saliva samples. 10 Time-weighted average change from baseline in copies / mL ●Viral shedding (log) from day 1 to day 22, as measured by RT-qPCR in nasal swab samples. 10 Time-weighted average change from baseline in copies / mL ●Time to negative RT-qPCR result in any tested sample (NP swab, saliva, or nasal swab) for which no positive RT-qPCR result was obtained afterward. ● Changes from baseline in SARS-CoV-2 virus shedding at each hospital visit up to day 29, as measured by RT-qPCR in NP swabs. ● Changes from baseline in SARS-CoV-2 virus shedding at each visit up to day 29, as measured by RT-qPCR in saliva samples. ● Changes from baseline in SARS-CoV-2 virus shedding at each visit up to day 29, as measured by RT-qPCR in nasal swabs. ● Correlation and agreement of RT-qPCR results across different sample types (NP, nasal cavity, and saliva) ●Viral shedding (log) from day 1 to the post-baseline study day (e.g., days 5, 7, 15, and 29) 10 Time-weighted average change from baseline in copies / mL clinical ● Percentage of patients who have had ≥1 visit requiring COVID-19-related medical intervention by day 29. A visit requiring COVID-19-related medical intervention is defined as an admission where the primary reason for admission is COVID-19, or an outpatient visit (including visits to the ER, UCC, clinic, or telemedicine visit) where the primary reason for the visit is COVID-19. ● Percentage of patients who have had ≥2 visits requiring COVID-19-related medical intervention by day 29 ●Total number of visits requiring COVID-19-related medical intervention up to day 29 ● Percentage of patients hospitalized due to COVID-19 by day 29 ●Percentage of patients who have visited an outpatient or telemedicine facility at least once due to COVID-19 by day 29 PK / ADA ●Concentrations of mAb10933, mAb10987, and mAb10989 in serum, and corresponding PK parameters ●Immunogenicity as measured by anti-drug antibodies (ADA) against mAb10933, mAb10987, and mAb10989 Phase 2 The secondary endpoints for Phase 2 were as follows: Virology ●Time until no positive RT-qPCR is found in the NP swab, and until a negative RT-qPCR is found. ● Changes from baseline in viral shedding at each visit up to day 29, as measured by RT-qPCR in NP samples. ●Viral shedding (log) from day 1 to the post-baseline study day (e.g., days 5, 7, 15, and 29) 10 Time-weighted average change from baseline in copies / mL clinical ●Percentage of patients who had ≥1 visits requiring COVID-19-related medical intervention by day 29 ● Percentage of patients who have had ≥2 visits requiring COVID-19-related medical intervention by day 29 ●Total number of visits requiring COVID-19-related medical intervention up to day 29 ● Percentage of patients hospitalized due to COVID-19 by day 29 ● Percentage of patients admitted to the ICU due to COVID-19 by day 29 ●Percentage of patients who have visited an outpatient or telemedicine facility at least once due to COVID-19 by day 29 ●Percentage of patients requiring mechanical ventilation due to COVID-19 by day 29 ● Number of days hospitalized due to COVID-19 ●Percentage of patients who died from all causes by day 29 ●Percentage of patients who developed SAEs during treatment up to day 29 ●Percentage of patients experiencing infusion-related reactions (grade ≥ 2) up to day 4 ●Percentage of patients experiencing hypersensitivity reactions (grade ≥ 2) up to day 29 ● Time to the first onset of any symptom of COVID-19 ● Duration of symptoms consistent with COVID-19 PK / ADA ●Concentrations of mAb10933, mAb10987, and mAb10989 in serum ●Immunogenicity as measured by anti-drug antibodies (ADA) against mAb10933, mAb10987, and mAb10989 Phase 3 The secondary endpoints for Phase 3 were as follows: Virology ●Viral shedding (log) from day 1 to day 22, as measured by RT-qPCR in NP swabs. 10 Time-weighted average change from baseline in copies / mL ●Time until no positive RT-qPCR is found in the NP swab, and until a negative RT-qPCR is found. ● Changes from baseline in SARS-CoV-2 virus shedding at each hospital visit up to day 29, as measured by RT-qPCR in NP swabs. ●Viral shedding (log) from day 1 to the post-baseline study day (e.g., days 5, 7, 15, and 29) 10 Time-weighted average change from baseline in copies / mL clinical ●Percentage of patients who have had ≥2 visits requiring COVID-19-related medical intervention by day 29 ●Total number of visits requiring COVID-19-related medical intervention up to day 29 ●Percentage of patients who have visited an outpatient or telemedicine facility at least once due to COVID-19 by day 29 ● Percentage of patients hospitalized due to COVID-19 by day 29 ● Percentage of patients admitted to the ICU due to COVID-19 by day 29 ●Percentage of patients requiring mechanical ventilation due to COVID-19 by day 29 ● Number of days hospitalized due to COVID-19 ●Percentage of patients who died from all causes by day 29 ●Percentage of patients who developed SAEs during treatment up to day 29 ●Percentage of patients experiencing infusion-related reactions (grade ≥ 2) up to day 4 ●Percentage of patients experiencing hypersensitivity reactions (grade ≥ 2) up to day 29 PK / ADA ●Concentrations of mAb10933, mAb10987, and mAb10989 in serum ●Immunogenicity as measured by anti-drug antibodies against mAb10933, mAb10987, and mAb10989

[0183] exploratory endpoints The exploratory endpoints for Phase 1 and Phase 2 were as follows: ●Percentage of patients with treatment failure who have mutations in the gene encoding the SARS-CoV-2 protein by day 29 ● Changes and percentage changes in neutrophil-lymphocyte ratio (NLR) at each visit up to day 29 ● Changes and rate of change of D-dimers at each visit up to day 29 ● Changes and rate of change in ferritin levels at each visit up to day 29 ● Changes and rate of change of C-reactive protein (CRP) at each visit up to day 29 ●Changes and percentage changes in lactate dehydrogenase (LDH) at each visit up to day 29 ● Changes in SE-C19 item scores over time ● Changes in PGIS scores over time ●PGIC score on day 29 ● Percentage of patients admitted to the ICU due to COVID-19 by day 29 (Phase 1 only) ●Percentage of patients requiring mechanical ventilation due to COVID-19 by day 29

[0184] Procedure and evaluation: Efficacy - Nasopharyngeal swabs (all phases), nasal swabs (Phase 1 only), and saliva samples (Phase 1 only) for SARS-CoV-2 RT-PCR, as well as details of COVID-19 hospital visits requiring medical intervention; Safety - Serious adverse events and adverse events of particular interest, blood samples for safety testing, and vital signs were recorded. Nasal swabs and saliva samples were used to collect secretions from patients to determine the presence or absence of SARS-CoV-2 virus and to measure viral shedding.

[0185] Statistical plan: Primary Efficacy Analysis – The primary efficacy variable for Phase 1 and Phase 2 was the time-weighted mean change from baseline in viral shedding (log10 copies / mL) from day 1 to day 22, as measured by RT-qPCR in NP swab samples. The primary hypothesis estimate was the mean difference in the primary efficacy variable between anti-S SARS-CoV-2 treatment and placebo, respectively, in the FAS. The primary efficacy variable was calculated using a trapezoidal scheme based on observed data and analyzed using an Analysis of Covariance (ANCOVA) model with treatment group and randomization stratification as fixed effects, and baseline viral shedding as a covariate. In Phase 2, analyses were performed separately for each cohort (symptomatic and asymptomatic) and combined for both cohorts. The least squares mean estimates of the time-weighted mean change in viral shedding from baseline in each treatment group, as well as the difference between each anti-spike mAb treatment group and placebo (in Phase 2, separately for each cohort and combined for both cohorts), are presented with the corresponding p-values, standard errors, and associated 95% confidence intervals. The primary efficacy variable in Phase 3 was the proportion of patients who visited the hospital due to worsening symptoms and signs of COVID-19 requiring medical intervention, and was compared between groups using a stratified Cochrane-Mantel-Henzel test at the two-sided 0.05 level. The p-values ​​and 95% confidence intervals for the treatment difference are presented below.

[0186] Safety analysis – List and summarize safety data, including serious adverse events and adverse events of particular interest, vital signs, and clinical laboratory tests, for each treatment group.

[0187] Results - The seamless Phase 1 / 2 / 3 trials described above demonstrated a significant reduction in SARS-CoV-2 viral load and time to symptom reduction in non-hospitalized patients with COVID-19 when treated with the combination of mAb10933 and mAb10987 (REGN-COV-2). REGEN-COV also significantly reduced hospital visits requiring COVID-19-related medical interventions. Randomized, double-blind trials measured the effect of adding REGEN-COV to standard care compared to adding placebo to standard care.

[0188] The final analysis of the Phase 1 / 2 portion included 799 patients: 275 (Group 1) and 524 (Group 2). Patients were randomized (1:1:1) to placebo, 2.4 g of mAb10933 + mAb10987 antibody cocktail (also known as REGEN-COV), or 8.0 g of REGEN-COV, and were characterized by baseline endogenous immune response to SARS-CoV-2 (serum antibody-positive / negative). Efficacy was evaluated in patients with positive baseline RT-qPCR results, and safety was evaluated in all patients. A pre-specified hierarchical analysis of virological endpoints in Group 2 was performed to confirm the descriptive analysis from Group 1, which had been previously reported. The proportion of patients with ≥1 medically-attended visit (MAV) up to day 29 was evaluated in Group 1 + 2.

[0189] The time-weighted average reduction in viral load (log10 copies / mL) up to day 7 is equivalent to a baseline viral load > 10. 7In patients with copies / mL (a pre-specified primary endpoint), the change was significantly greater with REGEN-COV (combined 2.4g + 8.0g dose groups) compared to placebo: -0.68 (95% CI, -0.94 to -0.41; P<0.0001). Across all baseline viral loads, this change was -0.73 (P<0.0001) in serologically negative patients and -0.36 (P=0.0003) in the overall population. The proportion of patients with Covid-19-related MAV ≥1 was 2.8% (12 / 434) for REGEN-COV compared to 6.5% (15 / 231) for placebo (P=0.024; relative risk reduction = 57%), and the relative risk reduction for MAV was greater in patients with ≥1 risk factors for hospitalization (72%) or in patients who were serologically negative (65%). Adverse events were similar across the groups.

[0190] Summary of Study Design: Patients were randomly assigned (1:1:1) to receive placebo, 2.4 g of REGEN-COV (1.2 g each of casirivimab and imudevimab), or 8.0 g of REGEN-COV (4.0 g each of casirivimab and imudevimab) (Figure 5). The 29-day Phase 2 study included a screening / baseline period (-1 to 1 day), a follow-up period (2 to 25 days), and a final visit (day 29). The Phase 1 and Phase 2 portions of the study were identical, except for additional pharmacokinetic analyses in Phase 1.

[0191] Patients: Eligible patients were ≥18 years old, non-hospitalized, confirmed SARS-CoV-2 positive nasopharyngeal (NP) PCR test results ≤72 hours prior to randomization and symptom onset ≤7 days prior. Randomization was stratified by country and by the presence or absence of ≥1 risk factor for severe Covid-19, age >50, obesity (BMI >30), immunosuppression, and chronic cardiovascular, metabolic, hepatic, renal, or pulmonary disease. All patients were assessed for the presence or absence of anti-SARS-CoV-2 antibodies: anti-spike[S1]IgA, anti-spike[S1]IgG, and anti-nucleocapsid IgG. Because these results were not available for randomization, patients were randomized regardless of baseline serum antibody status and then grouped for analysis as serum antibody-negative (if all available tests were negative), serum antibody-positive (if any of the tests were positive), or unknown (missing or indeterminate result). The demographic and medical characteristics of the patients are shown in Table 5A below.

[0192] [Table 7-1]

[0193] [Table 7-2] SD: standard deviation * The plus / minus values ​​represent ±SD. Due to rounding, percentages may not add up to 100. IQR represents the interquartile range, and RT-PCR represents the reverse transcriptase polymerase chain reaction. †Race and ethnicity were reported by the patients. ‡The obesity index is calculated by dividing body weight in kilograms by the square of the height in meters. § Obesity is defined as a body mass index (BMI) of 30 or higher. Risk factors for hospitalization include age over 50, obesity, cardiovascular disease (including hypertension), chronic lung disease (including asthma), chronic metabolic disease (including diabetes), chronic kidney disease (including dialysis), chronic liver disease, and immunodeficiency (immunosuppression or use of immunosuppressants).

[0194] Intervention: At baseline (day 1), mAb10933 (casiribimab) and mAb10987 (imdevimab) (diluted with 250 ml of standard physiological saline solution for co-administration) or physiological saline placebo were administered intravenously over 1 hour.

[0195] Evaluation items (Endpoint) The primary virological endpoint and two major secondary clinical endpoints were pre-specified in this Phase 1 + Phase 2 (collectively referred to as Phase 1 / 2) analysis and tested hierarchically as shown in Table 5B. The primary virological endpoint was defined as the time-weighted mean change in viral load (log10 copies per milliliter) from baseline (Day 1) to Day 7. The major secondary clinical endpoints were the proportion of patients with at least one COVID-19-related visit requiring medical intervention (MAV) by Day 29, and the proportion of patients with at least one COVID-19-related MAV consisting solely of hospitalization, emergency room (ER) visits, or emergency treatment visits. MAV was defined as hospitalization, ER, emergency treatment, or clinic / telemedicine visits confirmed by the principal investigator to be related to COVID-19.

[0196] [Table 8] mFAS, modified complete analysis set; MAV, visits requiring medical intervention.

[0197] The safety endpoints 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 particular interest (AESIs): Hypersensitivity reactions or infusion-related reactions of grade ≥ 2 were included.

[0198] statistical analysis The statistical analysis plan for the presented analysis was finalized before database locking and deblinding of the Phase II dataset for an additional 524 patients. The full analysis set (FAS) included patients with Covid-19 symptoms who were randomized. Patients with a positive SARS-CoV-2 nasopharyngeal (NP) PCR test ≤72 hours at randomization (baseline) but who were negative by baseline central laboratory qualitative PCR (limit of detection, 714 copies per ml) were excluded from the analysis of virological and clinical endpoints in the modified full analysis set (mFAS). Subgroup analyses by serological status and baseline viral load were pre-specified in the statistical analysis plan. Safety was assessed in patients in the FAS who received the study drug (active or placebo).

[0199] To confirm the virological efficacy observed in Analysis Group 1 (Patients 1–275), virological endpoint analysis was performed using data from patients 276–799 (comprehensive) (524 patients; Analysis Group 2). However, clinical endpoint and safety analysis utilized data from all available patients, including the first 275 patients (Patients 1–799; Analysis Groups 1+2).

[0200] The virological efficacy endpoint was calculated as discussed below. The primary secondary clinical endpoint was analyzed using Fisher's exact test. Analysis of virological and clinical endpoints was performed with a two-sided α=0.05 using a hierarchical trial strategy to control for type I errors. Statistical analysis was performed using SAS software, version 9.4 or later (SAS Institute).

[0201] Baseline characteristics 799 patients were randomized in the Phase 1 / 2 portion of the trial. In the pooled 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 the 799 patients (analysis groups 1+2), 87 (10.9%) were negative for the trial in central laboratory SARS-CoV-2 NP RT-qPCR assays at baseline, and 47 (5.9%) lacked central laboratory baseline viral load data. As a result, the modified full analysis (mFAS) set included 665 patients. Similarly, of the 524 patients in analysis group 2 (primary virological efficacy analysis), the mFAS set included 437 patients.

[0202] Of the 799 randomized patients, the median age was 42.0 years, 47% were male, 9% were identified as Black or African American, and 50% were identified as Hispanic or Latino (Table 5A). 483 patients (60.5%) had ≥1 risk factor for Covid-19-related hospitalization, including obesity (37.3%), >50 years old (29.3%), cardiovascular disease (20.5%), or chronic metabolic disease (13.1%). Baseline characteristics were similar between patient analysis group 1 (275 patients) and patient analysis group 2 (524 patients) (Table 5C).

[0203] [Table 9-1]

[0204] [Table 9-2] SD: standard deviation. * The plus / minus values ​​represent ±SD. Due to rounding, percentages may not add up to 100. IQR represents the interquartile range, and RT-PCR represents the reverse transcriptase polymerase chain reaction. †Race and ethnicity were reported by the patients. ‡The obesity index is calculated by dividing body weight in kilograms by the square of the height in meters. § Obesity is defined as a body mass index (BMI) of 30 or higher. Risk factors for hospitalization include age over 50, obesity, cardiovascular disease (including hypertension), chronic lung disease (including asthma), chronic metabolic disease (including diabetes), chronic kidney disease (including dialysis), chronic liver disease, and immunodeficiency (immunosuppression or use of immunosuppressants).

[0205] At randomization, 408 patients (51.1%) were serologically negative for antibodies, 304 (38.0%) were serologically positive, and 87 (10.9%) had unknown serological antibody status. The median baseline viral load was 5.48 log10 copies / mL (baseline data was missing for 47 out of 799 patients), and 256 patients (32.0%) had a baseline viral load of >107 copies / mL. The mean time from symptom onset to randomization was 3.4 days for the entire study population, 3.2 days for serologically negative patients, 3.6 days for serologically positive patients, 2.9 days for patients with a viral load of >107 copies / mL, and 3.8 days for patients with a viral load of ≤107 copies / mL. Among the 408 patients with ≥1 risk factor for hospitalization, 336 (82.3%) were either serologically negative or had a viral load of >104 copies / mL.

[0206] Natural process The natural course of Covid-19 among placebo-treated patients in this analysis confirmed that the presence of endogenous antibodies against SARS-CoV-2 at baseline is a key indicator of viral and clinical outcomes. Patients in the placebo group who were serologically negative at baseline had a higher median viral load at baseline (7.73 log10 copies / ml vs. 3.88 log10 copies / ml) and took substantially longer to reduce viral levels to LLQ or undetectable compared to patients who were serologically positive (Figures 7 and 8). Similarly, in clinical outcomes, placebo patients who were serologically negative at baseline had a substantially higher proportion of Covid-19-related MAVs than placebo patients who were serologically positive at baseline (2.4%; 2 / 83) (9.7%; 12 / 124). Since the endogenous immune response was associated with baseline viral titer, it was expected that the risk of Covid-19-related MAV would be associated with baseline viral load and the presence of risk factors. MAV occurred in 0% (0 / 55) of patients with baseline viral load ≤10⁴ copies / mL compared with 8.5% (15 / 176) of patients with baseline viral load >10⁴ copies / mL, and in 2.2% (2 / 89) of patients without risk factors compared with 9.2% (13 / 142) of patients with ≥1 risk factor (Figure 9).

[0207] Virological effectiveness Pre-specified comparisons of virological efficacy endpoints were hierarchically evaluated in analysis group 2 of 524 patients who were confirmed SARS-CoV-2 positive by NP RT-qPCR at baseline (mFAS; n=437) (Tables 5B and 5D). REGEN-COV treatment significantly reduced viral load by day 7 compared to placebo in all pre-specified virological efficacy comparisons (Table 5D; Figures 10A, 10B, and 11). In the first comparison, baseline viral load >10 7Among patients with 10 copies / mL, the least squares mean difference in daily change in time-weighted mean viral load (TWA) up to day 7 between REGEN-COV treatment (combination of 2.4g and 8.0g doses) and placebo was -0.68 log10 copies / mL (95% CI, -0.94 to -0.41; P<0.0001) (Table 5D). Similarly, the least squares mean difference in daily change in TWA from baseline between REGEN-COV treatment and placebo was -0.73 log10 copies / mL in patients who were serologically antibody-negative at baseline (n=256) (95% CI, -0.97 to -0.48; P<0.0001), while in the overall modified complete analysis set (n=437) it was -0.36 log10 copies / mL (95% CI, -0.56 to -0.16; P=0.0003). These data indicate that, as previously observed, the reduction in viral load observed with antibody cocktail therapy was primarily driven by the effect in seroantibody-negative patients (Table 5D, Figures 10A, 10B, and 11). The therapeutic effect was similar for low-dose and high-dose antibody cocktails across all virological efficacy endpoint comparisons (Table 5D). Results from additional key virological endpoints are provided in Table 5E, Figure 12, and Figure 13.

[0208] [Table 10-1]

[0209] [Table 10-2] * Time-weighted mean changes in viral load were analyzed using a covariance model with fixed effects including treatment group, risk factors, and baseline antibody status, and covariates including baseline viral load and treatment group based on baseline viral load. Confidence intervals were not adjusted for multiplicity. †The confidence interval for the difference (REGEN-COV-placebo) was not adjusted for multiplicity based on precise methods.

[0210] [Table 11] The p-values ​​are based on an MMRM model with fixed effects including baseline, baseline serological status, country, treatment, treatment during visits, base treatment, and base treatment during visits and consultations, as well as randomized effects related to the subjects. Cl, confidence interval; LS, least squares; SE, standard error.

[0211] [Table 12]

[0212] The virological efficacy endpoint of the daily change in time-weighted average (TWA) from baseline (day 1) to day 7 was calculated for each patient as the area under the concentration-time curve using a linear trapezoidal scheme (area under the curve obtained by dividing the change from baseline by the time interval of the observation period). This was analyzed using a covariance model with fixed effects of treatment group, country, and risk factors (no risk factors vs. at least one risk factor), and covariates of baseline viral load and baseline interactive therapy.

[0213] Clinical efficacy Two pre-specified clinical efficacy endpoints were available for the hierarchical trial of the proportion of patients with at least one COVID-19-related medical intervention (MAV) visit, and the proportion of patients with at least one COVID-19-related MAV visit consisting only of hospitalization or ER / emergency treatment visit (Tables 5B and 5D). Both endpoints were evaluated up to day 29 in a pooled group of 799 patients (analysis groups 1+2) who were confirmed SARS-CoV-2 positive by NP RT-qPCR at baseline (mFAS; n=665). Overall, 67% of COVID-19-related MAVs were hospitalization or ER visits (30% and 37%, respectively), 26% clinic / telemedication visits, and 7% emergency treatment visits. A description of COVID-19-related MAVs is included in Table 5F.

[0214] [Table 13-1]

[0215] [Table 13-2]

[0216] [Table 13-3]

[0217] [Table 13-4] * Analysis group 1 + 2; modified complete analysis set. †Only 12.7 mL was administered; treatment was discontinued due to a possible injection-related reaction. ER (Emergency Room); ICU (Intensive Care Unit); MAV (Medical Aid Visit).

[0218] The proportion of patients with ≥1 Covid-19-related MAV in the REGEN-COV treatment group (combined doses of 2.4g and 8.0g) was 2.8% (12 out of 434) compared to 6.5% (15 out of 231) in the placebo group, representing a relative reduction of 57% (absolute difference compared to placebo, -3.7 percentage points; 95% CI, -7.9% to -0.3%; P=0.024) (Table 5D). The therapeutic effect observed with REGEN-COV was more pronounced in baseline serum antibody-negative patients (3.4% vs. 9.7% placebo; 65% relative reduction) (Table 5G). Regarding the final hierarchical endpoint, the proportion of patients with Covid-19-related hospitalization or ER / emergency treatment visits was numerically lower in the REGEN-COV group (vs. placebo), but the difference was not statistically significant (Table 5D). Post-hoc analysis showed a reduction in the proportion of patients treated with antibody cocktail therapy who were hospitalized or died (combined dose group) (0.7% [3 out of 434] vs. 2.2% [5 out of 231]; a relative reduction of 68%), and a reduction in the proportion of patients who were hospitalized or had emergency room visits (1.8% [8 out of 434] vs. 4.3% [10 out of 231]; a relative reduction of 58%) (Table 5H).

[0219] [Table 14] * COVID-19-related MAVs included hospitalizations, ER visits, emergency clinic visits, and outpatient / clinic / telemedicine visits. †95%Cl and p-values ​​are based on precise methods. Cl: Confidence interval; ER: Emergency room; MAV: Visit requiring medical intervention.

[0220] [Table 15] * The 95% Cl and p-values ​​are based on precise methods. Cl, confidence interval.

[0221] Additional post-hoc analyses investigated the efficacy of antibody cocktail therapy against MAV in various high-risk subgroups. The proportion of patients with a risk factor of ≥1 for hospitalization due to Covid-19-related MAV (n=408) in the REGEN-COV group (combined dose) versus the placebo group was 2.6% versus 9.2% (absolute difference compared to placebo, -6.5 percentage points; 95% CI, -17 to 4; relative reduction of 72%) (Figures 14A, 14B, and 14C; Table 5I). The proportion of patients (n=217) with Covid-19-related MAV, who were baseline serologically negative, had a viral load of >10⁴ copies / mL, and possessed ≥1 risk factor, in the REGEN-COV group (combined dose) versus the placebo group was 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 of patients who experienced MAV (59%) had a viral load of ≥4log10 copies / mL per visit requiring medical intervention (Table 5F; Figures 15A, 15B, and 15C). Similar to virological endpoints, no significant differences in clinical outcomes were observed between low-dose and high-dose treatment.

[0222] [Table 16] * COVID-19-related MAVs included hospitalizations, ER visits, emergency clinic visits, and outpatient / clinic / telemedicine visits. †95%Cl and p-values ​​are based on precise methods. Cl: Confidence interval; ER: Emergency room; MAV: Visit requiring medical intervention.

[0223] [Table 17] * COVID-19-related MAVs included hospitalizations, ER visits, emergency clinic visits, and outpatient / clinic / telemedicine visits. †95%Cl and p-values ​​are based on precise methods. Cl: Confidence interval; ER: Emergency room; MAV: Visit requiring medical intervention.

[0224] The proportion of patients with hospital visits requiring medical intervention due to exacerbation of Covid-19 was compared between the REGEN-COV combination dose group and placebo, and between each REGEN-COV treatment group and placebo, using Fisher's exact test at a two-sided alpha level of 0.05. Similar analyses were performed for the proportion of patients with Covid-19-related hospitalizations or emergency room or emergency treatment visits, and for the proportion of patients with hospital visits requiring each type of medical intervention.

[0225] safety Serious adverse events (SAEs) were experienced in 4 out of 258 patients (1.6%) in the REGEN-COV 2.4g group, 2 out of 260 patients (0.8%) in the REGEN-COV 8.0g group, and more frequently in the placebo group (i.e., 6 out of 262 patients [2.3%]) (Tables 5K and 5L). All serious adverse events were considered to be due to progressive or progressive Covid-19 disease and / or associated clinical conditions and were not assessed as being related to the study drug treatment.

[0226] During the safety observation period, no adverse events of particular interest (AESIs) (infusion-related reactions and hypersensitivity reactions of grade ≥ 2) occurred or worsened in patients in the 2.4g group, while four patients (1.5%) in the 8.0g group and two patients (0.8%) in the placebo group were reported (Tables 5K and 5L).

[0227] [Table 18] * The event was a grade 2 or higher hypersensitivity reaction or infusion-related reaction. †The events listed herein were either not present at baseline or were exacerbations 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.

[0228] [Table 19] * Only serious adverse events and adverse events of particular interest (infusion-related reactions and hypersensitivity reactions of grade 2 or higher) were collected. IV, intravenously.

[0229] Pharmacokinetics: The mean concentrations of casirivimab and imudevimab increased in a dose-proportional manner, consistent with the linear pharmacokinetics of a single intravenous dose (Table 5M). The mean ± SD serum concentrations of casirivimab and imudevimab at day 29 were 79.7 ± 34.6 mg and 65.2 ± 28.1 mg / L per liter, respectively, at the low (1.2 g) dose, and 250 ± 97.4 and 205 ± 82.7 mg / L per liter, respectively, at the high (4.0 g) dose (Table 5M).

[0230] [Table 20] * The mean (SD) [N], where N is the number of observations. † The injection lasted for 1 hour. § Concentration observed 28 days after administration, i.e., on day 29.

[0231] Serum for drug concentration analysis was collected from all patients before administration (at screening or baseline visit), on day 1 at the end of infusion, and on day 29. Additional serum was collected only from Phase 1 patients on days 3, 5, 7, and 15. Human serum concentrations of REGN10933 (casiribimab) and REGN10987 (imdevimab) were measured using a validated immunoassay with streptavidin microplates from Meso Scale Discovery (MSD, Gaithersburg, MD, USA). This method utilized two anti-idiotype monoclonal antibodies specific to either mAb10933 or mAb10987 as capture antibodies. Captured mAb10933 and mAb10987 were detected using two different non-competitive anti-idiotype monoclonal antibodies specific to either mAb10933 or mAb10987. The bioanalysis method specifically quantifies the level of each anti-SARS-CoV-2 spike mAb separately, without interference from other antibodies. The assay had a lower limit of quantification (LLOQ) of 0.156 μg / mL for each analyte in undiluted serum samples.

[0232] Consideration Findings from this final Phase 1 / 2 analysis of the REGEN-COV antibody cocktail for the treatment of outpatients with Covid-19 confirmed and expanded upon findings from the initial 275 patients. To better understand the natural course of Covid-19 in outpatients, data from placebo patients in this trial were included. These data confirm previous findings that patients who had not yet initiated their own immune response at baseline (i.e., serologically negative at baseline) had nearly 3 log copies / mL higher median viral loads at baseline and took longer to reach low or undetectable levels compared to patients who were serologically positive at baseline. Similar to other viral infections such as HIV, Ebola virus disease, and influenza, high viral loads indicate that Covid-19-related MAV >10 4As evidenced by the fact that it was elevated in placebo patients with a baseline viral load of copies / ml, it appears to be a predictor of disease progression in Covid-19. The data also indicate risk factors for severe disease such as older age and obesity, which may help predict outpatients most likely to subsequently have Covid-19-related MAV. For example, 9.2% (13 / 142) of placebo patients with ≥1 risk factor had MAV compared to 2.2% (2 / 89) of placebo patients with no risk factors. In this trial, >80% of patients with risk factors were either serologically negative for antibodies or had a viral load >10 4 It had copies / mL. In the absence of rapid serological tests or quantitative PCR assays to identify patients at risk, identifying patients with risk factors for hospitalization may help identify outpatients who are most likely to benefit from early treatment with antibody cocktails.

[0233] The pre-specified hierarchical analyses described herein prospectively and with high statistical significance confirmed the virological efficacy of REGEN-COV, revealing similar virological efficacy for both 2.4 g and 8.0 g doses of the antibody cocktail. Viral load reduction was greatest in the first 5 days after treatment in patients who were serologically negative or had high viral load at baseline. Treatment did not provide any apparent additional biological benefit in patients who had already initiated an effective endogenous antibody response against infection (serologically positive). Viral load reduction after treatment with either dose of REGEN-COV was accompanied by a significant reduction in the proportion of patients requiring subsequent Covid-19-related hospital visits (the majority of which (67%) were hospitalization or ER visits). The REGEN-COV antibody cocktail reduced MAV by a relative 57% (6.5% in placebo vs. 2.8% in the combined dose group; P=0.0240). Interestingly, compared to placebo, the reduction in the proportion of patients with MAV treated with REGEN-COV occurred only after the first week of treatment. One possible explanation for this finding is that medical visits occurring in the first week are not modifiable despite promoting viral clearance. For example, among patients treated with the antibody cocktail, all three hospitalizations occurred within the first three days after treatment when the viral load was still ≥4log10 copies / mL, but no hospitalizations occurred after day 7 (Table 5F; Figures 15A, 15B, and 15C). In contrast, among patients treated with placebo, three of the five hospitalizations occurred after day 7 when the viral load remained high (≥4log10 copies / mL). These data support early identification and rapid treatment of outpatients with Covid-19 to optimize the effectiveness of REGEN-COV treatment.

[0234] Low incidences of serious adverse events, infusion-related reactions, and hypersensitivity reactions were observed. Similar to previously reported results, serum concentrations of each antibody at day 29 were well above the predicted neutralizing target concentrations based on in vitro and preclinical data.

[0235] The clinical evidence from this trial suggests that treatment is most beneficial when given to high-risk patients who are most likely to have a high viral load and who are seen early after diagnosis, before their own immune response has begun. Furthermore, no adverse findings were observed in patients who were serologically antibody-positive at baseline. Early treatment of outpatients with Covid-19 is important, and when viral load or serological antibody status cannot be rapidly determined, risk-benefit assessments support treatment to prevent MAV in high-risk patients.

[0236] Phase 3 Test Plan Cohort 1 patient population - The Cohort 1 patient population for the Phase 3 portion of the study consists of adult (≥18 years) male and female patients and has the following characteristics: ●SARS-CoV-2 positive antigen or molecular diagnostic test (by validated SARS-CoV-2 antigen, RT-PCR, or other molecular diagnostic assay) ≤ 72 hours prior to randomization, and ●Symptoms consistent with COVID-19, determined by the principal investigator, that developed ≤ 7 days prior to randomization, and ● Severe COVID-19 risk factor is ≥1

[0237] Risk factors are defined as follows: a. Age > 50 b. Obesity defined as Body Mass Index (BMI) > 30 kg / m2 c. Cardiovascular diseases, including hypertension d. Chronic lung diseases, including asthma e. Type 1 or Type 2 Diabetes Membrane Syndrome f. Chronic kidney disease, including those undergoing dialysis. g.Chronic liver disease h. Pregnancy i. Immunosuppression (examples include cancer treatment, bone marrow or organ transplantation, immunodeficiency, HIV (when poorly controlled or evidence of AIDS), sickle cell anemia, thalassemia, and long-term use of immune-suppressing drugs).

[0238] Primary and primary secondary endpoints for Cohort 1: In Cohort 1, the primary endpoint was COVID-19-related visits requiring medical intervention (MAV) up to day 29. A COVID-19-related MAV was defined as a visit primarily due to COVID-19, including hospitalization, emergency room (ER) visit, emergency treatment visit, clinic visit, or telemedicine visit. Patients with multiple MAVs were counted as having one event.

[0239] The primary pre-specified secondary endpoint was the cumulative incidence of COVID-19-related hospitalizations or emergency room visits up to day 29.

[0240] Other important pre-specified secondary endpoints included various types of COVID-19-related MAVs and associated outcomes.

[0241] Virological data provide clear evidence that mAb10933+mAb10987 significantly enhances SARS-CoV-2 viral clearance. Furthermore, data from pooled Phase 1 / 2 analyses showed that the reduction in viral load translated into clinical benefit by significantly reducing COVID-19-related MAVs, defined as hospitalizations, ER visits, emergency treatment visits, or clinic or teletreatment visits for COVID-19. Specifically, a pre-specified multiplicity-controlled analysis of pooled Phase 1 / 2 data (n=799) showed a statistically significant reduction in MAVs in the mAb10933+mAb10987 treatment group compared to placebo (2.8% combined dose group vs. 6.5% placebo; p=0.0240). The majority of MAVs occurred in high-risk patients defined as seronegative at baseline, patients with high baseline viral load, or patients with at least one pre-existing risk factor for severe COVID-19 (e.g., >50 years, obesity, comorbidities). In exploratory analyses, treatment with mAb10933+mAb10987 showed the greatest benefit in these high-risk groups, with a reduction in the proportion of patients with MAV compared to placebo: 62% in patients with baseline viral load >10⁴ copies / mL (combination dose 3.2% vs. placebo 8.5%), 65% in patients who were sero-negative at baseline (combination treatment 3.4% vs. placebo 9.7%), and 72% in patients with at least one risk factor for severe COVID-19 (combination treatment 2.6% vs. placebo 9.2%). Given the clinical benefits observed in Phase 2, Phase 3 will focus on confirming the clinical benefit of mAb10933+mAb10987 in reducing MAV in high-risk patients and thereby demonstrating the clinical benefit of reducing viral load.

[0242] The sample size for Phase 3 Cohort 1 was estimated to be approximately 5,400 patients. Cohort 1 was continued until at least 80 patients enrolled in the primary analysis population (mFAS patients with at least one risk factor) were observed to have been hospitalized or visited the emergency room, and until the total number of hospitalized or visited the emergency room during the study in the primary analysis population exceeded 120.

[0243] The primary efficacy endpoint for Phase 3 Cohort 1 was the cumulative incidence of COVID-19-related MAVs up to day 29 in mFAS (randomized and treated PCR-positive patients with at least one risk factor at baseline).

[0244] Based on the time to the first hospitalization / ER visit, we analyzed the cumulative incidence of COVID-19-related hospitalizations / ER visits up to day 29, which was the primary secondary endpoint of Phase 3 Cohort 1.

[0245] For Phase 3, the planned virological analyses were descriptive. The time-weighted mean change from baseline in viral load (log10 copies / mL) from day 1 to post-baseline hospital visit was analyzed separately for patients who underwent an intensive sampling schedule, using the same methodology as for the Phase 2 primary virological endpoint based on mFAS in seronegative and seropositive patients. Percentage endpoints based on observed virological data were compared between groups using the same methodology as for the percentage clinical endpoint. Analysis was performed for seronegative mFAS and mFAS.

[0246] To evaluate the time course of treatment efficacy in terms of viral load, the change from baseline in viral load (log10 copies / mL) at each visit of seronegative mFAS and mFAS was analyzed using a mixed model for repeated measures (MMRM) for baseline, randomization, treatment, visit, baseline-based treatment with dialogue, visit-based baseline with dialogue, and visit-based treatment with dialogue.

[0247] The Phase 3 portion of the study evaluated two dose levels of mAb10933+mAb10987, 1200 mg and 2400 mg, in a 1:1 ratio (600 mg and 1200 mg per mAb, respectively). In the Phase 1 and Phase 2 results, mAb10933+mAb10987 at doses of 2400 mg and 8000 mg demonstrated similar virological and clinical efficacy, as assessed by MAV, and both doses had similar tolerable safety profiles. Given the similarity between the 2400 mg and 8000 mg doses, the Phase 3 study included the 2400 mg dose as the highest dose, along with lower doses.

[0248] Pediatric patients aged 0 to <18 years may be included in the Phase 3 portion of the study as a separate cohort (Cohort 2) to evaluate the safety, pharmacokinetics, immunogenicity, and efficacy of mAb10933 + mAb10987. Both symptomatic patients with COVID-19 at baseline and asymptomatic patients who are SARS-CoV-2 positive may be included in this cohort. Pediatric patients with severe COVID-19 risk factors may be included in Cohort 2.

[0249] Pediatric patients in Cohort 2 may be randomized in a 1:1:1 allocation ratio to receive a single intravenous (IV) dose of mAb10933+mAb10987 combination therapy in low-dose, high-dose, or placebo. However, the mAb10933+mAb10987 treatment group may be stratified according to body weight, as defined in Table 6 below.

[0250] Dose selection in the pediatric population (<18 years) can utilize both high-dose and low-dose weight-stratified fixed-dose approaches. For each weight-stratified dose targeting a higher dose in adults (2400 mg), the goal is to select a dose predicted by population PK modeling to ensure that the 5th percentile of serum concentration at 28 days post-administration (C28) is similar to or greater than the observed 5th percentile of C28 in adults for the 2400 mg dose. An additional consideration is to ensure that the predicted Cmax and AUC0-28 for each weight-stratified dose do not exceed the values ​​previously achieved in adults. Both mAb10933 and mAb10987 exhibited linear PK, and therefore the same 50% reduction used in selecting the lower adult doses (2400 mg to 1200 mg) in Phase 3 was applied to each of the pediatric weight-stratified fixed doses targeting the adult dose of 1200 mg (Table 6).

[0251] [Table 21] 1 The dose value represents the total amount of the mAb10933 + mAb10987 combination therapy administered as a single IV dose.

[0252] The primary objective for patients in Cohort 2 was safety, and MAV was a descriptive secondary objective.

[0253] The primary endpoints for Cohort 2 were safety / tolerability and serum drug concentrations over time. ●Percentage of patients experiencing serious adverse events (SAEs) during treatment up to day 29 ●Percentage of patients experiencing infusion-related reactions (grade ≥ 2) up to day 4 ●Percentage of patients experiencing hypersensitivity reactions (grade ≥ 2) up to day 29 ● Concentrations of mAb10933 and mAb10987 in serum over time ● Immunogenicity measured by anti-drug antibodies (ADA), and neutralizing antibodies (NAb) against mAb10933 and mAb10987.

[0254] Cohort 2, with a maximum of approximately 180 pediatric patients (60 per treatment group), allows for the randomization of 45 patients to each PK-ADA sampling schedule.

[0255] Phase 3 Adult Data: Summary The objective of the confirmatory Phase 3 trial (Figures 31 and 32) was to prospectively demonstrate a clinically significant effect on the risk of COVID-19 hospitalization or all-cause mortality in high-risk outpatients and to confirm safety. The trial also prospectively evaluated the potential benefit for symptom duration. The seamless design began by comparing 8000 mg and 2400 mg against placebo and was adjusted to evaluate 2400 mg and 1200 mg against placebo based on the final analysis of the Phase 1 / 2 portion, which showed that the 8000 mg and 2400 mg doses were distinguishable based on antiviral and clinical endpoints (and that clinical events occurred primarily in high-risk patients). Data comparing 8000 mg and placebo were converted into descriptive analyses. Formal hierarchical analysis first evaluated the 2400 mg dose versus concurrent placebo (patients with ≥1 risk factor from the original and adjusted portions, n=approximately 2700), and then the 1200 mg dose versus concurrent placebo (patients with ≥1 risk factor, n=approximately 1500). An outpatient dose-range virological study further evaluated the antiviral efficacy (Example 7) of REGEN-COV doses ranging from 2400 mg to 300 mg IV (and 1200 mg to 600 mg subcutaneously). The main results are shown below.

[0256] [Table 22] 1. Based on a modified full analysis set (mFAS) population including all randomized patients with positive SARS-CoV-2 RT-qPCR testing from nasopharyngeal swabs at the time of randomization and all patients with ≥1 risk factor for severe COVID-19. 2. Formal hierarchical analysis was performed by first evaluating the 2,400 mg dose versus concurrent placebo, and then the 1,200 mg dose versus concurrent placebo. Based on a Phase 1 / 2 analysis showing that the 3.8,000 mg and 2,400 mg doses were indistinguishable, the Phase 3 protocol was modified to compare 2,400 mg and 1,200 mg versus placebo, and the 8,000 mg data was converted to a descriptive analysis.

[0257] In a Phase 3 trial involving 4,567 high-risk patients, mAb10933+mAb10987 (REGEN-COV) significantly reduced hospitalizations or all-cause mortality from COVID-19, shortened time to symptom resolution by 4 days, and confirmed the clinical benefits seen in Phase 1 / 2. In addition, REGEN-COV, administered as a single IV infusion of 1200 mg or 2400 mg, significantly reduced the proportion of patients with COVID-19-related hospitalizations or all-cause mortality in patients who were SARS-CoV-2 PCR-positive at baseline and had ≥1 risk factor for severe COVID-19. Similar therapeutic effects were observed at two dose levels: 2400 mg vs. placebo (PBO), 71.3% reduction (1.3% vs. 4.6%; p<0.0001); 1200 mg vs. PBO, 70.4% reduction (1.0% vs. 3.2%; p=0.0024). The reduction in COVID-19 hospitalization or all-cause mortality after day 3 of the study was greater (89.2%, 2400 mg vs. PBO, p<0.0001; 71.7%, 1200 mg vs. PBO, p=0.0101); initial events were less modifiable. See Figures 35, 36, and 37. The effect was more pronounced in patients with high viral load and / or seronegative status at baseline, but meaningful risk reduction was observed in seropositive patients. Furthermore, viral load at day 7 was significantly reduced across subgroups, consistently between the 2400 mg and 1200 mg doses (Figures 43, 44, 52, 53, 54, 55, 56, and 58). REGEN-COV administration resulted in faster symptom resolution at both doses: 2400 mg vs. PBO, median 10 vs. 14 days; p<0.0001; 1200 mg vs. PBO, median 10 vs. 14 days; p<0.0001 (Figures 38 and 39). A summary of these data is shown in Figure 33. Furthermore, serious adverse events (including fatal events) were more frequent in the placebo (PBO) group compared to the REGEN-COV dose group (PBO 4.0% vs. combined REGEN-COV group 1.4%) (Figures 40, 41, and 42). Demographics for this study are shown in Figure 34.

[0258] Phase 3 Adult Data: Complete Results and Discussion In the Phase 1 / 2 portion of this adaptive Phase 1-3 randomized placebo-controlled master protocol, REGEN-COV demonstrated efficacy in outpatients, rapidly reducing viral load and the need for Covid-19-related medical interventions. Indeed, on February 19, 2021, an independent data monitoring committee (IDMC) recommended halting patient enrollment in the placebo group for the Phase 3 portion of this master protocol due to the clear efficacy of REGEN-COV.

[0259] The Phase 3 portion of this adaptive randomized master protocol included 4,057 outpatients with COVID-19 who had one or more risk factors for severe disease. Patients were randomized to receive either a single intravenous placebo or various doses of REGEN-COV and followed for 29 days. Pre-specified hierarchical analyses compared REGEN-COV 2400 mg dose with concurrent placebo, followed by 1200 mg dose with concurrent placebo, for endpoints assessing the risk of hospitalization or death and time to symptom resolution. Safety was evaluated in all treated patients.

[0260] Both REGEN-COV 2400 mg and 1200 mg significantly reduced Covid-19-related hospitalizations or all-cause mortality compared to placebo (71% reduction, 1.0% vs. 3.2%, p<0.0024; 70% reduction, 1.3% vs. 4.6%, p<0.0001, respectively). The median time to resolution of Covid-19 symptoms was reduced by 4 days in both dose groups compared to placebo (10 vs. 14 days; p<0.0001). The efficacy of REGEN-COV was consistent across subgroups, including patients with serum antibodies. REGEN-COV reduced 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 rare (<2 patients in all groups).

[0261] Treatment with REGEN-COV was well-tolerated, significantly reduced Covid-19-related hospitalizations or all-cause mortality, rapidly resolved symptoms, and lowered viral load.

[0262] Study Design – This was an adaptive, multicenter, randomized, double-blind, placebo-controlled Phase 1 / 2 / 3 master protocol (NCT04425629) in outpatients with Covid-19. The Phase 3 portion included three cohorts: Cohort 1 (≥18 years), Cohort 2 (<18 years), and Cohort 3 (pregnant at randomization). Initially, Phase 3 patients were randomized in a 1:1:1 ratio to receive placebo, REGEN-COV 2400 mg (1200 mg each of casirivimab and imudevimab) IV, or REGEN-COV 8000 mg (4000 mg each of antibodies) IV (Figure 81). Based on 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 corrected on November 14, 2020, to modify the population and dose. As a result of the correction, subsequent enrolled patients who had ≥1 risk factor for severe Covid-19 were randomized in a 1:1:1 ratio to receive placebo, REGEN-COV 1200 mg (600 mg each antibody) IV, or REGEN-COV 2400 mg (1200 mg each antibody) IV. On February 19, 2021, in accordance with IDMC recommendations, patients were no longer randomized to receive placebo. The Phase 3 analysis presented herein consists of Cohort 1 patients (≥18 years old) randomized to REGEN-COV 2400 mg or 1200 mg, with their concurrent placebo group serving as a control.

[0263] Eligible patients (Cohort 1) were ≥18 years old and non-hospitalized, with confirmed local SARS-CoV-2 positive diagnostic test results ≤72 hours prior to randomization and ≤7 days prior to the onset of any Covid-19 symptoms. Randomization to the initial Phase 3 portion was stratified by country and the presence of severe Covid-19 risk factors. In the adjusted Phase 3 portion, only patients with ≥1 risk factor for severe Covid-19 were eligible. All patients were evaluated at baseline for anti-SARS-CoV-2 antibodies: anti-spike[S1]IgA, anti-spike[S1]IgG, and anti-nucleocapsid IgG. Because assay results were not available at randomization, patients were grouped as serological antibody negative (all available tests negative), serological antibody positive (any available tests positive), or other (uncertain / unknown results) for virological and subgroup analysis purposes.

[0264] At baseline (day 1), REGEN-COV (diluted with standard saline solution for co-administration) or saline placebo was administered intravenously. Covid-19-related hospitalizations were assessed by the principal investigator. Twenty-three Covid-19 symptoms were assessed daily using the Symptoms Evolution of COVID-19 (SE-C19) electronic journal. Quantitative virological analysis of nasopharyngeal (NP) swab samples and serum antibody tests was performed in the central laboratory and previously described.

[0265] The study hierarchically tested pre-specified primary and two primary secondary endpoints (Figure 89). The primary endpoint was the proportion of patients with ≥1 COVID-19-related hospitalization or all-cause death by day 29. The two primary secondary clinical endpoints were (1) the proportion of patients with ≥1 COVID-19-related hospitalization or all-cause death between day 4 and day 29, and (2) time to COVID-19 symptom resolution. Time to COVID-19 symptom resolution was defined as the time from randomization to the first day when a subject recorded "symptom-free" (score 0) for all symptoms except cough, fatigue, and headache (which could be "mild / moderate" (score 1) or "no symptoms" (score 0)). Safety endpoints for the Phase 3 portion of the study included serious adverse events (SAEs) that occurred or worsened during the observation period, and adverse events of particular interest (AESIs): hypersensitivity reactions and infusion-related reactions of grade ≥2, as well as adverse events that occurred during treatment requiring medical intervention at a healthcare facility.

[0266] The statistical analysis plan for the presented analysis was finalized before database locking and deblinding of Phase 3 Cohort 1, and the primary analysis did not include patients from the Phase 1 / 2 portion of previously reported trials. The full analysis set (FAS) included all randomized symptomatic patients. Efficacy analyses were performed based on the modified FAS (mFAS), defined as all randomized patients with ≥1 risk factors for severe Covid-19 and RT-qPCR trials determined at baseline in a central laboratory-positive SARS-CoV-2 test. Safety was assessed in treated patients within the FAS. The proportion of patients with ≥1 Covid-19-related hospitalization or all-cause mortality was compared between each dose group and placebo using the stratified Cochrane-Mantel-Haenszel (CMH) test with country as the stratification factor. The P-values ​​from the stratified CMH trial for relative risk reduction using the Farrington-Manning method and the 95% confidence intervals (CIs) are presented. Time to symptom resolution of Covid-19 was assessed in patients with a baseline total severity score > 3 and analyzed using a stratified log-rank test with country as the stratification factor. The median time and associated 95% CIs were derived from the Kaplan-Meier method. Hazard ratios and 95% CIs were estimated by Cox regression models. Analysis of primary and major clinical endpoints was performed with two-sided α=0.05 using a hierarchical trial strategy to control for type I errors (Figure 89). Statistical analysis was performed using SAS software, version 9.4 or later (SAS Institute).

[0267] Results (test group) Phase 3 patients were enrolled between September 24, 2020, and January 17, 2021. Initially, in the original Phase 3 portion, a total of 3088 patients, regardless of the presence or absence of severe Covid-19 risk factors, were randomized to receive a single dose of either placebo, REGEN-COV 8000 mg, or REGEN-COV 2400 mg. Subsequently, in the adjusted Phase 3 portion, an additional 2519 patients with ≥1 risk factor were randomized to receive a single dose of either placebo, REGEN-COV 2400 mg, or REGEN-COV 1200 mg (Figure 76). Patients had a median follow-up period of 45 days, and 96.6% of patients had a follow-up of >28 days.

[0268] The primary efficacy population included individuals with ≥1 risk factor for severe Covid-19 and baseline central laboratory test positive SARS-CoV-2 (mFAS) (Figure 76). Within the mFAS population (n=4057), demographic and baseline medical characteristics were balanced between the placebo and REGEN-COV groups (Figure 78). The median age was 50 years (interquartile range [IQR, 38-59]), with 52% male, 14% ≥65 years, 28% Hispanic, and 61% obese. The most common risk factors were obesity (58%), ≥50 years (52%), and cardiovascular disease (36%), and 3% of patients were immunosuppressed or receiving immunosuppressant medication (Figure 90). Similar demographic and baseline medical characteristics were observed in the overall complete analysis set (n=5607) and the REGEN-COV 8000 mg group (Figure 91).

[0269] The median NP viral load is 6.98log 10The viral load was 50 / 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 lack of endogenous immune response at baseline indicated that the enrolled individuals were in the early stages of infection. NP viral load and serum antibody negativity were similar across treatment groups. Patients had a median of 3 days (IQR 2–5) of Covid-19 symptoms at randomization, which was well-balanced across treatment groups.

[0270] Results (natural course) There was an association between baseline viral load and the risk of COVID-19-related hospitalization or all-cause mortality: a greater proportion of patients with high viral loads experienced hospitalization and / or death compared to patients with lower baseline viral loads (baseline viral load > 10%). 6 In the simultaneous placebo groups receiving 2400 mg and 1200 mg of copies / mL, the rates were 6.3% [55 / 876] and 4.2% [20 / 471], respectively; baseline viral load ≤ 10 6 In the concurrent placebo groups receiving 2400 mg and 1200 mg of copy / mL, the prevalence was 1.3% [6 / 457] and 1.5% [4 / 273] of patients, respectively (Figure 92).

[0271] Patients in the placebo group who were serologically negative at baseline had a higher median viral load at baseline (7.45 log) compared to patients who were serologically positive. 10 copy / ml vs 4.96log 10 (copies / ml), it took longer for the virus level to fall below the lower limit of quantification (LLQ) (Figure 82).

[0272] Baseline serum antibody status in placebo patients did not predict subsequent Covid-19-related hospitalization or all-cause mortality because these ratios were similar in serum antibody-negative and antibody-positive patients (antibody-negative: 5.3% [49 / 930] and 3.5% [18 / 519] in the 2400 mg and 1200 mg concurrent placebo groups, respectively; antibody-positive: 4.0% [12 / 297] and 3.7% [6 / 164] in the 2400 mg and 1200 mg concurrent placebo groups, respectively). However, we argue that serum antibody-positive placebo patients who subsequently required hospitalization or died had high viral loads at baseline and on day 7, similar to serum antibody-negative patients who required hospitalization or died, suggesting that some serum antibody-positive patients may have an ineffective innate antibody response (Figure 93).

[0273] Efficacy (primary endpoint) REGEN-COV 2400 mg and 1200 mg similarly reduced Covid-19-related hospitalizations or all-cause mortality by 71.3% (placebo 1.3% vs. 4.6%; 95% CI: 51.7% and 82.9%; p<0.0001) and 70.4% (placebo 1.0% vs. 3.2%; 95% CI: 31.6% and 87.1%; p<0.0024), respectively (Figures 79, 77A, 77B, and 94). Similar reductions in Covid-19-related hospitalizations or all-cause mortality were observed across subgroups (including patients who were serum antibody-positive at baseline) (Figures 79, 83A, 83B, and 83C).

[0274] Efficacy (primary secondary endpoint) A reduction in the proportion of patients with Covid-19-related hospitalizations or all-cause deaths was observed approximately 1–3 days after treatment with REGEN-COV (Figures 77A, 77B, and 79). During these initial 1–3 days, patients in the placebo group continued to experience Covid-19-related hospitalizations or deaths throughout the study period (46 / 1340 [3.4%]), while events were rare in the 2400 mg and 1200 mg REGEN-COV treatment groups (5 / 1351 [0.4%] and 5 / 735 [0.7%], respectively) (Figures 79, 84A, and 84B).

[0275] The median time to resolution of Covid-19 symptoms was 4 days earlier in both REGEN-COV groups than in placebo (10 days vs. 14 days; p<0.0001 for 2400 mg and 1200 mg, respectively) (Figures 79 and 77C). The more rapid resolution of Covid-19 symptoms with either REGEN-COV dose was evident by day 3. Both REGEN-COV doses were associated with similar improvements in symptom resolution across subgroups (Figure 85).

[0276] All REGEN-COV dose levels (1200 mg, 2400 mg, and 8000 mg) resulted in a similar and rapid reduction in viral load compared to placebo (Figures 86A, 86B, 86C, 87, 88A, 88B, and 88C).

[0277] Efficacy (other secondary endpoints) REGEN-COV treatment was associated with a lower proportion of patients having COVID-19-related hospitalizations (Figure 95). Among patients hospitalized due to COVID-19, those in the REGEN-COV group had shorter hospital stays and a lower rate of admission to the intensive care unit (Figure 96).

[0278] REGEN-COV treatment was associated with a lower proportion of patients having Covid-19-related hospitalizations, emergency room visits, or all-cause deaths up to day 29 (Figure 97), and a lower proportion of patients requiring visits for any medical intervention due to Covid-19 exacerbation (hospitalization, emergency room visits, emergency treatment visits, or clinic / telemedicine visits) or all-cause deaths (Figures 95, 98, and 99).

[0279] safety Serious adverse events (SAEs) were experienced by more patients in the placebo group (4.0%) compared to the REGEN-COV dose groups: 1.1% at 1200 mg, 1.3% at 2400 mg, and 1.7% at 8000 mg (Figure 80). More patients in the placebo group (5 patients, 0.3%) experienced treatment emergent adverse events (TEAEs) that resulted in death, compared to the REGEN-COV dose groups: 1 patient (0.1%) at 1200 mg, 1 patient (<0.1%) at 2400 mg, and 0 patients at 8000 mg (Figures 80 and 100). Most adverse events were consistent with complications of Covid-19 (Figures 101 and 102) and were not considered to be related to the study drug. Only a small number of patients experienced infusion-related reactions (0 in placebo; 2, 1, and 3 in 1200 mg, 2400 mg, and 8000 mg) and hypersensitivity reactions (1 in placebo and 1 in 2400 mg) (Figure 91). There were no discernible disparities in safety events, and similar safety profiles were observed across REGEN-COV doses. No safety signals were observed in safety laboratory parameters collected up to day 29.

[0280] Pharmacokinetics The mean serum concentrations of casirivimab and imudevimab on day 29 increased in a dose-proportional manner, consistent with linear pharmacokinetics (Figure 103). The mean serum concentrations of casirivimab and imudevimab on day 29 were 46.4±SD22.5 and 38.3±SD19.6 mg / L, respectively, at the 1200 mg dose, and 73.2±SD27.2 and 60.0±SD22.9 mg / L, respectively, at the 2400 mg dose. The mean estimated half-lives were 28.8 days for casirivimab and 25.5 days for imudevimab (Figure 103).

[0281] Consideration Previous Phase 1 / 2 data showed that REGEN-COV significantly reduced viral load and decreased the need for medical intervention in outpatients with Covid-19, strongly suggesting a reduction in the risk of hospitalization despite a small number of events. These clinical outcome data clearly demonstrate that early treatment with REGEN-COV in outpatients with severe Covid-19 risk factors may dramatically reduce the risk of hospitalization or all-cause mortality. Both 1200 mg IV and 2400 mg IV doses of REGEN-COV resulted in approximately a 70% reduction (vs. placebo) in Covid-19 hospitalization or all-cause mortality over 28 days post-treatment. In hospitalized patients, REGEN-COV treatment also shortened hospital stays and reduced the proportion of patients requiring intensive care. In addition, REGEN-COV at both doses resulted in faster resolution of Covid-19 symptoms at a median of 4 days. Therefore, a single dose of REGEN-COV in outpatients with Covid-19 has the potential to substantially reduce the healthcare cost burden experienced during this pandemic by improving patient outcomes and reducing morbidity and mortality, including hospitalization and intensive care. Furthermore, as evidence grows suggesting that some patients, including those with mild symptoms, have a variablely long recovery process, REGEN-COV may substantially accelerate recovery from Covid-19, which would represent further benefits to patients.

[0282] While we do not wish to be bound by theory, we previously hypothesized that while host factors play a role in the disease course, SARS-CoV-2 morbidity and mortality are caused by high viral load, and that early treatment with an anti-spike monoclonal antibody cocktail can significantly improve this risk. In the placebo group, patients with hospitalization or all-cause mortality were found to have significantly higher viral loads at baseline and slower viral clearance, regardless of baseline serological status. Placebo patients who initiated their own endogenous antibody response to SARS-CoV-2 (serum antibody positive) had similar hospitalization or mortality rates compared to serum antibody negative patients, suggesting that some serum antibody positive patients had an ineffective immune response. Furthermore, placebo patients who were serum antibody positive and had Covid-19-related hospitalizations or deaths also had similarly high baseline viral load levels as serum antibody negative patients who had these events, supporting the idea that high viral load is a major driver of severe Covid-19. Furthermore, this study demonstrates the clinical benefit of REGEN-COV regardless of baseline serum antibody status, making serological testing at the time of Covid-19 diagnosis irrelevant to clinical treatment decisions. This is important considering the prevalence of vaccine use that results in baseline serum antibody positivity, which may not effectively prevent severe infection in some patients (presumably certain patients with innate immunity that did not respond in this study) or due to novel variants of interest (VOCs).

[0283] Both the 1200 mg and 2400 mg doses of REGEN-COV exhibit similar antiviral and clinical efficacy, suggesting they well above the minimum effective dose. Both doses rapidly reduce viral load and accelerate the time to viral clearance compared to placebo. In addition to providing clinical benefit to individual patients receiving REGEN-COV, the rapid antiviral effect is likely to contribute to public health benefits through reduced risk of SARS-CoV-2 VOC transmission and containment.

[0284] A low incidence of serious adverse events, as well as hypersensitivity and infusion-related reactions, was observed. Serum concentrations of each antibody on day 29 were well above the predicted neutralizing target concentrations based on in vitro and preclinical data.

[0285] The emergence of resistance variants of SARS-CoV-2 during antiviral treatment or through circulation within global regions remains a challenge to the success of Covid-19 therapeutics and vaccines. In vitro or in vivo animal studies using recombinant viruses have shown that non-competitive antibody combinations such as REGEN-COV can suppress the emergence of resistance variants, but questions remain about the relevance of these studies to natural human infection. Therefore, we recently investigated and reported the overall genetic diversity of the spike protein across samples from 1,000 outpatients enrolled in either the outpatient REGEN-COV trial described in this example or a separate inpatient Covid-19 REGEN-COV trial (described in Example 1). Analysis of 4,882 samples from these 1,000 patients treated with REGEN-COV or placebo demonstrated that REGEN-COV prevented the selection of resistance mutations, as evidenced by the similar number of receptor-binding domain (RBD) mutations observed in placebo-treated patients compared to patients treated with 1200 mg and 2400 mg of REGEN-COV (15 RBDs in placebo vs. 12 in the 1200 mg REGEN-COV treatment group and 12 in the 2400 mg REGEN-COV treatment group). Three of these RBD mutations were found only in the REGEN-COV treatment group, but were identified at baseline or immediately after treatment (<5 days), and their frequency did not increase over time, suggesting that the development of these mutations was not due to treatment pressure.

[0286] The 2400 mg REGEN-COV antibody cocktail received Emergency Use Authorization (EUA) from the US FDA in November 2020 for the treatment of mild to moderate Covid-19. On April 8, 2021, the NIH treatment guidelines recommended the use of 2400 mg REGEN-COV for the treatment of high-risk outpatients with Covid-19, prioritizing its use in areas where VOCs are common. Clinical evidence from this clinical outcome trial, the largest randomized controlled phase 3 Covid-19 outpatient treatment trial to date, indicates that 1200 mg REGEN-COV is well-tolerated, can significantly reduce Covid-19-related hospitalizations or deaths, accelerates time to recovery, and is less likely to promote the emergence of treatment-resistant SARS-CoV-2 variants. With an acceptable safety profile, clear phase 3 data show a significant reduction in the risk of hospitalization or all-cause mortality, therefore physicians should treat all high-risk SARS-CoV-2 positive individuals.

[0287] Supplementary details The Symptoms Evolution of COVID-19 (SE-C19) device was an electronic diary, a complete daily log completed from day 1 to day 29. SE-C19 was initially developed based on the CDC Symptoms List and is available public literature for patient identification with COVID-19. This included a list of 23 symptoms (feverish, chills, sore throat, cough, shortness of breath or difficulty breathing, nausea, vomiting, diarrhea, headache, red or watery eyes, body aches, loss of taste or smell, fatigue, loss of appetite, confusion, dizziness, chest tightness or constriction, chest pain, stomach pain, rash, sneezing, sputum or phlegm, runny nose). Patients indicated which of the 23 symptoms they had experienced in the past 24 hours, and then rated each selected symptom on a mild, moderate, or severe scale at the worst time during that period. 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 psychometric validation was performed using blinded Phase 1 / 2 data to explore the reliability and validity of the measurements and refine the symptom endpoints. The results showed that 19 of the original 23 items were most effective, reliable, and relevant to outpatients with COVID-19 (i.e., sneezing, rash, vomiting, and confusion were excluded), and the response ...

Claims

1. A pharmaceutical composition comprising a first antigen-binding molecule that binds to the SARS-CoV-2 spike glycoprotein and a second antigen-binding molecule that binds to the SARS-CoV-2 spike glycoprotein, for improving one or more clinical parameters of COVID-19 in a patient with COVID-19, The first antigen-binding molecule is a first anti-SARS-CoV-2 spike glycoprotein antibody or its antigen-binding fragment, comprising a heavy chain variable region (HCVR) containing three complementarity-determining regions HCDR1, HCDR2, and HCDR3, and a light chain variable region (LCVR) containing three complementarity-determining regions LCDR1, LCDR2, and LCDR3, wherein HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 each comprise the amino acid sequences of SEQ ID NOs: 4, 6, 8, 12, 14, and 16; The pharmaceutical composition wherein the second antigen-binding molecule is a second anti-SARS-CoV-2 spike glycoprotein antibody or an antigen-binding fragment thereof, comprising an HCVR containing three complementarity-determining regions HCDR1, HCDR2, and HCDR3, and an LCVR containing three complementarity-determining regions LCDR1, LCDR2, and LCDR3, wherein HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 each contain the amino acid sequences of SEQ ID NOs. 24, 26, 28, 32, 34, and 36, respectively.

2. The subjects are human patients who have SARS-CoV-2 and one or more COVID-19 symptoms confirmed by testing; the one or more COVID-19 symptoms include fever, cough, or shortness of breath; and the subjects are selected from a group consisting of (a) human COVID-19 patients requiring low-flow oxygen supplementation; (b) human COVID-19 patients requiring high-load oxygen therapy but not receiving mechanical ventilation; and (c) human COVID-19 patients requiring mechanical ventilation. The pharmaceutical composition according to claim 1, wherein the subject is hospitalized due to one or more symptoms of COVID-19; or the subject is an outpatient.

3. A first antigen-binding molecule that binds to the SARS-CoV-2 spike glycoprotein, for preventing SARS-CoV-2 infection or COVID-19 in the target population, and SARS- A pharmaceutical composition comprising a second antigen-binding molecule that binds to the CoV-2 spike glycoprotein, The first antigen-binding molecule is a first anti-SARS-CoV-2 spike glycoprotein antibody or its antigen-binding fragment, comprising a heavy chain variable region (HCVR) containing three complementarity-determining regions HCDR1, HCDR2, and HCDR3, and a light chain variable region (LCVR) containing three complementarity-determining regions LCDR1, LCDR2, and LCDR3, wherein HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 each comprise the amino acid sequences of SEQ ID NOs: 4, 6, 8, 12, 14, and 16; The pharmaceutical composition wherein the second antigen-binding molecule is a second anti-SARS-CoV-2 spike glycoprotein antibody or an antigen-binding fragment thereof, comprising an HCVR containing three complementarity-determining regions HCDR1, HCDR2, and HCDR3, and an LCVR containing three complementarity-determining regions LCDR1, LCDR2, and LCDR3, wherein HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 each contain the amino acid sequences of SEQ ID NOs. 24, 26, 28, 32, 34, and 36, respectively.

4. The pharmaceutical composition according to claim 3, wherein the subject is an uninfected individual at high risk of SARS-CoV-2 infection; or the subject is a healthcare worker, first responder, or a family member of an individual who is at high risk of SARS-CoV-2 infection and has tested positive for SARS-CoV-2 infection.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the spike glycoprotein of SARS-CoV-2 is a spike (S) glycoprotein comprising a receptor-binding domain having at least 80% the same amino acid sequence as SEQ ID NO:

59.

6. The pharmaceutical composition according to any one of claims 1 to 4, wherein the first anti-SARS-CoV-2 spike glycoprotein antibody or its 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 spike glycoprotein antibody or its antigen-binding fragment comprises an HCVR / LCVR amino acid sequence pair comprising the amino acid sequence of SEQ ID NO: 22 / 30.

7. The pharmaceutical composition according to claim 6, wherein the first and second anti-SARS-CoV-2 spike glycoprotein antibodies comprise a human IgG heavy chain constant region; the first and second anti-SARS-CoV-2 spike glycoprotein antibodies comprise a heavy chain constant region of an IgG1 or IgG4 isotype; or the first anti-SARS-CoV-2 spike glycoprotein antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20, and the second anti-SARS-CoV-2 spike glycoprotein antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain comprising the amino acid sequence of SEQ ID NO:

40.

8. The composition is 1 mg to 10 g of the antigen-binding molecule; 1.2 g of the first antigen-binding molecule and 1.2 g of the second antigen-binding molecule; 150 mg of the first antigen-binding molecule and 150 mg of the second antigen-binding molecule; 300 mg of the first antigen-binding molecule and 300 mg of the second antigen-binding molecule; 600 mg of the first antigen-binding molecule and 600 mg of the second antigen-binding molecule; or The first antigen-binding molecule in an amount of 150 mg to 1200 mg and the second antigen-binding molecule in an amount of 150 mg to 1200 mg A pharmaceutical composition according to any one of claims 1 to 4, comprising:

9. A pharmaceutical composition according to any one of claims 1 to 4, which is formulated to be administered to the subject by intravenous injection or subcutaneous injection.

10. The group consisting of the following in the above subject: (a) Reduction from baseline in SARS-CoV-2 virus shedding; (b) Improvement of at least 1 point on a 7-point ordinal scale of clinical condition; (c) Reduction or elimination of the need for oxygen supplementation; (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 concentration of one or more disease-related biomarkers This yields one or more effectiveness parameters selected from, The aforementioned 7-point ordinal scale is, [1] Death; [2] Hospitalization requiring invasive mechanical ventilation or extracorporeal membrane oxygenation; [3] Hospitalization requiring non-invasive ventilation or a high-flow oxygen device; [4] Hospitalization requiring oxygen supplementation; [5] Hospitalization requiring ongoing medical treatment (COVID-19 related or not) but not requiring oxygen supplementation; [6] Hospitalizations that do not require oxygen supplementation and no longer require ongoing medical treatment; and [7] The pharmaceutical composition according to claim 1 or 2, wherein hospitalization is not required.

11. The one or more efficacy parameters are measured 21 days after the first dose of the composition; The reduction in SARS-CoV-2 virus shedding from baseline is determined by real-time quantitative PCR (RT-qPCR) of nasopharyngeal swab samples, nasal cavity samples, or saliva samples; A change in the serum concentration of one or more disease-related biomarkers is a change in C-reactive protein, lactate dehydrogenase, D-dimer, or ferritin; The subject becomes negative in a SARS-CoV-2 test within 2 days to 3 weeks after the first dose of the composition; or The pharmaceutical composition according to claim 10, wherein the subject becomes negative in a SARS-CoV-2 test within 2 days to 3 weeks after the first dose of the composition, and the negative result of the SARS-CoV-2 test is determined by RT-qPCR of a nasopharyngeal swab sample, nasal cavity sample, or saliva sample.

12. The pharmaceutical composition according to claim 2, wherein the subject is an outpatient, and the composition results in the subject having fewer than five visits, telemedicine visits, hospitalizations, and / or intensive care unit (ICU) admissions requiring COVID-19-related medical interventions.

13. The aforementioned five or fewer COVID-19-related medical interventions, including hospital visits, telemedicine visits, hospitalizations, and / or intensive care unit (ICU) admissions, are indicated by the subject within 29 days following the first dose of the composition; or The pharmaceutical composition according to claim 12, wherein the subject refers to fewer than four, three, two, or one visit to a hospital, telemedicine visit, hospitalization, and / or intensive care unit (ICU) hospitalization requiring COVID-19-related medical intervention.

14. The pharmaceutical composition according to claim 1 or 2, administered to a subject together with an additional therapeutic agent.

15. The pharmaceutical composition according to claim 14, wherein the additional therapeutic agent is the antiviral compound remdesivir, the IL-6 or IL-6R inhibitor tocilizumab, sarilumab, or a steroid.

16. The pharmaceutical composition according to claim 14, wherein the additional therapeutic agent is administered before the composition.

17. The pharmaceutical composition according to claim 14, wherein the additional therapeutic agent is administered after or simultaneously with the composition.

18. The pharmaceutical composition according to any one of claims 1 to 4, wherein the subject is seronegative for SARS-CoV-2 infection.

19. The composition improves COVID-19 more rapidly in a seronegative control population compared to an equivalent seronegative control population administered a placebo; The composition improves COVID-19 more rapidly in a seronegative control group compared to an equivalent seropositive control group; or The pharmaceutical composition according to claim 1 or 2, wherein the composition reduces the viral load in the target population by 7 days after administration (7th day) compared to the day of administration (day 0).

20. A composition that reduces the viral load in the target population by 7 days after administration (day 7) compared to the day of administration (day 0), In the seronegative control population, the time-weighted mean change from baseline nasopharyngeal (NP) viral load up to day 7 was at least 0.86 log 10 copies / mL greater in patients treated with 0.6 g of the first anti-SARS-CoV-2 spike glycoprotein antibody and 0.6 g of the second anti-SARS-CoV-2 spike glycoprotein antibody compared to an equivalent control population treated with placebo, with a p-value of less than 0.0001; The change from baseline nasopharyngeal (NP) viral load up to day 7 in the seronegative control population was at least 1.04 log 10 copies / mL greater in patients treated with 1.2 g of the first anti-SARS-CoV-2 spike glycoprotein antibody and 1.2 g of the second anti-SARS-CoV-2 spike glycoprotein antibody compared to an equivalent control population treated with placebo, with a p-value of less than 0.0001; The mean change from baseline nasopharyngeal (NP) viral load up to day 7 in the aforementioned control population is at least 0.71 log 10 copies / mL greater in patients treated with 0.6 g of the first anti-SARS-CoV-2 spike glycoprotein antibody and 0.6 g of the second anti-SARS-CoV-2 spike glycoprotein antibody compared to an equivalent control population treated with placebo, with a p-value of less than 0.0001; or The pharmaceutical composition according to claim 19, wherein the mean change from baseline nasopharyngeal (NP) viral load up to day 7 in the control population is 0.86 log 10 copies / mL greater in patients treated with 1.2 g of the first anti-SARS-CoV-2 spike glycoprotein antibody and 1.2 g of the second anti-SARS-CoV-2 spike glycoprotein antibody compared to an equivalent control population treated with placebo, and the p-value is less than 0.0001.

21. A pharmaceutical composition according to claim 1 or 2, which reduces the viral load in a target population.

22. Administered as 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, resulting in an average reduction of the viral load on day 7 after administration compared to the baseline viral load measured on day 0 before administration, of at least 3.00 log 10 copies / mL, at least 3.50 log 10 copies / mL, or at least 3.90 log 10 copies / mL; 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 were administered, with a baseline level of at least 3.50 log 10 copies / mL, at least 3.75 log 10 copies / mL, or at least 4.09 log 10 copies / mL, as measured on day 0 prior to administration. This results in an average reduction in the viral load on day 7 after administration compared to the viral load; or The pharmaceutical composition according to claim 21, wherein the subject and / or subject group includes subjects who are not hospitalized with COVID-19.

23. The pharmaceutical composition according to claim 1 or 2, which reduces the median time of COVID-19 symptom relief by 4 days in a control group treated with 0.6 g of the first anti-SARS-CoV-2 spike glycoprotein antibody and 0.6 g of the second anti-SARS-CoV-2 spike glycoprotein antibody, or 1.2 g of the first anti-SARS-CoV-2 spike glycoprotein antibody and 1.2 g of the second anti-SARS-CoV-2 spike glycoprotein antibody, compared to an equivalent control group treated with placebo.

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