WO2022232557A1

WO2022232557A1 - Compounds specific to coronavirus s protein and uses thereof

Info

Publication number: WO2022232557A1
Application number: PCT/US2022/027004
Authority: WO
Inventors: Lynn Elizabeth CONNOLLY; Edward Samuel CAMPANARO; Paul G. AMBROSE; Elham HERSHBERGER; Laura Walker; Chengzi I. KAKU
Original assignee: Adagio Therapeutics, Inc.
Priority date: 2021-04-30
Filing date: 2022-04-29
Publication date: 2022-11-03
Also published as: TW202309075A

Abstract

The present disclosure is directed to antibodies, and antigen binding fragments thereof, having binding specificity for the S protein of coronaviruses (CoV-S), such as the S protein of the SARS coronavirus (SARS-CoV-S) and/or the S protein of the SARS coronavirus 2 (SARS-CoV-2-S), including neutralizing antibodies and antibodies that bind to and/or compete for binding to the same linear or conformational epitope(s) on CoV-S. Further disclosed are conjugates of anti-CoV-S antibodies, and binding fragments thereof, conjugated to one or more functional or detectable moieties. Methods of making said anti-CoV-S antibodies and antigen binding fragments thereof are also contemplated. Other embodiments of the disclosure include the use of anti-CoV-S antibodies, and binding fragments thereof, for the diagnosis, assessment, and treatment of diseases and disorders associated with coronaviruses, or the S protein thereof, and conditions where neutralization or inhibition of coronaviruses, or the S protein thereof, would be therapeutically and/or prophylactically beneficial.

Description

COMPOUNDS SPECIFIC TO CORONA VIRUS S PROTEIN AND USES THEREOF

RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application 63/182,033, filed April 30, 2021; U.S. Provisional Application No. 63/191,410, filed May 21, 2021; U.S. Provisional Application No. 63/197,717, filed June 7, 2021; U.S. Provisional Application No. 63/211,334, filed June 16, 2021; U.S. Provisional Application No. 63/233,443, filed August 16, 2021; U.S. Provisional Application No. 63/243,259, filed September 13, 2021; U.S. Provisional Application No. 63/245,509, filed September 17, 2021; US Provisional Application No. 63/249,158, filed September 28, 2021; US Provisional Application No. 63/256,753, filed October 18, 2021; US Provisional Application No. 63/279,202, filed November 15, 2021; US Provisional Application No. 63/281,914, filed November 22, 2021; US Provisional Application No. 63/283,433, filed November 27, 2021; U.S. Provisional Application No. 63/292,781, filed December 22, 2021; US Provisional Application No. 63/298,832, filed January 12, 2022; US Provisional Application No. 63/302,714, filed January 25, 2022; US Provisional Application No. 63/316,067, filed March 3, 2022; US Provisional Application No. 63/324,569, filed March 28, 2022; U.S. Provisional Application No. 63/324,995, filed March 29, 2022; U.S. Provisional Application No. 63/327,436, filed April 5, 2022; and U.S. Provisional Application No. 63/332,312, filed April 19, 2022. The entire contents of each of these applications are incorporated herein by reference.

SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on April 25, 2022, is named 132280_00420_SL.txt and is 234,693 bytes in size.

FIELD

[0003] This disclosure generally pertains to antibodies and antigen-binding fragments thereof, preferably human antibodies and antigen-binding fragments and/or affinity-matured variants thereof, recombinant cells engineered to express such antibodies, and compositions containing such antibodies and antigen-binding fragments thereof, wherein such antibodies and antigen-binding fragments thereof specifically bind to the S protein of coronaviruses (“CoV-S”) and therapeutic and diagnostic uses for the antibodies, antigen-binding fragments, and compositions thereof.

BACKGROUND

[0004] Coronaviruses (“CoV”) are genetically classified into four major genera: the Alphacoronavirus genus (ACoV genus); the Betacoronavirus genus (BCoV genus); the Gammacoronavirus genus (CCoV genus); and Deltacoronavirus genus (DCoV genus), and while ACoV and BCoV primarily infect a als CCoV and DCoV predominantly infect birds (Wu A. et al, Cell Host Microbe. 2020 Mar ll;27(3):325-328). Coronaviruses that infect humans were first identified in the mid-1960s, and currently, seven confirmed CoV species are known as human pathogens. Four CoV species, the HCoV-HKUl and HCoV-OC43 from the BCoV genus and the HCoV-229E and HCoV-NL63 from the ACoV genus, are endemic species in humans and cause mild respiratory symptoms, mostly in pediatric patients (Brielle E.S., et al, BioRxiv reprint, doi: https://doi.org/10.1101/2020.03.10.986398). The other three human CoV species, the SARS-CoV, the MERS-CoV, and the SARS-CoV-2 (also known as “2019-nCoV”), all of which are from the BCoV genus, have caused severe outbreaks, including the Severe Acute Respiratory Syndrome (SARS) outbreak in 2002-2003, the Middle East Respiratory Syndrome (MERS) outbreak in 2012-2013, and the current (2019-) pandemic of the coronavirus disease of 2019 (“COVID-19”).

[0005] The genome of coronaviruses, whose size ranges between approximately 26,000 and 32,000 bases, includes a variable number (from 6 to 11) of open reading frames (“ORFs”) (Wu A. et al. , Cell Host Microbe. 2020 Mar ll;27(3):325-328). The first ORF encodes 16 non-structural proteins (“nsps”), and the remaining ORFs encode accessory proteins and structural proteins. The four major structural proteins are the spike surface glycoprotein (“S protein” or “S” or “spike protein”), small envelope protein (“E protein” or “E”), matrix protein (“M protein” or “M”), and nucleocapsid protein (“N protein”, or “N”).

[0006] The S protein, which plays an essential role in binding to receptors on the host cell and determines host tropism (Zhu Z. et al, Infect Genet Evol. 2018 Jul;61 : 183-184), forms homotrimers protruding from the viral surface (Li F. Annu Rev Virol. 2016 Sep 29;3(1):237-261). The S protein is processed into two non-covalently associated subunits, SI and S2, and each monomer in the trimeric S assembly is a heterodimer of SI and S2 subunits. Cryo-EM studies have revealed that the SI subunit is comprised of four domains: an N-terminal domain (NTD), a C-terminal domain (CTD), and two subdomains (Walls A. C. et al, Nature 531, 114-117 (2016).; Tortorici M. A. and Veesler D.,

Adv Virus Res. 2019;105:93-116; Wrapp D. et al, Science 367, 1260-1263 (2020)). The CTD functions as the receptor-binding domain (RBD) for both SARS-CoV and SARS-CoV-2 (Li F. J Virol. 2015 Feb;89(4): 1954-64). The S2 subunit contains the fusion peptide, heptad repeat 1 and 2, and a transmembrane domain, all of which are required to mediate fusion of the viral and host cell membranes.

[0007] SARS-CoV and SARS-CoV-2 bind to and use angiotensin-converting enzyme 2 (ACE2) of a host cell as a receptor to enter the host cells (Ge X.Y. et al, Nature. 2013 Nov 28;503(7477):535-8; Hoffmann M. et al, Cell. 2020 Mar 4. pii: S0092-8674(20)30229-4). The motif within the RBD that particularly binds to RCE2 is often referred to as the “ACE2-binding motif’. SARS-CoV can also use CD209L (also known as L-SIGN) as an alternative receptor (Jeffers S. A. et al, Proc Natl Acad Sci U S A. 2004 Nov 2;101(44):15748-53). In contrast, MERS-CoV binds dipeptidyl peptidase 4 (“DPP4”, also known as CD26) of the host cell via a different RBD of the S protein.

[0008] Cell entry of coronaviruses often depends also on priming of the S protein by host cell proteases. Recently, SARS-CoV-2 was found to use the serine protease TMPRSS2 for S protein priming and ACE2 for entry (Wu A. et al, Cell Host Microbe. 2020 Mar ll;27(3):325-328;

Hoffmann M. et al, Cell. 2020 Mar 4. pii: S0092-8674(20)30229-4).

[0009] The genome of SARS-CoV-2 is about 29.8 kb nucleotides and encodes 15 nsps, four structural proteins (S, E, M, and N) and eight accessory proteins (3a, 3b, p6, 7a, 7b, 8b, 9b, and orfl4) (Wu A. et al, Cell Host Microbe. 2020 Mar ll;27(3):325-328). While SARS-CoV-2 is genetically close to a SARS-like bat CoV and also to SARS-CoV, a number of sequence differences have been identified. When SARS-CoV-2 is compared to SARS-CoV or SARS-like bat CoV, 380 amino acid differences or substitutions were found, 27 of which are in the S protein, including 6 substitutions in the RBD at amino acid region 357-528 (but not in the receptor-binding motifs that directly interact with ACE2) and 6 substitutions in the underpinning subdomain (SD) at amino acid region 569-655. [0010] One of the few drugs approved by the U.S. Food and Drug Administration (“FDA”) for use in treating COVID-19 is the viral replication inhibitor remdesivir. Clinical trials demonstrated that remdesivir shortens the time to recovery in hospitalized patients, but more effective therapy is in great need. Convalescent plasma received the emergency use authorization status by the FDA. Other treatments given to COVID-19 patients include anti-inflammatories such as corticosteroids and other treatments for managing symptoms such as supplemental oxygen and mechanical ventilatory support. Several drugs, particularly those that have been approved for preventing or treating other infectious disease, are currently being tested in the clinic, which includes e.g., lopinavir-ritonavir (HIV protease inhibitor), ABX464 (viral RNA splicer), favilavir (RNA-dependent RNA polymerase inhibitor used for influenza virus infection), niclosamide and ivermectin (antihelmintic), and BCG vaccine (vaccine for tuberculosis). Also, other ongoing clinical trials reportedly are using IL-6 receptor antagonist antibodies, an anti-GM-CSF or anti-GM-CSF receptor antibody, an anti-TNF antibody, an anti-IL- lbeta antibody, or an anti-complement component 5 antibody, in an effort to inhibit inflammation and thereby potentially inhibit cytokine storm and sepsis which can manifest in some SARS-CoV-2- infected patients and may cause death.

SUMMARY

[0011] In one aspect, the present disclosure relates to a compound which binds to coronavirus (CoV) or the spike protein (S protein) of a CoV (“CoV-S”). In some embodiments, the compound may be an isolated antibody or antigen-binding antibody fragment which binds to a CoV-S. In some embodiments, the antibody or antigen-binding antibody fragment may comprise a heavy chain variable region (VH), or fragments thereof, and/or a light chain variable region (VL), or fragments thereof. In certain embodiments, the VH or fragment thereof may comprise a complementarity determining region 1 (CDR1), a complementarity-determining region 2 (CDR2), and a complementarity-determining region 3 (CDR3), which may also be referred to as VH CDR1, VH CDR2, and VH CDR3, respectively. In certain embodiments, the VL or fragment thereof may comprise a CDR1, a CDR2, and a CDR3, which may also be referred to as VL CDR1, VL CDR2, and VL CDR3, respectively. In some embodiments, the antibody, or antigen-binding antibody fragment thereof, may comprise a heavy chain CDR1, a heavy chain CDR2, a heavy chain CDR3, a light chain CDR1, a light chain CDR2, and a light chain CDR3.

[0012] In some embodiments, the antibody or antigen-binding antibody fragment may comprise an antibody or antigen-binding antibody fragment thereof, or an affinity-matured variant of an anti-Co V- S antibody or antigen-binding antibody fragment thereof; selected from the group consisting of ADI- 58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI- 58128, ADI-58129, ADI-58130, ADI-58131, optionally wherein the CoV-S is SARS-CoV-S or SARS-CoV-2-S.

[0013] In some embodiments, the antibody, or antigen-binding antibody fragment thereof, may comprise a VH and/or VL. In certain embodiments, the VH may comprise a CDR3 having an amino acid sequence identical to the VH CDR3 of any one of anti-CoV-S antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, ADI-58131, and optionally, the VL CDR3 may comprise a CDR3 having an amino acid sequence identical to the VL CDR3 of the same anti-CoV-S antibody that the VH CDR3 is derived from, and the anti-CoV-S antibody may be selected from any one of anti-CoV-S antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI- 58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI- 58130, ADI-58131. Here, the CoV-S may be the spike protein (“S protein”) of Severe Acute Respiratory Syndrome (SARS) coronavirus (“SARS-CoV”), which may be referred to as “SARS- CoV-S”, or the S protein of SARS-CoV -2 (also known as “n2019-nCoV”), which may be referred to as “SARS-CoV -2-S”. Optionally, the CoV-S may comprise a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to, comprising, or consisting of the amino acid sequence of SEQ ID NO: 401 (SARS-CoV-S, 1288 amino acids, Accession# PDB: 6VSB_B) or having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to, comprising, or consisting of SEQ ID NO: 403 (SARS-CoV -2-S, 1273 amino acids, GenBank: QHD43416.1).

[0014] In some embodiments, the SARS-CoV -2-S is a B.1.1.7 variant, a B. 1.351 variant, a B.1.1.28 variant, a B. 1.429 variant, a P.l varaint, a B.1.617 variant ( e.g ., B.1.617.1 and B.1.617.2), a C.37 variant, a 1.621 variant, a AY.l variant, a 1.623 variant, a C.36 variant, a A.27 variant, a AV.l variant, a B.1.1.482 variant, a B.1.1.523 variant, a B.1.427 variant, a AY.4 variant, a AY.ll variant, variant, a D614G variant of SEQ ID NO: 403, a B.1.1.529/BA.1 variant (also known as the Omicron variant), a BA.1.1 variant, or a BA.2 variant.

[0015] In some embodiments, the antibody or antigen-binding antibody fragment, optionally an affinity-matured variant of any of the anti-CoV-S antibodies disclosed herein, may comprise at least 1, 2, 3, 4, 5 or all 6 complementarity-determining regions (CDRs) of any one of anti-CoV-S antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, ADI-58131, optionally wherein the CoV-S is SARS-CoV-S or SARS-CoV-2-S. Optionally, the CoV-S may comprise the amino acid sequence of SEQ ID NO: 401 (SARS-CoV-S, 1288 amino acids, Accession# PDB: 6VSB_B) or SEQ ID NO: 403 (SARS-CoV-2-S, 1273 amino acids, GenBank: QHD43416.1). [0016] In some embodiments, the isolated antibody or antigen-binding antibody fragment, optionally an affinity-matured variant of any of the anti-CoV-S antibodies disclosed herein, may comprise: (a) a VH CDR1 polypeptide; (b) a VH CDR2 polypeptide; (c) a VH CDR3 polypeptide; (d) a VL CDR1 polypeptide; (e) a VL CDR2 polypeptide; and (f) a VL CDR3 polypeptide. The amino acid sequences of the VH CDR1, the VH CDR2, the VH CDR3, the VL CDR1, the VL CDR2, and the VL CDR3 may be identical to the amino acid sequences of the VH CDR1, VH CDR2, VH CDR3, VL CDR1,

VL CDR2, and VL CDR3, respectively, of any one of anti-CoV-S antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, ADI-58131. Optionally, the CoV-S may be SARS- CoV-S or of “SARS-CoV-2-S”. Lurther optionally, the CoV-S may comprise the amino acid sequence of SEQ ID NO: 401 (SARS-CoV-S, 1288 amino acids, Accession# PDB: 6VSB_B) or SEQ ID NO: 403 (SARS-CoV-2-S, 1273 amino acids, GenBank: QHD43416.1).

[0017] In certain embodiments, the isolated antibody or antigen-binding antibody fragment, optionally an affinity-matured variant of any of the anti-CoV-S antibodies disclosed herein, which specifically binds to CoV-S, may comprise: (a) a VH comprising a VH CDR1, VH CDR2, and VH CDR3; and (b) a VL comprising a VL CDR1, VL CDR2, and VL CDR3.

[0018] In some exemplary embodiments, the amino acid sequences of the VH CDR1, the VH CDR2, the VH CDR3, the VL CDR1, the VL CDR2, and the VL CDR3 may be identical to the amino acid sequences of: (1) SEQ ID NOS: 2, 4, 6, 202, 204, and 206, respectively; (2) SEQ ID NOS: 12, 14, 16, 212, 214, and 216, respectively; (3) SEQ ID NOS: 22, 24, 26, 222, 224, and 226, respectively; (4)

SEQ ID NOS: 32, 34, 36, 232, 234, and 236, respectively; (5) SEQ ID NOS: 42, 44, 46, 242, 244, and 246, respectively; (6) SEQ ID NOS: 52, 54, 56, 252, 254, and 256, respectively; (7) SEQ ID NOS: 62, 64, 66, 262, 264, and 66, respectively; (8) SEQ ID NOS: 72, 74, 76, 272, 274, and 276, respectively; (9) SEQ ID NOS: 82, 84, 86, 282, 284, and 286, respectively; (10) SEQ ID NOS: 92, 94, 96, 292,

294, and 296, respectively; (11) SEQ ID NOS: 102, 104, 106, 302, 304, and 306, respectively; or (12) SEQ ID NOS: 112, 114, 116, 312, 314, and 316, respectively. [0019] In other words, the amino acid sequences of the VH CDR1, the VH CDR2, the VH CDR3, the VL CDR1, the VL CDR2, and the VL CDR3 may be identical to the VH CDR1, the VH CDR2, the VH CDR3, the VL CDR1, the VL CDR2, and the VL CDR3 and VL amino acid sequences of any one of anti-CoV-S antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, ADI-58131.

[0020] In some embodiments, the isolated antibody or antigen-binding antibody fragment, optionally an affinity-matured variant of any of the anti-CoV-S antibodies disclosed herein, may possess one of the following structural features:

(1) (a) the VH may comprise an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 8, and (b) the VL may comprise an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 208;

(2) (a) the VH may comprise an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 18, and (b) the VL may comprise an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 218;

(3) (a) the VH may comprise an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 28, and (b) the VL may comprise an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 228;

(4) (a) the VH may comprise an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 38, and (b) the VL may comprise an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 238;

(5) (a) the VH may comprise an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 48, and (b) the VL may comprise an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 248;

(6) (a) the VH may comprise an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 58, and (b) the VL may comprise an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 258;

(7) (a) the VH may comprise an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 68, and (b) the VL may comprise an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 268;

(8) (a) the VH may comprise an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 78, and (b) the VL may comprise an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 278;

(9) (a) the VH may comprise an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 88, and (b) the VL may comprise an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 288;

(10) (a) the VH may comprise an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 98, and (b) the VL may comprise an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 298;

(11) (a) the VH may comprise an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 108, and (b) the VL may comprise an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 308; or

(12) (a) the VH may comprise an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 118, and (b) the VL may comprise an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 318.

[0021] In some exemplary embodiments, the isolated antibody or antigen-binding antibody fragment, optionally an affinity-matured variant, may be human, humanized, primatized or chimeric.

[0022] In some exemplary embodiments, the isolated antibody or antigen-binding antibody fragment, optionally an affinity-matured variant, may be bispecific or multispecific.

[0023] In some exemplary embodiments, the isolated antibody or antigen-binding antibody fragment, optionally an affinity-matured variant, may comprise at least one first antigen-binding domain (“ABD”) and at least one second ABD.

[0024] Here, the following features (a) and (b) may be met:

(a) the first ABD may comprise the VH CDR1, the VH CDR2, the VH CDR3, the VL CDR1, the VL CDR2, and the VL CDR3 of a first anti-CoV-S antibody selected from any one of anti-CoV-S antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, ADI-58131; and/or

(b) the second ABD may comprise the VH CDR1, the VH CDR2, the VH CDR3, the VL CDR1, the VL CDR2, and the VL CDR3 of a second anti-CoV-S antibody selected from any one of anti-CoV-S antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, ADI-58131. [0025] Optionally, the first anti-CoV-S antibody may be same as the second anti-CoV-S antibody or may be different from the second anti-CoV-S antibody.

[0026] The first anti-CoV-S antibody and the second anti-CoV-S antibody may bind to the same or different coronavirus species. Optionally, the first CoV-S and the second CoV-S may be (i) both of SARS-CoV or (ii) both of SARS-CoV-2.

[0027] Further optionally, the first anti-CoV-S antibody may be same as the second anti-CoV-S antibody or may be different from the second anti-CoV-S antibody. Still further optionally, these antibodies may bind to the same or different epitopes on a CoV-S expressed by said SARS-CoV or SARS-CoV-2. Alternatively, the first anti-CoV-S antibody and the second anti-CoV-S antibody may bind to different coronaviruses, optionally wherein the first CoV-S and the second CoV-S are (i) SARS-CoV and of SARS-CoV-2 coronaviruses, respectively, or are (ii) SARS-CoV-2 and of SARS- CoV coronaviruses, respectively.

[0028] In some embodiments, the bispecific or multispecific isolated antibody or antigen-binding antibody fragment may comprise at least one first ABD and at least one second ABD.

[0029] In certain embodiments, (a) the first ABD may comprise the VH CDR1, the VH CDR2, the VH CDR3, the VL CDR1, the VL CDR2, and the VL CDR3 of a first anti-CoV-S antibody selected from any one of anti-CoV-S antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, ADI-58131, or an affinity-matured variant of any of the foregoing; and/or (b) the second ABD binds to an antigen which may not be a CoV-S, optionally wherein the antigen is a cytokine, a cytokine receptor, or an immunomodulatory polypeptide.

[0030] In some embodiments, the isolated antibody or antigen-binding antibody fragment may comprise a Fab, Fab’, F(ab’)2, scFv, sc(Fv)2, minibody, diabody, sdAb, BITE.

[0031] In some embodiments, the isolated antibody or antigen-binding antibody fragment may comprise a constant region or Fc region or at least one domain thereof.

[0032] In certain embodiments, the constant region or Fc region may comprise a mutation which impairs or enhances at least one effector function, optionally FcR binding, FcRn binding, complement binding, glycosylation, complement-dependent cytotoxicity (“CDC”), or antibody-dependent cellular cytotoxicity (“ADCC”).

[0033] In some embodiments, the constant or Fc region is primate derived, preferably human.

[0034] The human constant or Fc region optionally may be selected from a human IgGl, IgG2, IgG3 or IgG4 constant or Fc region which optionally may be modified, optionally such as by domain deletion or by introducing one or more mutations which impair or enhance at least one effector function. [0035] The present disclosure further relates to chimeric antigen receptors (“CARs”) comprising at least one antibody or antigen-binding antibody fragment described herein.

[0036] The present disclosure further relates to antibody-drug conjugates (“ADCs”) comprising: (a) at least one antibody or antigen-binding antibody fragment described herein; and (b) a drug.

[0037] In some embodiments, the drug may be: (i) an antiviral drug, which is optionally, remdesivir, favipiravir, darunavir, nelfinavir, saquinavir, lopinavir or ritonavir; (ii) an antihelminth drug, which may be optionally ivermectin; (iii) an antiparasite drug, which may be optionally hydroxychloroquine, chloroquine, or atovaquone; (iv) antibacterial vaccine, which may be optionally the tuberculosis vaccine BCG; or (v) an anti-inflammatory drug, which may be optionally a steroid such as ciclesonide, a TNF inhibitor (e.g., adalimumab), a TNF receptor inhibitor (e.g., etanercept), an IL-6 inhibitor (e.g., clazakizumab), an IL-6 receptor inhibitor (e.g., toclizumab), or metamizole; (vi) an antihistamine drug, which may be optionally bepotastine; (vii) an ACE inhibitor, which may be optionally moexipril; (viii) a drug that inhibits priming of CoV-S, which may be optionally a serine protease inhibitor such as nafamostat; or (ix) a cytotoxic drug, which may be optionally daunorubicin, mitoxantrone, doxorubicin, cucurbitacin, chaetocin, chaetoglobosin, chlamydocin, calicheamicin, nemorubicin, cryptophyscin, mensacarcin, ansamitocin, mitomycin C, geldanamycin, mechercharmycin, rebeccamycin, safracin, okilactomycin, oligomycin, actinomycin, sandramycin, hypothemycin, polyketomycin, hydroxyellipticine, thiocolchicine, methotrexate, triptolide, taltobulin, lactacystin, dolastatin, auristatin, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), telomestatin, tubastatin A, combretastatin, maytansinoid, MMAD, MMAF, DM1, DM4, DTT, 16-GMB -APA-GA, 17-DMAP-GA, JW 55, pyrrolobenzodiazepine, SN-38, Ro 5-3335, puwainaphycin, duocarmycin, bafilomycin, taxoid, tubulysin, ferulenol, lusiol A, fumagillin, hygrolidin, glucopiericidin, amanitin, ansatrienin, cinerubin, phallacidin, phalloidin, phytosphongosine, piericidin, poronetin, phodophyllotoxin, gramicidin A, sanguinarine, sinefungin, herboxidiene, microcolin B, microcystin, muscotoxin A, tolytoxin, tripolin A, myoseverin, mytoxin B, nocuolin A, psuedolaric acid B, pseurotin A, cyclopamine, curvulin, colchicine, aphidicolin, englerin, cordycepin, apoptolidin, epothilone A, limaquinone, isatropolone, isofistularin, quinaldopeptin, ixabepilone, aeroplysinin, arruginosin, agrochelin, or epothilone.

[0038] The present disclosure also relates to isolated nucleic acids encoding any of the antibodies or antigen-binding antibody fragments disclosed herein.

[0039] In some embodiments, the nucleic acid may comprise:

(1) (a) a nucleic acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the nucleic acid sequence of SEQ ID NO: 9, and/or (b) a nucleic acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the nucleic acid sequence of SEQ ID NO: 209; (2) (a) a nucleic acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the nucleic acid sequence of SEQ ID NO: 19, and/or (b) a nucleic acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the nucleic acid sequence of SEQ ID NO: 219;

(3) (a) a nucleic acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the nucleic acid sequence of SEQ ID NO: 29, and/or (b) a nucleic acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the nucleic acid sequence of SEQ ID NO: 229;

(4) (a) a nucleic acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the nucleic acid sequence of SEQ ID NO: 39, and/or (b) a nucleic acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the nucleic acid sequence of SEQ ID NO: 239;

(5) (a) a nucleic acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the nucleic acid sequence of SEQ ID NO: 49, and/or (b) a nucleic acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the nucleic acid sequence of SEQ ID NO: 249;

(6) (a) a nucleic acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the nucleic acid sequence of SEQ ID NO: 59, and/or (b) a nucleic acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the nucleic acid sequence of SEQ ID NO: 259;

(7) (a) a nucleic acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the nucleic acid sequence of SEQ ID NO: 69, and/or (b) a nucleic acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the nucleic acid sequence of SEQ ID NO: 269;

(8) (a) a nucleic acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the nucleic acid sequence of SEQ ID NO: 79, and/or (b) a nucleic acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the nucleic acid sequence of SEQ ID NO: 279;

(9) (a) a nucleic acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the nucleic acid sequence of SEQ ID NO: 89, and/or (b) a nucleic acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the nucleic acid sequence of SEQ ID NO: 289;

(10) (a) a nucleic acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the nucleic acid sequence of SEQ ID NO: 99, and/or (b) a nucleic acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the nucleic acid sequence of SEQ ID NO: 299; (11) (a) a nucleic acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the nucleic acid sequence of SEQ ID NO: 109, and/or (b) a nucleic acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the nucleic acid sequence of SEQ ID NO: 309; or

(12) (a) a nucleic acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the nucleic acid sequence of SEQ ID NO: 119, and/or (b) a nucleic acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the nucleic acid sequence of SEQ ID NO: 319.

[0040] The present disclosure also relates to isolated cells which may comprise any of the nucleic acids disclosed herein.

[0041] In some embodiments the cell may be a bacterial, yeast, insect, fungal, or mammalian cell, optionally a human cell, further optionally a CHO or HEK cell.

[0042] In some embodiments the cell may be a human immune cell, optionally a T, NK, B or dendritic cell.

[0043] The present disclosure further relates to methods of expressing the antibody or antigen binding antibody fragment or the CAR disclosed herein.

[0044] In some embodiments, the method may comprise: (a) culturing the cell expressing an antibody or antigen-binding antibody fragment or CAR of the present disclosure under conditions that permit expression; and (b) optionally isolating the antibody or antigen-binding antibody fragment or the CAR from the cell or the culture medium containing the cell.

[0045] The present disclosure further relates to methods of identifying an antibody or an antigen binding antibody fragment which specifically binds to CoV-S.

[0046] In some embodiments, the method may comprise: (a) obtaining antisera and/or B cells obtained from a patient infected with SARS-CoV or SARS-CoV-2, optionally wherein the patient recovered from SARS-CoV or SARS-CoV-2 infection or the patient is a convalescent patient infected with SARS-CoV or SARS-CoV-2; (b) contacting the antisera and/or B cells with the CoV-S; and (c) isolating an antibody or antigen-binding fragment thereof which specifically bind to the CoV-S. Optionally, the CoV-S is the spike protein of SARS-CoV (“SARS-CoV-S”) or of SARS-CoV-2 (“SARS-CoV-2-S”). Further optionally, the CoV-S may comprise the amino acid sequence of SEQ ID NO: 401 (SARS-CoV-S, 1288 amino acids, Accession# PDB: 6VSB_B) or SEQ ID NO: 403 (SARS- CoV -2-S, 1273 amino acids, GenBank: QHD43416.1).

[0047] In some embodiments, the method may further detect that the antibody or antigen-binding fragment thereof which specifically binds to CoV-S neutralizes, blocks or inhibits coronavirus infectivity or coronavirus proliferation, optionally wherein the coronavirus is SARS-CoV or SARS- CoV-2. [0048] In certain embodiments, the method may further detect whether the antibody or antigen binding antibody fragment thereof which specifically binds to the CoV-S binds to other coronaviruses, optionally selected from the group consisting of MERS-CoV, HCoV-HKUl, HCoV- OC43, HCoV-229E, and HCoV-NL63.

[0049] In any of such detection methods, the method may further comprise determining the sequence of the antibody or antigen-binding antibody fragment thereof may be determined.

[0050] In some embodiments these sequences may be affinity-matured or mutated to enhance binding affinity and/or potentially increase specificity to a particular CoV-S.

[0051] The present disclosure further provides compositions comprising: (a) at least one antibody or antigen-binding antibody fragment of the present disclosure; and (b) a pharmaceutically acceptable carrier or excipient.

[0052] The present disclosure further provides methods of determining whether a subject has been infected with SARS-CoV or SARS-CoV-2 or another coronavirus by detecting whether a biological sample from the subject may comprise SARS-CoV-S protein or SARS-CoV-S-2 protein or another coronavirus S protein homologous thereto based on its immunoreaction with at least one antibody or antigen-binding antibody fragment disclosed herein. The sample may optionally be blood, plasma, lymph, mucus, urine, and/or feces. Optionally, the SARS-CoV S may comprise the amino acid sequence of SEQ ID NO: 401 (SARS-CoV-S, 1288 amino acids, Accession# PDB: 6VSB_B),

[0053] Alternatively, the SARS-CoV-2 may comprise the amino acid sequence of SEQ ID NO: 403 (SARS-CoV -2-S, 1273 amino acids, GenBank: QHD43416.1).

[0054] Such determination methods optionally may comprise an ELISA or radioimmunoassay.

[0055] In such determination methods, the subject optionally may be human, a companion animal (e.g., a dog or cat), an agricultural animal, e.g., animals used in meat production, or may comprise an animal in a zoo, e.g. , a tiger or lion.

[0056] In such determination methods, the samples optionally may be collected at different times from the subject and the presence or absence or the level of SARS-CoV-S or SARS-CoV-S-2 or another coronavirus S protein homologous thereto may be detected in order to assess whether the subject has recovered. Here, the SARS-CoV S may comprise the amino acid sequence of SEQ ID NO: 401 (SARS-CoV-S, 1288 amino acids, Accession# PDB: 6VSB_B), and optionally the SARS-CoV-2 may comprise the amino acid sequence of SEQ ID NO: 403 (SARS-CoV -2-S, 1273 amino acids, GenBank: QHD43416.1).

[0057] The present disclosure further provides methods of inducing an immune response against SARS-CoV or SARS-CoV-2 or another coronavirus, which may be selected from MERS-CoV, HCoV-HKUl, HCoV-OC43, HCoV-229E, and HCoV-NL63, in a subject in need thereof.

[0058] In some embodiments, the methods may comprise administering at least one antibody or antigen-binding antibody fragment of the present disclosure. [0059] In some embodiments, the methods may comprise administering a cocktail of different antibodies or antigen-binding antibody fragments of the present disclosure, e.g., which bind to the same or different epitopes on the same or different CoV-Ss.

[0060] In certain embodiments, the immune response elicits immunoprotection, optionally prolonged, against at least one coronavirus, optionally SARS-CoV or SARS-CoV-2, further optionally against another coronavirus.

[0061] The present disclosure further provides methods of inhibiting or blocking infection of susceptible cells by SARS-CoV or SARS-CoV-2 or another coronavirus, such as MERS-CoV, HCoV- HKU1, HCoV-OC43, HCoV-229E, and HCoV-NL63, in a subject in need thereof.

[0062] In some embodiments, the method may comprise administering at least one antibody or antigen-binding antibody fragment, of the present disclosure, e.g., a cocktail as above-described. [0063] The present disclosure further provides methods of treating infection by SARS-CoV or SARS-CoV-2 or another coronavirus optionally such as MERS-CoV, HCoV-HKUl, HCoV-OC43, HCoV-229E, and HCoV-NL63, or treating a condition, symptom, disease, or disorder associated with said infection in a subject in need thereof.

[0064] In some embodiments, the method may comprise administering to the subject a therapeutically effective amount of at least one antibody or antigen-binding antibody fragment, an ADC or a CAR, of the present disclosure, e.g., a cocktail as above-described.

[0065] In some embodiments, the condition, symptom, disease, or disorder comprises at least one of bronchitis, pneumonia, respiratory failure, acute respiratory failure, organ failure, multi-organ system failure, pediatric inflammatory multisystem syndrome, acute respiratory distress syndrome, blood clot, a cardiac condition, myocardial injury, myocarditis, heart failure, cardiac arrest, acute myocardial infarction, dysrhythmia, venous thromboembolism, post-intensive care syndrome, shock, anaphylactic shock, cytokine release syndrome, septic shock, disseminated intravascular coagulation, ischemic stroke, intracerebral hemorrhage, microangiopathic thrombosis, psychosis, seizure, nonconvulsive status epilepticus, traumatic brain injury, stroke, anoxic brain injury, encephalitis, posterior reversible leukoencephalopathy, necrotizing encephalopathy, post-infectious encephalitis, autoimmune mediated encephalitis, acute disseminated encephalomyelitis, acute kidney injury, acute liver injury, pancreatic injury, immune thrombocytopenia, subacute thyroiditis, a gastrointestinal complication, aspergillosis, increased susceptibility to infection with another virus or bacteria, and/or a pregnancy-related complication.

[0066] The present disclosure also provides methods of preventing infection by SARS-CoV or SARS-CoV-2 or another coronavirus optionally selected from the group consisting of MERS-CoV, HCoV-HKUl, HCoV-OC43, HCoV-229E, and HCoV-NL63 in a subject in need thereof. [0067] In some embodiments, the method may comprise administering to the subject a prophylactically effective amount of at least one antibody or antigen-binding antibody fragment, an ADC or a CAR, of the present disclosure, e.g., a cocktail as above-described.

[0068] The present disclosure also provides methods of preventing the need for a subject infected with SARS-CoV or SARS-CoV-2 or another coronavirus optionally selected from the group consisting of MERS-CoV, HCoV-HKUl, HCoV-OC43, HCoV-229E, and HCoV-NL63 to be placed on a ventilator, or reducing the time that a subject infected with SARS-CoV or SARS-CoV-2 or another coronavirus optionally selected from the group consisting of MERS-CoV, HCoV-HKUl, HCoV-OC43, HCoV-229E, and HCoV-NL63 is on a ventilator.

[0069] In some embodiments, the method may comprise administering to the subject a prophylactically or therapeutically effective amount of at least one antibody or antigen-binding antibody fragment, an ADC or a CAR, of the present disclosure, e.g., a cocktail as above-described. [0070] The present disclosure provides methods of preventing the onset of pneumonia in a subject infected SARS-CoV or SARS-CoV-2 or another coronavirus optionally selected from the group consisting of MERS-CoV, HCoV-HKUl, HCoV-OC43, HCoV-229E, and HCoV-NL63, or treating pneumonia and/or the symptoms of pneumonia in a subject for a subject infected SARS-CoV or SARS-CoV-2 or another coronavirus optionally selected from the group consisting of MERS-CoV, HCoV-HKUl, HCoV-OC43, HCoV-229E, and HCoV-NL63.

[0071] In some embodiments, the antibody, or antigen-binding fragment thereof, is administered within 5 days of symptom onset. In some embodiments, the antibody, or antigen-binding fragment thereof, is administered within 4 days of symptom onset. In some embodiments, the antibody, or antigen-binding fragment thereof, is administered within 3 days of symptom onset. In some embodiments, the antibody, or antigen-binding fragment thereof, is administered within 2 days of symptom onset. In some embodiments, the antibody, or antigen-binding fragment thereof, is administered within 1 day of symptom onset.

[0072] In some embodiments, the method may comprise administering to the subject a prophylactically or therapeutically effective amount of at least one antibody or antigen-binding antibody fragment, an ADC or a CAR, of the present disclosure, e.g., a cocktail as above-described. [0073] In any of such methods, the subject optionally may be human or may comprise a companion animal, agricultural animal or animal in a zoo.

[0074] In some embodiments, the subject is an adult. In some embodiment, the subject is an adolescent. In some embodiments, the subject is a child, or a pediatric subject. In one embodiment, the subject is a child, e.g., from birth to age of 11 years old, e.g., birth to < 1 month, 1 month to <2 years, 5-11 years old, or 2-11 years old. In other embodiments, the adolescent is 12-17 years old or 12-15 years old. In one embodiment, the adult is over the age of 18. In some embodiments, the subject has no known recent exposure to COVID-19. In some embodiments, the subject has a known recent exposure to COVID-19. In one embodiment, recent exposure is within the last 14 days, within the last 10 days, within the last 7 days, within the last 6 days, 5 days, 4 days, 3 days, 2 days, or 24 hours. In some embodiments, the subject has COVID-19 symptoms or an active COVID-19 infection. In some embodiments, the subject, e.g., the adult, the adolescent, or the child, is vaccinated or has received a COVID-19 vacination. In some embodiments, the subject, e.g., the adult, the adolescent, or the child, is not vaccinated or has not received a COVID-19 vacination.

[0075] In some embodiments, the subject is immunocompromised. In some embodiments, the subject is a significantly immune compromised subject, e.g., adult subject or pediatric subject, but whose underlying medical condition(s) put them at increased risk of developing severe symptomatic COVID-19. In some embodiments, the subject has no known recent exposure to COVID-19. In some embodiments, the subject has a known recent exposure to COVID-19. In one embodiment, recent exposure is within the last 14 days, within the last 10 days, within the last 7 days, within the last 6 days, 5 days, 4 days, 3 days, 2 days, or 24 hours. In some embodiments, the subject has COVID-19 symptoms or an active COVID-19 infection. In some embodiments, the immunocompromsed subject includes, but is not limited to, an individual who is actively treated for solid tumor or hematologic malignancies; solid organ transplant (SOT) recipient taking immunosuppressive therapy; CAR-T-cell therapy or HCT recipient; subjects having moderate or severe primary immunodeficiency; subjects having advanced or untreated HIV infection, or who are taking high-dose corticosteroids, alkylating agents, antimetabolites, or TNF blockers. In some embodiments, the immunocompromised subject is vaccinated or has received a COVID-19 vacination. In some embodiments, the immunocompromised subject is not vaccinated or has not received a COVID-19 vacination.

[0076] In some embodiments, the subject is at a high risk of COVID progression. In some embodiments, the subjects at a high risk of disease progression are age 50 years old or above with no comorbid conditions or additional risk factors for progression of COVID-19.

[0077] In some embodiments, the subjects at a high risk of disease progression are those about 18 to about 50 years old and with one or more preexisting medical conditons selected from the group consisting of (i) obesity (body mass index (BMI) > 30 kg/m²), (ii) diabetes (type 1 or type 2); (iii) chronic kidney disease (eGFR calculated by modification of diet in renal disease (MDRD) of 59 mL/min/1.73 m² or less, including end-stage renal disease on hemodialysis); (iv) chronic lung disease (emphysema/chronic obstructive pulmonary disease, chronic bronchitis, interstitial lung disease [including idiopathic pulmonary fibrosis], cystic fibrosis, or moderate to severe asthma [defined as requiring daily therapy]); (v) cardiac disease (heart failure, coronary artery disease, cardiomyopathies, or hypertension [with at least one medication prescribed or recommended]); (vi) sickle cell disease or thalassemia; (vii) solid organ or blood stem cell transplant recipients; (viii) other immunodeficiency due to underlying illness or immunosuppressant medication (e.g., corticosteroids >20 mg/day prednisone or equivalent); (ix) Down Syndrome, (x) stroke or cerebrovascular disease, which affects blood flow to the brain; (xi) substance use disorder; or (xii) pregnant.

[0078] In some embodiments, the subjects at a high risk of disease progression are those about 12 to about 17 years old (inclusive) and with one or more preexisting medical conditions selected from the group consisting of (i) BMI >85th percentile for age and sex based on United States Center for Disease Control (CDC) growth charts; (ii) diabetes (Type 1 or Type 2); (iii) chronic kidney disease; (iv) sickle cell disease or thalassemia; (v) congenital or acquired heart disease; (vi) neurodevelopmental disorders (e.g., cerebral palsy, Down syndrome); (vii) a medically-related technological dependence (e.g., tracheostomy, gastrostomy, or positive pressure ventilation not related to COVID-19); (viii) asthma, reactive airway or other chronic respiratory disease that requires daily medication for control; (ix) solid organ or blood stem cell transplant recipients; (x) other immunodeficiency due to underlying illness or immunosuppressant medication; (xi) substance use disorder; or (xii) pregnant.

[0079] In some embodiments, the subject is age 50 or above with no comorbid conditions or additional risk factors for progression of COVID-19.

[0080] In some embodiments, the subject has hypertension with at least one medication prescribed or recommended.

[0081] In some embodiments, the subject has moderate to severe asthma requiring daily therapy. [0082] Optionally the subject may have at least one risk factor which renders them more prone to a poor clinical outcome.

[0083] In certain embodiments, wherein the risk factors may comprise one or more of (i) advanced age such as over 55, 60 or 65 years old, (ii) diabetes, (iii) a chronic respiratory condition such as asthma, cystic fibrosis, another fibrotic condition, or COPD, (iv) obesity, (iv) hypertension, (v) a cardiac or cardiovascular condition, such as heart defects or abnormalities, (vi) a chronic inflammatory or autoimmune condition, e.g., lupus or multiple sclerosis, and (vii) an immunocompromised status which optionally may be caused by cancer, chemotherapy, smoking, bone marrow or organ transplantation, immune deficiencies, poorly controlled HIV infection or AIDS, or prolonged use of corticosteroids or other immunosuppressive medications.

In certain embodiments, the subject may further be treated with at least one other drug. In certain embodiments, the method further comprises administering to the subject at least one other drug. Optionally, such one other drug may be: (i) an antiviral drug, optionally, remdesivir, favipiravir, darunavir, nelfinavir, saquinavir, lopinavir, or ritonavir; (ii) an antihelminth drug, optionally ivermectin; (iii) an antiparasitic drug, optionally hydroxychloroquine, chloroquine, or atovaquone;

(iv) antibacterial vaccine, optionally the tuberculosis vaccine BCG; (v) an anti-inflammatory drug, optionally a steroid such as ciclesonide, a TNF inhibitor (e.g., adalimumab), a TNF receptor inhibitor (e.g., etanercept), an IL-6 inhibitor (e.g., clazakizumab), an IL-6 receptor inhibitor (e.g., tocilizumab), or metamizole; (vi) an antihistamine drug, optionally bepotastine; (vii) an ACE inhibitor, optionally moexipril; and/or (viii) a drug that inhibits priming of CoV-S, optionally a serine protease inhibitor, further optionally nafamostat.

[0084] In certain embodiments, the subject may further be treated with: (I) an antiviral agent, optionally, remdesivir, favipiravir, darunavir, nelfinavir, saquinavir, lopinavir, or ritonavir; and (II) at least one other drug. In certain embodiments, the method may further comprise administering to the subject (I) an antiviral agent, optionally, remdesivir, favipiravir, darunavir, nelfinavir, saquinavir, lopinavir, or ritonavir; and (II) at least one other drug. Optionally, the at least one other drug may be (i) an antihelminth drug, further optionally ivermectin; (ii) an antiparasitic drug, optionally hydroxychloroquine, chloroquine, or atovaquone; (iii) an antibacterial vaccine, which is optionally the tuberculosis vaccine BCG; or (iv) an anti-inflammatory drug, optionally a steroid such as ciclesonide, a TNF inhibitor (e.g., adalimumab), a TNF receptor inhibitor (e.g., etanercept), an IF-6 inhibitor (e.g., clazakizumab), an IF-6 receptor inhibitor (e.g., toclizumab), or metamizole; (v) an antihistamine drug, optionally bepotastine; (vi) an ACE inhibitor, optionally moexipril; and/or (vii) a drug that inhibits priming of CoV-S, which is optionally a serine protease inhibitor such as nafamostat. In some embodiments, the subject may further be treated with a vaccine, or has been treated with a vaccine, e.g., a COVID-19 vaccine. In some embodiments, the anti-CoV-S antibodies or antigen-binding fragments thereof are administered as a vaccine supplement. As used herein, the term “vaccine supplement” refers to a treatment that is administered prior to, concurrently with, or after, receving a vaccine treatment, e.g., a COVID-19 vaccine. The vaccine supplement may be administered instead of a vaccine booster or an additional dose.

[0085] In some embodiments, the anti-CoV-S antibody, or antigen-binding fragment thereof, is administered in combination with a vaccine. In some embodiments, the anti-CoV-S antibody, or antigen-binding fragment thereof, is administered concurrently with a COVID-19 vaccine. In some embodiments, the anti-CoV-S antibody, or antigen-binding fragment thereof, is administered after a COVID-19 vaccine. In some embodiments, the anti-CoV-S antibody, or antigen-binding fragment thereof, is administered prior to COVID-19 vaccine.

[0086] In one embodiment, the anti-CoV-S antibodies, or antigen -binding fragments thereof, are administered concurrently with a COVID-19 vaccine, within 24 hours of a COVID-19 vaccine, within 48 hours of a COVID-19 vaccine, within 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months of a COVID-19 vaccine. In one embodiment, the COVID-19 vaccine is an mRNA vaccine. In one embodiment, the COVID- 19 vaccine is COMIRNATY (by PFIZER, also known as BNT 162b2), the Moderna COVID-19 vaccine (mRNA-1273), the Johnson & Johnson COVID-19 vaccine (JNJ-78436735), or the AstraZeneca COVID-19 vaccine. [0087] In some embodiments, anti-CoV-S antibodies or antigen-binding antibody fragments of the present disclosure may be characterized by having a certain VH CDR3 sequences or having a VH CDR3 sequences that are similar to a certain VH CDR3.

[0088] In certain embodiments, antibody or antigen-binding antibody fragment of the present disclosure may comprise an Fc region. The Fc region may comprise a wild type sequence or a variant sequence and optionally may comprise an amino acid sequence of SEQ ID NOs: 411, 412, 413, 414, 415, 416, or 417.

[0089] In certain embodiments, the isolated antibody or antigen-binding antibody fragment may bind to the SI subunit of SARS-CoV-S or of SARS-CoV-2-S.

[0090] In certain embodiments, the isolated antibody or antigen-binding antibody fragment may bind to the receptor binding domain (RBD) or the N-terminal domain (NTD) of SARS-CoV-S or of SARS- CoV-2-S.

[0091] In certain embodiments, the isolated antibody or antigen-binding antibody fragment may bind to the ACE2-binding motif of SARS-CoV-S or of SARS-CoV-2-S and optionally further binds to the epitope of the antibody CR3022.

[0092] In further embodiments, the isolated antibody or antigen-binding antibody fragment may compete with ACE2.

[0093] In further embodiments, the isolated antibody or antigen-binding antibody fragment may compete with: (i) ACE2 and the antibody CR3022; or (ii) ACE2 but not the antibody CR3022. In certain embodiments, the isolated antibody or antigen-binding antibody fragment (a) may bind to the S protein of SARS-CoV and/or of SARS-CoV-2; and (b) may not bind to any of the S proteins of HCoV-229E, HCoV-HKUl, HCoV-NL63, and HCoV-OK43.

[0094] In certain embodiments, the isolated antibody or antigen-binding antibody fragment may (a) bind to the S protein of SARS-CoV and/or of SARS-CoV-2; and also (b) bind to the S protein of at least one of HCoV-229E, HCoV-HKUl, HCoV-NL63, and HCoV-OK43.

[0095] In further embodiments, the isolated antibody or antigen-binding antibody fragment may neutralize SARS-CoV and/or SARS-CoV-2.

[0096] In further embodiments, the isolated antibody or antigen-binding antibody fragment may neutralize SARS-CoV and/or SARS-CoV-2 at 100 nM in vitro.

[0097] In further embodiments, the isolated antibody or antigen-binding antibody fragment may neutralize SARS-CoV and/or SARS-CoV-2 at: (i) an IC50 of about 100 nM or lower, of about 50 nM or lower, of about 20 nM or lower, of about 10 nM or lower, of about 5 nM or lower, of about 2 nM or lower, of about 1 nM or lower, of about 500 pM or lower, of about 200 pM or lower, of about 100 pM or lower, of about 50 pM or lower, of about 20 pM or lower, of about 10 pM or lower, of about 5 pM or lower, of about 2 pM or lower, or of about 1 pM or lower; and/or (ii) an IC50 of about 5 μg/mL or lower, of about 4.5 μg/mL or lower, of about 4 μg/mL or lower, of about 3.5 μg/mL or lower, of about 3 mg/mL or lower, of about 2.5 mg/mL or lower, about 2 mg/mL or lower, of about 1.5 mg/mL or lower, of about 1 mg/mL or lower, of about about 500 ng/mL or lower, of about 400 ng/mL or lower, of about 200 ng/mL or lower, of about 100 ng/mL or lower, of about 50 ng/mL or lower, of about 20 ng/mL or lower, of about 10 ng/mL or lower, of about 5 ng/mL or lower, of about 2 ng/mL or lower, or of about 1 ng/mL or lower, or about 0.6 ng/mL or lower, or of about 0.1 ng/mL to about 5 mg/mL, of about 0.5 ng/mL to about 4.5 mg/mL, of about 0.5 ng/mL to about 4 mg/mL, of about 0.5 ng/mL to about 3.5 mg/mL, of about 0.5 ng/mL to about 3 mg/mL, of about 0.5 ng/mL to about 2.5 mg/mL, of about 0.5 ng/mL to about 2 mg/mL, of about 1 ng/mL to about 2 mg/mL, of about 1 ng/mL to about 1.5 mg/mL, of about 100 ng/mL to about 1.1 mg/mL, of about 100 ng/mL to about 1 mg/mL, of about 100 ng/mL to about 500 ng/mL, of about 400 ng/mL to about 1.1 mg/mL, of about 350 ng/mL to about 1.1 mg/mL, of about 300 ng/mL to about 1.1 mg/mL, of about 250 ng/mL to about 1.1 mg/mL, or of about 200 ng/mL to about 1.1 mg/mL, in vitro, optionally as measured by any of the neutralization assays described in the Examples herein. In another embodiment, the isolated antibody or antigen-binding antibody fragment may neutralize SARS-CoV and/or SARS-CoV-2 at an IC90 of about 10 μg/mL or less, an IC90 of about 1 to about 10 μg/mL, an IC90 of about 2 to about 10 μg/mL, an IC90 of about 3 to about 10 μg/mL, an IC90 of about 5 to 10 μg/mL, an IC90 of about 7 to 10 μg/mL, an IC90 of about 8 to 10 μg/mL, an IC90 of about 9 to 10 μg/mL, an IC90 of about 10 μg/mL, 9 μg/mL, 8 μg/mL, 7, μg/mL, 6 μg/mL, or 5 μg/mL.

[0098] In further embodiments, the isolated antibody or antigen-binding antibody fragment may bind to CoV-S (S protein of any CoV, such as but not limited to SARS-CoV-S and/or SARS-CoV -2-S) with a KD value of: (i) 100 nM or lower; (ii) 10 nM or lower; (iii) 1 nM or lower; (iv) 100 pM or lower; (v) 10 pM or lower; (vi) 1 pM or lower; or (vii) 0.1 pM or lower.

[0099] In some embodiments, the antibody, or antigen-binding fragment thereof, is administered intravenously. In other embodiments, the antibody, or antigen-binding fragment thereof, is administered intramuscularly.

[0100] In some embodiments, at least one of the antibody, or antigen-binding fragment thereof, is administered. In some embodiments, at least two of the antibody, or antigen-binding fragment thereof, are administered. In some embodiments, the anti-CoV-S antibody and antigen-binding fragment thereof, e.g., ADI-58125, may be used in combination with a second antibody, or antigen-binding fragment thereof, wherein the second antibody, or antigen-binding fragment thereof, is selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, ADI-58131, or a combination thereof. In some embodiment, the second antibody, or antigen-binding fragment thereof, is ADI-58122. In one embodiment, the second antibody, or antigen-binding fragment thereof, is ADI-58127. In one embodiment, the second antibody, or antigen-binding fragment thereof, is ADI-58129. In one embodiment, the second antibody, or antigen-binding fragment thereof, is ADI-58131. [0101] In some embodiments, the antibody, or antigen-binding fragment thereof, is administered at a dose of about 100 mg to about 5000 mg, about 100 mg to about 4500 mg, about 100 mg to about 4000 mg, about 100 mg to about 3500 mg, about 100 mg to about 3000 mg, about 100 mg to about 2500 mg, about 300 mg to about 4500 mg, about 500 mg to about 4500 mg, about 600 mg to about 4500 mg, about 1200 mg to about 4500 mg, about 100 mg to about 2000 mg, about 200 mg to about 1500 mg, about 300 mg to about 600 mg, about 500 mg to about 1200 mg, or about 300 mg to about 1200 mg. In some embodiments, the antibody, or antigen-binding fragment thereof, is administered at a dose of about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2500 mg, about 3000 mg, about 3500 mg, about 4000 mg, about 4500 mg, or about 5000 mg.

[0102] In some embodiments, the antibody, or antigen-binding fragment thereof, is administered at a dose of about 150 mg intramuscularly, about 300 mg intramuscularly, about 450 mg intramuscularly, about 500 mg intravenously, about 600 mg intramuscularly, about 1200 mg intramuscularly, about 1200 mg intravenously, about 4500 mg intramuscularly, or about 4500 mg intravenously.

[0103] In some embodiments, the antibody, or antigen-binding fragment thereof, is administered at a dosage determined based on the current coronavirus variant(s) that is (are) currently circulating in the population (also referred to herein as “variant-based dosing”). For example, in one embodiment, the antibody, or antigen-binding fragment thereof, is administered intramuscularly as a single 1200 mg dose. In another embodiment, the antibody, or antigen-binding fragment thereof, is administered intravenously as a 1200 mg dose. In another embodiment, the antibody, or antigen-binding fragment thereof, is administered intravenously as a single 600 mg dose. In another embodiment, the antibody, or antigen-binding fragment thereof, is administered intravenously as a single 500 mg dose. In another embodiment, the antibody, or antigen-binding fragment thereof, is administered intramuscularly as two 600 mg doses (for example, a first 600 mg dose in the right thigh or right arm, and a second 600 mg dose in the left thigh or left arm; or a first 600 mg dose in the left thigh or left arm, and a second 600 mg dose in the right thigh or right arm) on the same day, for a total dosage of 1200 mg. In another embodiment, the antibody, or antigen-binding fragment thereof, is administered intramuscularly as two 300 mg doses (for example, a first 300 mg dose in the right thigh or right arm, and a second 300 mg dose in the left thigh or left arm; or a first 300 mg dose in the left thigh or left arm, and a second 300 mg dose in the right thigh or right arm) on the same day, for a total dosage of 600 mg.

[0104] In one embodiment, the antibody, or antigen-binding fragment thereof, is administered once. In one embodiment, the antibody, or antigen-binding fragment thereof, is administered weekly. In another embodiment, the antibody, or antigen-binding fragment thereof, is administered daily, weekly, every two weeks, monthly, or every two months. In one embodiment, the antibody, or antigen-binding fragment thereof, is administered weekly for about four weeks, once weekly for about a month, weekly for about 5 weeks, weekly for about 6 weeks, weekly for about 7 weeks, or weekly for about two months.

[0105] In one embodiment, the methods further comprise obtaining a serum sample from the subject. [0106] In some embodiments, the antibody, or antigen-binding fragment thereof, reaches a maximum concentration (Cmax) of about 10 μg/mL to about 1000 μg/mL, about 20 μg/mL to about 500 μg/mL, about 30 μg/mL to about 400 μg/mL, about 40 μg/mL to about 300 μg/mL, about 50 μg/mL to about 200 μg/mL, about 30 μg/mL to about 200 μg/mL, about 100 μg/mL to about 200 μg/mL, about 50 μg/mL to about 100 μg/mL, or about 30 μg/mL to about 70 μg/mL, about 100 μg/mL to about 400 μg/mL, or about 150 μg/mL to about 350 μg/mL in the serum sample of the subject. In some embodiments, the antibody, or antigen-binding fragment thereof, reaches a maximum concentration (Cmax) of about 30 μg/mL, about 40 μg/mL, about 50 μg/mL, about 60 μg/mL, about 70 μg/mL, about 80 μg/mL, about 90 μg/mL, about 100 μg/mL, about 110 μg/mL, about 120 μg/mL, about 130 μg/mL, about 140 μg/mL, about 150 μg/mL, about 160 μg/mL, about 170 μg/mL, about 180 μg/mL, about 190 μg/mL, or about 200 μg/mL, about 210 μg/mL, about 220 μg/mL, about 230 μg/mL, about 240 μg/mL, about 250 μg/mL, about 260 μg/mL, about 270 μg/mL, about 280 μg/mL, about 290 μg/mL, about 300 μg/mL, about 350 μg/mL, or about 400 μg/mL in the serum sample of the subject. [0107] In some embodiments, the median time for the antibody, or antigen-binding fragment thereof, to reach a maximum concentration in the serum sample of the subject is about 0.01-30 days, about 0.01-0.05 days, about 5-30 days, about 3-20 days, about 6-20 days, about 7-18 days, or about 8-15 days, or about 13-15 days after administration. In some embodiments, the median time for the antibody, or antigen-binding fragment thereof, to reach a maximum concentration in the serum sample of the subject is about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 days after administration. In some embodiments, the median time for the antibody, or antigen-binding fragment thereof, to reach a maximum concentration in the serum sample of the subject is less than about 1 day, e.g., about 0.01, about 0.02, about 0.03, about 0.04, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, or about 0.9 days after administration.

[0108] In some embodiments, the antibody, or antigen-binding fragment thereof, reaches a maximum concentration (Cmax) of about 30 μg/mL to about 200 μg/mL, about 100 μg/mL to about 200 μg/mL, about 30 μg/mL to about 100 μg/mL, about 40 μg/mL to about 80 μg/mL, about 50 μg/mL to about 70 μg/mL, or about 30 μg/mL to about 65 μg/mL in the serum sample of the subject in about about 0.01-20 days, about 3-20 days, about 6-20 days, about 7-18 days, about 8-15 or about 13-15 days after administration. [0109] In some embodiments, the area under the serum concentration-time curve from day 0 to day 21 (AUCo -2i _d) is about 100-2000 day* mg/mL, about 1000-2000 day* mg/mL, about 1400-2000 day* mg/mL, about 200-1500 day* mg/mL, about 400-1400 day* mg/mL, about 500-1300 day* mg/mL, about 600-1000 day* mg/mL, or about 800-900 day* mg/mL.

[0110] In some embodiments, the area under the serum concentration-time curve from day 0 to day 90 (AUCo 90_d) is about 1000-10000 day* mg/mL, about 2000-8000 day* mg/mL, about 2000-5000 day* mg/mL, about 3000-4000 day* mg/mL, about 5000-10000 day* mg/mL, about 2000-4000 day* mg/mL, about 5000-8000 day* mg/mL, or about 6000-8000 day* mg/mL.

[0111] In some embodiments, the area under the serum concentration-time curve from day 0 to day 180 (AUCo i80_d) is about 1000-10000 day* mg/mL, about 2000-5000 day* mg/mL, about 3000-6000 day* mg/mL, about 5000-10000 day* mg/mL, about 5000-8000 day* mg/mL, or about 4000-6000 day* mg/mL.

[0112] In some embodiments, the area under the serum concentration-time curve from day 0 to day 365 (AUCo 365_d) is about 1000-30000 day* mg/mL, about 5000-30000 day* mg/mL, about 10000- 30000 day* mg/mL, about 10000-15000 day* mg/mL, about 20000-30000 day* mg/mL, or about 25000-30000 day* mg/mL.

[0113] In some embodiments, the antibody, or antigen-binding fragment thereof, has a virus neutralizing titer of about 100-2000, about 200-1500, about 300-1500, or about 500-1500 in the serum sample of the subject about 6 months after administration. In some embodiments, the antibody, or antigen-binding fragment thereof, has a virus neutralizing titer of about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900 or 2000 in the serum sample of the subject about 6 months after administration.

[0114] In some embodiments, the antibody, or antigen-binding fragment thereof, has a serum half- life of about 50-200 days, about 50-160 days, about 50-140 days, about 40-130 days, about 50-100 days, about 60-100 days, about 60-90 days, about 70-90 days, about 90-100 days, about 70-80 days, about 80-130 days, about 100-150 days, about 110-140 days, or about 120-140 days.

[0115] In some embodiments, the method further comprises obtaining an epithelial lining fluid (ELF) sample from the subject. In some embodiments, the ELF sample comprises an ELF sample from an upper airway, an lower airway, and/or an alveolar tissue.

[0116] In some embodiments, the antibody, or antigen-binding fragment thereof, reaches a concentrationof about 1 μg/mL to about 100 μg/mL, about 1 μg/mL to about 80 μg/mL, about 80 μg/mL to about 100 μg/mL, about 50 μg/mL to about 100 μg/mL, about 1 μg/mL to about 50 μg/mL, about 2 μg/mL to about 25 μg/mL, or about 2 μg/mL to about 10 μg/mL in the ELF sample of the subject.

[0117] In some embodiments, the antibody, or antigen-binding fragment thereof, has a receptor occupancy of at least 50%, 60%, 70%, 80%, or 90% in the ELF sample. In some embodiments, the antibody, or antigen-binding ragment thereof, has a receptor occupancy of at least 50%, 60%, 70%, 80%, or 90% in the ELF sample for about 28 days after administration.

[0118] In some embodiments, the 80% virus neutralization titer (MN80) of the antibody, or antigen binding fragment thereof, at about days 0-14, about days 7-21, about 3 months, or about 6 months after administration, is about 10-6000, about 50-600, about 500-1500, about 1000-2500, about 100- 2500, about 500-2000, about 500-1500, about 400-1200, about 200-1500, about 300-1000, about 400- 800, about 400-1000, or about 500-600 in the subject.

[0119] In some embodiments, the 80% virus neutralization titer (MN80) of the antibody, or antigen binding fragment thereof, at about day 7, day 14, or day 21 after administration, is about 300-2000, about 400-600, about 600-1500, about 1100-1700, about 500-1700, about 500-1500, about 400-1200, about 400-800, about 400-1000, or about 500-600 in the serum sample of the subject.

[0120] In some embodiments, the 80% virus neutralization titer (MN80) of the antibody, or antigen binding fragment thereof, at about 3 months after administration, is about 200-1000, about 200-800, about 200-500, about 400-900, or about 400-600 in the serum sample of the subject.

[0121] In some embodiments, the 80% virus neutralization titer (MN80) of the antibody, or antigen binding fragment thereof, at about 6 months after administration, is about 10-500, about 300-500, or about 50-200 in the serum sample of the subject.

[0122] In some embodiments, the 50% virus neutralization titer (MN50) of the antibody, or antigen binding fragment thereof, at about days 0-14, about days 7-21, about 3 months, about 6 months, or about 12 months after administration, is about 100-6000, about 300-1500, about 1700-3800, about 3800-5200, about 300-5500, about 1200-4500, about 1300-4300, about 1200-4000, about 100-2500, about 500-2500, about 800-2000, about 1000-1800, about 800-1300, about 900-1100, or about 1300- 1500 in the serum sample of the subject.

[0123] In some embodiments, the 50% virus neutralization titer (MN50) of the antibody, or antigen binding fragment thereof, at about day 7, day 14 or day 21 after administration, is about 1000-4500, about 1200-4500, about 1300-4300, about 1200-3900, about 1500-4000, about 1800-3800, about 3800-4500, about 1000-1800 or about 1200-1500 in the serum sample of the subject.

[0124] In some embodiments, the 50% virus neutralization titer (MN50) of the antibody, or antigen binding fragment thereof, at about 3 months after administration, is about 800-1300 or about 900- 1100 in the serum sample of the subject.

[0125] In some embodiments, the 50% virus neutralization titer (MN50) of the antibody, or antigen binding fragment thereof, at about 6 months after administration, is about 200-500 or about 300-600 in the serum sample of the subject.

[0126] In some embodiments, the 50% virus neutralization titer (MN50) of the antibody, or antigen binding fragment thereof, at about 12 months after administration, is about 150-500 or about 200-400 in the serum sample of the subject. [0127] In some embodiments, the neutralization titer is determined using a plaque reduction neutralization test (PRNT).

[0128] In some embodiments, the serum concentration of the antibody, or antigen-binding fragment thereof, is about 1-300 mg/L, about 1-250 mg/L, about 1-200 mg/L, about 1-100 mg/L, about 100-250 mg/L, about 150-200 mg/L, about 120-170 mg/L, about 1-90 mg/L, about 1-80 mg/L, about 1-70 mg/L, about 1-60 mg/L, about 1-50 mg/L, about 1-40 mg/L, about 1-30 mg/L, about 1-20 mg/L, about 1-10 mg/L, about 2-9 mg/L, about 3-8 mg/L, about 4-6 mg/L, about 5-80 mg/L, about 10-70 mg/L, or about 10-60 mg/L in the subject about 3 months after administration.

[0129] In some embodiments, the serum concentration of the antibody, or antigen-binding fragment thereof, is about 1 mg/L, about 2 mg/L, about 3 mg/L, about 4 mg/L, about 5 mg/L, about 6 mg/L, about 7 mg/L, about 8 mg/L, about 9 mg/L, about 10 mg/L, about 11 mg/L, about 12 mg/L, about 13 mg/L, about 14 mg/L, about 15 mg/L, about 16 mg/L, about 17 mg/L, about 18 mg/L, about 19 mg/L, about 20 mg/L, about 25 mg/L, about 30 mg/L, about 35 mg/L, about 40 mg/L, about 45 mg/L, about 50 mg/L, about 55 mg/L, about 60 mg/L, about 65 mg/L, about 70 mg/L, about 75 mg/L, about 80 mg/L, about 85 mg/L, about 90 mg/L, about 95 mg/L, about 100 mg/L, about 110 mg/L, about 120 mg/L, about 130 mg/L, about 140 mg/L, about 150 mg/L, about 160 mg/L, about 170 mg/L, about 180 mg/L, about 190 mg/L, about 200 mg/L, about 210 mg/L, about 220 mg/L, about 230 mg/L, about 240 mg/L, about 250 mg/L, about 300 mg/L in the subject about 3 months after administration. [0130] In some embodiments, the serum concentration of the antibody, or antigen-binding fragment thereof, is about 1-100 mg/L, about 1-90 mg/L, about 1-80 mg/L, about 1-70 mg/L, about 1-60 mg/L, about 1-50 mg/L, about 1-40 mg/L, about 1-30 mg/L, about 1-20 mg/L, about 1-10 mg/L, about 2-9 mg/L, about 3-8 mg/L, about 4-6 mg/L, about 5-80 mg/L, about 10-70 mg/L, about 10-60 mg/L, about 5-25 mg/L, about 10-30 mg/L, about 15-25 mg/L, about 20-100 mg/L, about 30-100 mg/L, about 50- 80 mg/L, or about 60-70 mg/L in the subject about 6 months after administration.

[0131] In some embodiments, the serum concentration of the antibody, or antigen-binding fragment thereof, is about 1 mg/L, about 2 mg/L, about 3 mg/L, about 4 mg/L, about 5 mg/L, about 6 mg/L, about 7 mg/L, about 8 mg/L, about 9 mg/L, about 10 mg/L, about 11 mg/L, about 12 mg/L, about 13 mg/L, about 14 mg/L, about 15 mg/L, about 16 mg/L, about 17 mg/L, about 18 mg/L, about 19 mg/L, about 20 mg/L, about 25 mg/L, about 30 mg/L, about 35 mg/L, about 40 mg/L, about 45 mg/L, about 50 mg/L, about 55 mg/L, about 60 mg/L, about 65 mg/L, about 70 mg/L, about 75 mg/L, about 80 mg/L, about 85 mg/L, about 90 mg/L, about 95 mg/L, or about 100 mg/L in the subject about 6 months after administration.

[0132] In some embodiments, the serum concentration of the antibody, or antigen-binding fragment thereof, is about 0.1-30 mg/L, about 1-30 mg/L, about 1-20 mg/L, about 1-10 mg/L, about 10-20 mg/L, about 0.1-3 mg/L, about 0.5-8 mg/L, about 0.5-10 mg/L, about 2-9 mg/L, about 5-15 mg/L, about 3-8 mg/L, or about 4-6 mg/L in the subject about 12 months after administration. [0133] In some embodiments, the serum concentration of the antibody, or antigen-binding fragment thereof, is about 0.1 mg/L, about 0.2 mg/L, about 0.3 mg/L, about 0.4 mg/L, about 0.5 mg/L, about 0.6 mg/L, about 0.7 mg/L, about 0.8 mg/L, about 0.9 mg/L, about 1 mg/L, about 2 mg/L, about 3 mg/L, about 4 mg/L, about 5 mg/L, about 6 mg/L, about 7 mg/L, about 8 mg/L, about 9 mg/L, about 10 mg/L, about 15 mg/L, about 20 mg/L, about 25 mg/L, or about 30 mg/L in the subject about 12 months after administration.

[0134] In some embodiments, the clearance rate for the antibody, or antigen-binding fragment thereof, is about 0.1-10 mL/d, about 0.1-5.0 mL/d, about 0.1-3.0 mL/d, about 0.5-2.5 mL/d, or about 1.0-2.0 mL/d.

[0135] In some embodiments, the steady state volume of distribution for the antibody, or antigen binding fragment thereof, is about 1-10 L, about 2-8 L, about 4-9 L, about 4-8 L, or about 5-7L.

[0136] In some embodiments, administration of the antibody, or antigen-binding fragment thereof, reduces pulmonary inflammation in the subject.

[0137] In some embodiments, administration of the antibody, or antigen-binding fragment thereof, reduces the risk of COVID-19 hospitalization or death of the subject. In some embodiments, the risk of COVID-19 hospitalization or death is reduced by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%.

[0138] In some embodiments, administration of the antibody, or antigen-binding fragment thereof, reduces viral load in the subject. In some embodiments, the viral load is reduced by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%. In some embodiments, the viral load is reduced by at least about 0.5 loglO copies/mL, at least about 0.6 loglO copies/mL, at least about 0.7 loglO copies/mL, at least about 0.8 loglO copies/mL, at least about 0.9 loglO copies/mL, at least about 1.0 loglO copies/mL, at least about 1.1 loglO copies/mL, at least about 1.2 loglO copies/mL, at least about 1.3 loglO copies/mL, at least about 1.4 loglO copies/mL, at least about 1.5 loglO copies/mL, at least about 1.6 loglO copies/mL, at least about 1.7 loglO copies/mL, at least about 1.8 loglO copies/mL, at least about 1.9 loglO copies/mL, at least about 2.0 loglO copies/mL, at least about 2.1 loglO copies/mL, at least about 2.2 loglO copies/mL, at least about 2.3 loglO copies/mL, at least about 2.4 loglO copies/mL, at least about 2.5 loglO copies/mL, at least about 2.6 loglO copies/mL, at least about 2.7 loglO copies/mL, at least about 2.8 loglO copies/mL, at least about 2.9 loglO copies/mL, or at least about 3.0 loglO copies/mL.

[0139] In one aspect, the present disclosure also relates to kits comprising: (a) at least one isolated antibody or antigen-binding antibody fragment disclosed herein; and (b) an instruction for using the antibody or antigen-binding antibody fragment.

[0140] In some embodiments, the kit may be for use in: (i) determining whether a CoV is present in a subject; (ii) diagnosing whether a subject has CoV infection; (iii) predicting whether a CoV vaccine will elicit a protective immune response; or (iv) predicting whether a CoV vaccine will elicit a neutralizing antibody response.

[0141] In one aspect, the present disclosure provides a method of inducing an immune response against a coronavirus (CoV) in a subject in need thereof, the method comprising administering to the subject an isolated antibody, or antigen-binding fragment thereof, which binds to the spike protein of a coronavirus (“CoV-S”), wherein said antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising a VH CDR1 comprising SEQ ID NO:52, a VH CDR2 comprising SEQ ID NO:54, and a VH CDR3 comprising SEQ ID NO:56, and a light chain variable region (VL) comprising a VL CDR1 comprising SEQ ID NO:252, a VL CDR2 comprising SEQ ID NO:254, and a VL CDR3 comprising SEQ ID NO:256; (a) wherein the antibody, or antigen-binding fragment thereof, reaches a maximum concentration (Cmax) of about 10 μg/mL to about 1000 μg/mL, about 20 μg/mL to about 500 μg/mL, about 30 μg/mL to about 400 μg/mL, about 40 μg/mL to about 300 μg/mL, about 50 μg/mL to about 200 μg/mL, about 50 μg/mL to about 100 μg/mL, or about 30 μg/mL to about 70 μg/mL, about 100 μg/mL to about 400 μg/mL, about 150 μg/mL to about 350 μg/mL in serum of the subject; (b) wherein the median time (Tmax) for the antibody, or antigen binding fragment thereof, to reach a maximum concentration in serum of the subject is about 0.01-30 days, about 3-20 days, about 6-20 days, about 7-18 days, about 8-15 or about 13-15 days; (c) wherein the antibody, or antigen-binding fragment thereof, reaches a maximum concentration of about 30 μg/mL to about 200 μg/mL, about 100 μg/mL to about 200 μg/mL, about 30 μg/mL to about 100 μg/mL, about 40 μg/mL to about 80 μg/mL, about 50 μg/mL to about 70 μg/mL, or about 30 μg/mL to about 65 μg/mL in serum of the subject in about 0.01-20 days, about 3-20 days, about 6-20 days, about 7-18 days, about 8-15 or about 13-15 days after administration; (d) wherein the area under the serum concentration-time curve from day 0 to day 21 (AUC0-21d) is about 100-2000 day* μg/mL, about 1000-2000 day* μg/mL, about 1400-2000 day* μg/mL, about 200-1500 day* μg/mL, about 400-1400 day* μg/mL, about 500-1300 day* μg/mL, about 600-1000 day* μg/mL, or about 800-900 day* μg/mL; (e) wherein the area under the serum concentration-time curve from day 0 to day 90 (AUC0-90d) is about 1000-10000 day* μg/mL, about 2000-8000 day* μg/mL, about 2000-5000 day* μg/mL, about 3000-4000 day* μg/mL, about 5000-10000 day* μg/mL, about 2000-4000 day* μg/mL, about 5000-8000 day* μg/mL, or about 6000-8000 day* μg/mL; (f) wherein the area under the serum concentration-time curve from day 0 to day 180 (AUC0-180d) is about 1000-10000 day* μg/mL, about 2000-5000 day* μg/mL, about 3000-6000 day* μg/mL, about 5000-10000 day* μg/mL, about 5000-8000 day* μg/mL, or about 4000-6000 day* μg/mL; (g) wherein the area under the serum concentration-time curve from day 0 to day 365 (AUC0-365d) is about 1000-30000 day* μg/mL, about 5000-30000 day* μg/mL, about 10000-30000 day* μg/mL, about 10000-15000 day* μg/mL, about 20000-30000 day* μg/mL, or about 25000-30000 day* μg/mL; and/or (h) wherein the antibody, or antigen-binding fragment thereof, has a serum half-life of about 50-200 days, about 50- 160 days, about 50-140 days, about 40-130 days, about 50-100 days, about 60-100 days, about 60-90 days, about 70-90 days, about 90-100 days, about 70-80 days, about 80-130 days, about 100-150 days, about 110-140 days, or about 120-140 days.

[0142] In one aspect, the present disclosure provides a method of preventing a coronavirus infection in a subject in need thereof, the method comprising administering to the subject an isolated antibody, or antigen-binding fragment thereof, which binds to the spike protein of a coronavirus (“CoV-S”), wherein said antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising a VH CDR1 comprising SEQ ID NO:52, a VH CDR2 comprising SEQ ID NO:54, and a VH CDR3 comprising SEQ ID NO: 56, and a light chain variable region (VL) comprising a VL CDR1 comprising SEQ ID NO:252, a VL CDR2 comprising SEQ ID NO:254, and a VL CDR3 comprising SEQ ID NO:256; (a) wherein the antibody, or antigen-binding fragment thereof, reaches a maximum concentration (Cmax) of about 10 μg/mL to about 1000 μg/mL, about 20 μg/mL to about 500 μg/mL, about 30 μg/mL to about 400 μg/mL, about 40 μg/mL to about 300 μg/mL, about 50 μg/mL to about 200 μg/mL, about 50 μg/mL to about 100 μg/mL, or about 30 μg/mL to about 70 μg/mL, about 100 μg/mL to about 400 μg/mL, about 150 μg/mL to about 350 μg/mL in serum of the subject; (b) wherein the median time (Tmax) for the antibody, or antigen-binding fragment thereof, to reach a maximum concentration in serum of the subject is about 0.01-30 days, about 3-20 days, about 6-20 days, about 7-18 days, about 8-15 or about 13-15 days; (c) wherein the antibody, or antigen binding fragment thereof, reaches a maximum concentration of about 30 μg/mL to about 200 μg/mL, about 100 μg/mL to about 200 μg/mL, about 30 μg/mL to about 100 μg/mL, about 40 μg/mL to about 80 μg/mL, about 50 μg/mL to about 70 μg/mL, or about 30 μg/mL to about 65 μg/mL in serum of the subject in about 0.01-20 days, about 3-20 days, about 6-20 days, about 7-18 days, about 8-15 or about 13-15 days after administration; (d) wherein the area under the serum concentration-time curve from day 0 to day 21 (AUC0-21d) is about 100-2000 day* μg/mL, about 1000-2000 day* μg/mL, about 1400-2000 day* μg/mL, about 200-1500 day* μg/mL, about 400-1400 day* μg/mL, about 500-1300 day* μg/mL, about 600-1000 day* μg/mL, or about 800-900 day* μg/mL; (e) wherein the area under the serum concentration-time curve from day 0 to day 90 (AUC0-90d) is about 1000-10000 day* μg/mL, about 2000-8000 day* μg/mL, about 2000-5000 day* μg/mL, about 3000-4000 day* μg/mL, about 5000-10000 day* μg/mL, about 2000-4000 day* μg/mL, about 5000-8000 day* μg/mL, or about 6000-8000 day* μg/mL; (f) wherein the area under the serum concentration-time curve from day 0 to day 180 (AUC0-180d) is about 1000-10000 day* μg/mL, about 2000-5000 day* μg/mL, about 3000-6000 day* μg/mL, about 5000-10000 day* μg/mL, about 5000-8000 day* μg/mL, or about 4000-6000 day* μg/mL; (g) wherein the area under the serum concentration-time curve from day 0 to day 365 (AUC0-365d) is about 1000-30000 day* μg/mL, about 5000-30000 day* μg/mL, about 10000-30000 day* μg/mL, about 10000-15000 day* μg/mL, about 20000-30000 day* μg/mL, or about 25000-30000 day* μg/mL; and/or (h) wherein the antibody, or antigen-binding fragment thereof, has a serum half-life of about 50-200 days, about 50-160 days, about 50-140 days, about 40- 130 days, about 50-100 days, about 60-100 days, about 60-90 days, about 70-90 days, about 90-100 days, about 70-80 days, about 80-130 days, about 100-150 days, about 110-140 days, or about 120- 140 days.

[0143] In one aspect, the present disclosure provides a method of beating a coronavirus infection in a subject in need thereof, the method comprising administering to the subject an isolated antibody, or antigen-binding fragment thereof, which binds to the spike protein of a coronavirus (“CoV-S”), wherein said antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising a VH CDR1 comprising SEQ ID NO:52, a VH CDR2 comprising SEQ ID NO:54, and a VH CDR3 comprising SEQ ID NO: 56, and a light chain variable region (VL) comprising a VL CDR1 comprising SEQ ID NO:252, a VL CDR2 comprising SEQ ID NO:254, and a VL CDR3 comprising SEQ ID NO:256; (a) wherein the antibody, or antigen-binding fragment thereof, reaches a maximum concentration (Cmax) of about 10 μg/mL to about 1000 μg/mL, about 20 μg/mL to about 500 μg/mL, about 30 μg/mL to about 400 μg/mL, about 40 μg/mL to about 300 μg/mL, about 50 μg/mL to about 200 μg/mL, about 50 μg/mL to about 100 μg/mL, or about 30 μg/mL to about 70 μg/mL, about 100 μg/mL to about 400 μg/mL, about 150 μg/mL to about 350 μg/mL in serum of the subject; (b) wherein the median time (Tmax) for the antibody, or antigen-binding fragment thereof, to reach a maximum concentration in serum of the subject is about 0.01-30 days, about 3-20 days, about 6-20 days, about 7-18 days, about 8-15 or about 13-15 days; (c) wherein the antibody, or antigen binding fragment thereof, reaches a maximum concentration of about 30 μg/mL to about 200 μg/mL, about 100 μg/mL to about 200 μg/mL, about 30 μg/mL to about 100 μg/mL, about 40 μg/mL to about 80 μg/mL, about 50 μg/mL to about 70 μg/mL, or about 30 μg/mL to about 65 μg/mL in serum of the subject in about 0.01-20 days, about 3-20 days, about 6-20 days, about 7-18 days, about 8-15 or about 13-15 days after administration; (d) wherein the area under the serum concentration-time curve from day 0 to day 21 (AUC0-21d) is about 100-2000 day* μg/mL, about 1000-2000 day* μg/mL, about 1400-2000 day* μg/mL, about 200-1500 day* μg/mL, about 400-1400 day* μg/mL, about 500-1300 day* μg/mL, about 600-1000 day* μg/mL, or about 800-900 day* μg/mL; (e) wherein the area under the serum concentration-time curve from day 0 to day 90 (AUC0-90d) is about 1000-10000 day* μg/mL, about 2000-8000 day* μg/mL, about 2000-5000 day* μg/mL, about 3000-4000 day* μg/mL, about 5000-10000 day* μg/mL, about 2000-4000 day* μg/mL, about 5000-8000 day* μg/mL, or about 6000-8000 day* μg/mL; (f) wherein the area under the serum concentration-time curve from day 0 to day 180 (AUC0-180d) is about 1000-10000 day* μg/mL, about 2000-5000 day* μg/mL, about 3000-6000 day* μg/mL, about 5000-10000 day* μg/mL, about 5000-8000 day* μg/mL, or about 4000-6000 day* μg/mL; (g) wherein the area under the serum concentration-time curve from day 0 to day 365 (AUC0-365d) is about 1000-30000 day* μg/mL, about 5000-30000 day* μg/mL, about 10000-30000 day* μg/mL, about 10000-15000 day* μg/mL, about 20000-30000 day* μg/mL, or about 25000-30000 day* mg/mL; and/or (h) wherein the antibody, or antigen-binding fragment thereof, has a serum half-life of about 50-200 days, about 50-160 days, about 50-140 days, about 40- 130 days, about 50-100 days, about 60-100 days, about 60-90 days, about 70-90 days, about 90-100 days, about 70-80 days, about 80-130 days, about 100-150 days, about 110-140 days, or about 120- 140 days.

[0144] In one aspect, the present disclosure provides a method of treating a symptom of a coronavirus infection in a subject in need thereof, the method comprising administering to the subject an isolated antibody, or antigen-binding fragment thereof, which binds to the spike protein of a coronavirus (“CoV-S”), wherein said antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising a VH CDR1 comprising SEQ ID NO:52, a VH CDR2 comprising SEQ ID NO:54, and a VH CDR3 comprising SEQ ID NO:56, and a light chain variable region (VL) comprising a VL CDR1 comprising SEQ ID NO:252, a VL CDR2 comprising SEQ ID NO:254, and a VL CDR3 comprising SEQ ID NO:256; (a) wherein the antibody, or antigen-binding fragment thereof, reaches a maximum concentration (Cmax) of about 10 μg/mL to about 1000 μg/mL, about 20 μg/mL to about 500 μg/mL, about 30 μg/mL to about 400 μg/mL, about 40 μg/mL to about 300 μg/mL, about 50 μg/mL to about 200 μg/mL, about 50 μg/mL to about 100 μg/mL, or about 30 μg/mL to about 70 μg/mL, about 100 μg/mL to about 400 μg/mL, about 150 μg/mL to about 350 μg/mL in serum of the subject; (b) wherein the median time (Tmax) for the antibody, or antigen binding fragment thereof, to reach a maximum concentration in serum of the subject is about 0.01-30 days, about 3-20 days, about 6-20 days, about 7-18 days, about 8-15 or about 13-15 days; (c) wherein the antibody, or antigen-binding fragment thereof, reaches a maximum concentration of about 30 μg/mL to about 200 μg/mL, about 100 μg/mL to about 200 μg/mL, about 30 μg/mL to about 100 μg/mL, about 40 μg/mL to about 80 μg/mL, about 50 μg/mL to about 70 μg/mL, or about 30 μg/mL to about 65 μg/mL in serum of the subject in about 0.01-20 days, about 3-20 days, about 6-20 days, about 7-18 days, about 8-15 or about 13-15 days after administration; (d) wherein the area under the serum concentration-time curve from day 0 to day 21 (AUC0-21d) is about 100-2000 day* μg/mL, about 1000-2000 day* μg/mL, about 1400-2000 day* μg/mL, about 200-1500 day* μg/mL, about 400-1400 day* μg/mL, about 500-1300 day* μg/mL, about 600-1000 day* μg/mL, or about 800-900 day* μg/mL; (e) wherein the area under the serum concentration-time curve from day 0 to day 90 (AUC0-90d) is about 1000-10000 day* μg/mL, about 2000-8000 day* μg/mL, about 2000-5000 day* μg/mL, about 3000-4000 day* μg/mL, about 5000-10000 day* μg/mL, about 2000-4000 day* μg/mL, about 5000-8000 day* μg/mL, or about 6000-8000 day* μg/mL; (f) wherein the area under the serum concentration-time curve from day 0 to day 180 (AUC0-180d) is about 1000-10000 day* μg/mL, about 2000-5000 day* μg/mL, about 3000-6000 day* μg/mL, about 5000-10000 day* μg/mL, about 5000-8000 day* μg/mL, or about 4000-6000 day* μg/mL; (g) wherein the area under the serum concentration-time curve from day 0 to day 365 (AUC0-365d) is about 1000-30000 day* μg/mL, about 5000-30000 day* mg/mL, about 10000-30000 day* mg/mL, about 10000-15000 day* mg/mL, about 20000-30000 day* mg/mL, or about 25000-30000 day* mg/mL; and/or (h) wherein the antibody, or antigen-binding fragment thereof, has a serum half-life of about 50-200 days, about 50-160 days, about 50-140 days, about 40-130 days, about 50-100 days, about 60-100 days, about 60-90 days, about 70-90 days, about 90-100 days, about 70-80 days, about 80-130 days, about 100-150 days, about 110-140 days, or about 120-140 days.

[0145] In some embodiments, the symptom comprises at least one of bronchitis, pneumonia, respiratory failure, acute respiratory failure, organ failure, multi-organ system failure, pediatric inflammatory multisystem syndrome, acute respiratory distress syndrome, blood clot, a cardiac condition, myocardial injury, myocarditis, heart failure, cardiac arrest, acute myocardial infarction, dysrhythmia, venous thromboembolism, post-intensive care syndrome, shock, anaphylactic shock, cytokine release syndrome, septic shock, disseminated intravascular coagulation, ischemic stroke, intracerebral hemorrhage, microangiopathic thrombosis, psychosis, seizure, nonconvulsive status epilepticus, traumatic brain injury, stroke, anoxic brain injury, encephalitis, posterior reversible leukoencephalopathy, necrotizing encephalopathy, post-infectious encephalitis, autoimmune mediated encephalitis, acute disseminated encephalomyelitis, acute kidney injury, acute liver injury, pancreatic injury, immune thrombocytopenia, subacute thyroiditis, a gastrointestinal complication, aspergillosis, increased susceptibility to infection with another virus or bacteria, and/or a pregnancy-related complication.

[0146] In one aspect, the present disclosure provides a method of decreasing the risk of mortality, hospitalization, mechanical ventilation, or a combination thereof, in a subject infected by a coronavirus, the method comprising administering to the subject an isolated antibody, or antigen binding fragment thereof, which binds to the spike protein of a coronavirus (“CoV-S”), wherein said antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising a VH CDR1 comprising SEQ ID NO:52, a VH CDR2 comprising SEQ ID NO:54, and a VH CDR3 comprising SEQ ID NO: 56, and a light chain variable region (VL) comprising a VL CDR1 comprising SEQ ID NO:252, a VL CDR2 comprising SEQ ID NO:254, and a VL CDR3 comprising SEQ ID NO:256; (a) wherein the antibody, or antigen-binding fragment thereof, reaches a maximum concentration (Cmax) of about 10 μg/mL to about 1000 μg/mL, about 20 μg/mL to about 500 μg/mL, about 30 μg/mL to about 400 μg/mL, about 40 μg/mL to about 300 μg/mL, about 50 μg/mL to about 200 μg/mL, about 50 μg/mL to about 100 μg/mL, or about 30 μg/mL to about 70 μg/mL, about 100 μg/mL to about 400 μg/mL, about 150 μg/mL to about 350 μg/mL in serum of the subject; (b) wherein the median time (Tmax) for the antibody, or antigen-binding fragment thereof, to reach a maximum concentration in serum of the subject is about 0.01-30 days, about 3-20 days, about 6-20 days, about 7-18 days, about 8-15 or about 13-15 days; (c) wherein the antibody, or antigen binding fragment thereof, reaches a maximum concentration of about 30 μg/mL to about 200 μg/mL, about 100 mg/mL to about 200 mg/mL, about 30 mg/mL to about 100 mg/mL, about 40 mg/mL to about 80 mg/mL, about 50 mg/mL to about 70 mg/mL, or about 30 mg/mL to about 65 mg/mL in serum of the subject in about 0.01-20 days, about 3-20 days, about 6-20 days, about 7-18 days, about 8-15 or about 13-15 days after administration; (d) wherein the area under the serum concentration-time curve from day 0 to day 21 (AUC0-21d) is about 100-2000 day* mg/mL, about 1000-2000 day* mg/mL, about 1400-2000 day* mg/mL, about 200-1500 day* mg/mL, about 400-1400 day* mg/mL, about 500-1300 day* mg/mL, about 600-1000 day* mg/mL, or about 800-900 day* mg/mL; (e) wherein the area under the serum concentration-time curve from day 0 to day 90 (AUC0-90d) is about 1000-10000 day* mg/mL, about 2000-8000 day* mg/mL, about 2000-5000 day* mg/mL, about 3000-4000 day* mg/mL, about 5000-10000 day* mg/mL, about 2000-4000 day* mg/mL, about 5000-8000 day* mg/mL, or about 6000-8000 day* mg/mL; (f) wherein the area under the serum concentration-time curve from day 0 to day 180 (AUC0-180d) is about 1000-10000 day* mg/mL, about 2000-5000 day* mg/mL, about 3000-6000 day* mg/mL, about 5000-10000 day* mg/mL, about 5000-8000 day* mg/mL, or about 4000-6000 day* mg/mL; (g) wherein the area under the serum concentration-time curve from day 0 to day 365 (AUC0-365d) is about 1000-30000 day* mg/mL, about 5000-30000 day* mg/mL, about 10000-30000 day* mg/mL, about 10000-15000 day* mg/mL, about 20000-30000 day* mg/mL, or about 25000-30000 day* mg/mL; and/or (h) wherein the antibody, or antigen-binding fragment thereof, has a serum half-life of about 50-200 days, about 50-160 days, about 50-140 days, about 40- 130 days, about 50-100 days, about 60-100 days, about 60-90 days, about 70-90 days, about 90-100 days, about 70-80 days, about 80-130 days, about 100-150 days, about 110-140 days, or about 120- 140 days.

[0147] In some embodiments, the CoV-S is the spike protein of SARS-CoV (“SARS-CoV-S”) or the spike protein of SARS-CoV-2 (“SARS-CoV-2-S”).

[0148] In some embodiments, the antibody, or antigen-binding fragment thereof, cross-reacts with SARS-CoV-S and SARS-CoV-2-S.

[0149] In some embodiments, SARS-CoV-S comprises an amino acid sequence of SEQ ID NO: 401, and wherein SARS-CoV-2-S comprises an amino acid sequence of SEQ ID NO: 403.

[0150] In some embodiments, the SARS-CoV -2-S is a B.1.1.7 variant, a B. 1.351 variant, a B.1.1.28 variant, a B. 1.429 variant, a P.l variant, a B.1.617 variant, a B.1.617.2 variant, a C.37 variant, a 1.621 variant, a AY.l variant, a 1.623 variant, a C.36 variant, a A.27 variant, a AV.l variant, a B.1.1.482 variant, a B.1.1.523 variant, a B.1.427 variant, a AY.4 variant, a AY.ll variant, a D614G variant of SEQ ID NO: 403, a B.1.1.529/BA.1 variant, a BA.1.1 variant, or a BA.2 variant.

[0151] In one aspect, the present disclosure provides a method for inducing an immune response against a coronavirus Omicron variant in a subject in need thereof, for treating a coronavirus infection caused by an Omicron variant in a subject in need thereof, for preventing a coronavirus infection caused by an Omicron variant in a subject in need thereof, for treating a symptom of an infection of a subject by an Omicron variant in a subject in need thereof, and/or for decreasing the risk of mortality, hospitalization, mechanical ventilation, or a combination thereof, in a subject infected by an Omicron variant, the method comprising administering to the subject an isolated antibody, or antigen-binding fragment thereof, wherein said antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising a VH CDR1 comprising SEQ ID NO:52, a VH CDR2 comprising SEQ ID NO:54, and a VH CDR3 comprising SEQ ID NO:56, and a light chain variable region (VL) comprising a VL CDR1 comprising SEQ ID NO:252, a VL CDR2 comprising SEQ ID NO:254, and a VL CDR3 comprising SEQ ID NO:256.

[0152] In some embodiments, the Omicron variant comprises a B.1.1.529/BA.1 variant, a BA.1.1 variant, or a BA.2 variant.

[0153] In some embodiments, the VH comprises a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:58 and the VL comprises a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:258. In some embodiments, the VH comprises or consists of SEQ ID NO:58 and the VL comprises or consists of SEQ ID NO:258.

[0154] In any method described herein, the method may further comprise selecting a subject. In one embodiment, the method may further comprise selecting a subject that would benefit from administration of the antibody, or antigen-binding fragment thereof.

[0155] In some embodiments, the subject is a human subject. In some embodiments, the subject is an adult, an adolescent, or a child.

[0156] In some embodiments, the subject has at least one risk factor which renders them more prone to a poor clinical outcome. In some embodiments, the at least one risk factor is selected from the group consisting of: an old age selected from the group consisting of over 55, over 60 or over 65 years old; diabetes, a chronic respiratory condition, obesity, hypertension, a cardiac or cardiovascular condition, a chronic inflammatory or autoimmune condition, and an immune compromised status. [0157] In some embodiments, the subject is immunocompromised. In some embodiments, the subject is at a high risk of disease progression. In some embodiments, the subject is (a) age 50 years or above with no comorbid conditions or additional risk factors for progression of COVID-19; (b) between about 18 to about 50 years old and with one or more preexisting medical conditions selected from the group consisting of obesity, diabetes, chronic kidney disease, chronic lung disease, cardiac disease, sickle cell disease or thalassemia, solid organ or blood stem cell transplant recipient, other immunodeficiency due to underlying illness or immunosuppressant medication, Down Syndrome, stroke or cerebrovascular disease, substance use disorder, and pregnancy; or (c) between about 12 to about 17 years old and with one or more preexisting medical conditions selected from the group consisting of obesity, diabetes, chronic kidney disease, sickle cell disease or thalassemia, congenital or acquired heart disease, neurodevelopmental disorder, a medically-related technological dependence, asthma or chornic respiratory disease, solid organ or blood stem cell transplant recipient, other immunodeficiency due to underlying illness or immunosuppressant medication, Down Syndrome, stroke or cerebrovascular disease, substance use disorder, and pregnancy.

[0158] In some embodiments, the subject is age 50 or above with no comorbid conditions or additional risk factors for progression of COVID-19.

[0159] In some embodiments, the subject has hypertension with at least one medication prescribed or recommended.

[0160] In some embodiments, the subject has moderate to severe asthma requiring daily therapy. [0161] In some embodiments, the antibody, or the antigen-binding fragment thereof, is administered intramuscularly or intravenously.

[0162] In some embodiments, the antibody, or the antigen-binding fragment thereof, is administered at a dose of about 100 mg to about 5000 mg, about 300 mg to about 4500 mg, about 500 mg to about 4500 mg, about 1200 mg to about 4500 mg, about 100 mg to about 2000 mg, about 200 mg to about 1500 mg, about 300 mg to about 600 mg, about 500 mg to about 1200 mg, about 300 mg to about 1200 mg; or at a dose of about 4500 mg, a dose of about 1200 mg, a dose of about 600 mg, or a dose of about 500 mg; or as two doses of 600 mg each on the same day, or as two doses of 300 mg each on the same day.

[0163] In some embodiments, the antibody, or antigen-binding fragment thereof, is administered once, or is administered weekly.

[0164] In some embodiments, the method further comprises obtaining an epithelial lining fluid (ELF) sample from the subject.

[0165] In some embodiments, the ELF sample comprises an ELF sample from an upper airway, an lower airway, and/or an alveolar tissue.

[0166] In some embodiments, the antibody, or antigen-binding fragment thereof, reaches a concentration of about 1 μg/mL to about 100 μg/mL, about 1 μg/mL to about 80 μg/mL, about 80 μg/mL to about 100 μg/mL, about 50 μg/mL to about 100 μg/mL, about 1 μg/mL to about 50 μg/mL, about 2 μg/mL to about 25 μg/mL, or about 2 μg/mL to about 10 μg/mL, in the ELF sample of the subject.

[0167] In some embodiments, the antibody, or antigen-binding fragment thereof, has a receptor occupancy of at least 50%, 60%, 70%, 80%, or 90% in the ELF sample.

[0168] In some embodiments, the antibody, or antigen-binding fragment thereof, has a receptor occupancy of at least 50%, 60%, 70%, 80%, or 90% in the ELF sample for about 28 days after administration.

[0169] In some embodiments, the antibody, or antigen-binding fragment thereof, has a virus neutralizing titer of about 100-2000, about 200-1500, about 300-1500, or about 500-1500 in serum of the subject about 6 months after administration. [0170] In some embodiments, the 80% virus neutralization titer (MN80) of the antibody, or antigen binding fragment thereof, at about days 0-14, about days 7-21, about 3 months, or about 6 months after administration, is about 10-6000, about 50-600, about 500-1500, about 1000-2500, about 100- 2500, about 500-2000, about 500-1500, about 400-1200, about 200-1500, about 300-1000, about 400- 800, about 400-1000, or about 500-600 in the subject.

[0171] In some embodiments, the 80% virus neutralization titer (MN80) of the antibody, or antigen binding fragment thereof, at about day 7, day 14, or day 21 after administration, is about 300-2000, about 400-600, about 600-1500, about 1100-1700, about 500-1700, about 500-1500, about 400-1200, about 400-800, about 400-1000, or about 500-600 in the serum sample of the subject.

[0172] In some embodiments, the 80% virus neutralization titer (MN80) of the antibody, or antigen binding fragment thereof, at about 3 months after administration, is about 200-1000, about 200-800, about 200-500, about 400-900, or about 400-600 in the serum sample of the subject.

[0173] In some embodiments, the 80% virus neutralization titer (MN80) of the antibody, or antigen binding fragment thereof, at about 6 months after administration, is about 10-500, about 300-500, or about 50-200 in the serum sample of the subject.

[0174] In some embodiments, the 50% virus neutralization titer (MN50) of the antibody, or antigen binding fragment thereof, at about days 0-14, about days 7-21, about 3 months, about 6 months, or about 12 months after administration, is about 100-6000, about 300-1500, about 1700-3800, about 3800-5200, about 300-5500, about 1200-4500, about 1300-4300, about 1200-4000, about 100-2500, about 500-2500, about 800-2000, about 1000-1800, about 800-1300, about 900-1100, or about 1300- 1500 in the serum sample of the subject.

[0175] In some embodiments, the 50% virus neutralization titer (MN50) of the antibody, or antigen binding fragment thereof, at about day 7, day 14 or day 21 after administration, is about 1000-4500, about 1200-4500, about 1300-4300, about 1200-3900, about 1500-4000, about 1800-3800, about 3800-4500, about 1000-1800 or about 1200-1500 in the serum sample of the subject.

[0176] In some embodiments, the 50% virus neutralization titer (MN50) of the antibody, or antigen binding fragment thereof, at about 3 months after administration, is about 800-1300, or about 900- 1100 in the serum sample of the subject.

[0177] In some embodiments, the 50% virus neutralization titer (MN50) of the antibody, or antigen binding fragment thereof, at about 6 months after administration, is about 200-500, or about 300-600 in the serum sample of the subject.

[0178] In some embodiments, the 50% virus neutralization titer (MN50) of the antibody, or antigen binding fragment thereof, at about 12 months after administration, is about 150-500, or about 200-400 in the serum sample of the subject.

[0179] In some embodiments, the virus neutralization titer is determined using a plaque reduction neutralization test (PRNT). [0180] In some embodiments, the serum concentration of the antibody, or antigen-binding fragment thereof, is about 1-300 mg/L, about 1-250 mg/L, about 1-200 mg/L, about 1-100 mg/L, about 100-250 mg/L, about 150-200 mg/L, about 120-170 mg/L, about 1-90 mg/L, about 1-80 mg/L, about 1-70 mg/L, about 1-60 mg/L, about 1-50 mg/L, about 1-40 mg/L, about 1-30 mg/L, about 1-20 mg/L, about 1-10 mg/L, about 2-9 mg/L, about 3-8 mg/L, about 4-6 mg/L, about 5-80 mg/L, about 10-70 mg/L, or about 10-60 mg/L in the subject about 3 months after administration.

[0181] In some embodiments, the serum concentration of the antibody, or antigen-binding fragment thereof, is about 1-100 mg/L, about 1-90 mg/L, about 1-80 mg/L, about 1-70 mg/L, about 1-60 mg/L, about 1-50 mg/L, about 1-40 mg/L, about 1-30 mg/L, about 1-20 mg/L, about 1-10 mg/L, about 2-9 mg/L, about 3-8 mg/L, about 4-6 mg/L, about 5-80 mg/L, about 10-70 mg/L, about 10-60 mg/L, about 5-25 mg/L, about 10-30 mg/L, about 15-25 mg/L, about 20-100 mg/L, about 30-100 mg/L, about 50- 80 mg/L, or about 60-70 mg/L in the subject about 6 months after administration.

[0182] In some embodiments, the serum concentration of the antibody, or antigen-binding fragment thereof, is about 0.1-30 mg/L, about 1-30 mg/L, about 1-20 mg/L, about 1-10 mg/L, about 10-20 mg/L, about 0.1-3 mg/L, about 0.5-8 mg/L, about 0.5-10 mg/L, about 2-9 mg/L, about 5-15 mg/L, about 3-8 mg/L, or about 4-6 mg/L in the subject about 12 months after administration.

[0183] In some embodiments, the clearance rate for the antibody, or antigen-binding fragment thereof, is about 0.1-10 mL/d, about 0.1-5.0 mL/d, about 0.1-3.0 mL/d, about 0.5-2.5 mL/d, or about 1.0-2.0 mL/d.

[0184] In some embodiments, the steady state volume of distribution for the antibody, or antigen binding fragment thereof, is about 1-10 L, about 2-8 L, about 4-9 L, about 4-8 L, or about 5-7L.

[0185] In some embodiments, the antibody, or antigen-binding fragment thereof, is administered in combination with at least one antibody selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130 and ADI-58131.

[0186] In some embodiments, the antibody, or antigen-binding fragment thereof, is administered in combination with a vaccine.

[0187] In some embodiments, the antibody, or antigen-binding fragment thereof, is administered (a) concurrently with a COVID-19 vaccine; (b) after administration of a COVID-19 vaccine, or (c) prior to administration of a COVID-19 vaccine.

[0188] In some embodiments, administration of the antibody, or antigen-binding fragment thereof, reduces pulmonary inflammation in the subject.

[0189] In some embodiments, administration of the antibody, or antigen-binding fragment thereof, reduces the risk of COVID-19 hospitalization or death of the subject.

[0190] In some embodiments, administration of the antibody, or antigen-binding fragment thereof, reduces viral load in the subject. [0191] In one aspect, provided herein are methods of predicting the in vivo efficacy of an anti-CoV-S antibody or antigen-binding antibody fragment in preventing or treating CoV infection.

[0192] In some embodiments, the method may comprise: (a) providing at least one first test subject and at least one second subject or a cell sample derived from at least one first test subject and at least one second subject; (b) administering the antibody or antigen-binding antibody fragment to said at least one first test subject and said at least one second subject or contacting a cell sample from said first and second subject with the antibody or antigen-binding antibody fragment; (c) infecting said at least one first test subject and said at least one second subject with CoV or pseudo CoV or a cell sample obtained from said at least one first test subject and said at least one second subject with CoV or pseudo CoV ; (d) determining whether administration of the antibody or antigen-binding antibody fragment in (b) results in one or more of the following compared to a suitable control: (I) reduction in a CoV-associated symptom; (II) reduction in the CoV viremia; (III) increase in the survival; (IV) increase in the body weight; or (V) reduced infection of cells or virus proliferation in cells of the tested cell sample compared to a control cell sample not contacted with the antibody or antigen binding antibody fragment.

[0193] In some embodiments, the method may comprise: (a) providing at least one first cell sample and at least one second cell sample; (b) contacting the at least one first cell sample with the antibody or antigen-binding antibody fragment; (c) infecting said at least one first cell sample and at least one second cell sample with CoV or pseudo CoV ; (d) determining whether the antibody or antigen binding antibody fragment results in one or more of the following compared to a suitable control: (I) increase in the cell survival; (II) reduced infection of cells; (III) reduced virus proliferation; (IV) reduced cell stress or death markers; or (V) reduced inflammatory cytokines, in cells of the tested cell sample compared to a control cell sample not contacted with the antibody or antigen-binding antibody fragment.

[0194] In some embodiments, the method may comprise: (a) providing at least one first test subject and at least one second subject or a cell sample derived from at least one first test subject and at least one second subject; (b) infecting said at least one first test subject and said at least one second subject with CoV or pseudo CoV or a cell sample derived from at least one first test subject and at least one second subject; (c) administering the antibody or antigen-binding antibody fragment to said at least one second subject or contacting a cell sample derived from at least one first test subject and at least one second subject with the antibody or antigen-binding antibody fragment; (d) determining whether administration of the antibody or antigen-binding antibody fragment in (c) results in one or more of the following: (I) reduction in a CoV-associated symptom; (II) reduction in the CoV viremia; (III) increase in the survival;(IV) increase in the body weight; or (V) reduced infection of cells or virus proliferation in cells in the tested cell sample compared to a control cell sample not contacted with the antibody or antigen-binding antibody fragment. [0195] In some embodiments, the method may comprise: (a) providing at least one first cell sample and at least one second cell sample; (b) infecting said at least one first cell sample and at least one second cell sample with CoV or pseudo CoV ; (c) contacting the at least one first cell sample with the antibody or antigen-binding antibody fragment; (d) determining whether the antibody or antigen binding antibody fragment results in one or more of the following compared to a suitable control: (I) increase in the cell survival; (II) reduced infection of cells; (III) reduced virus proliferation; (IV) reduced cell stress or death markers; or (V) reduced inflammatory cytokines, in cells of the tested cell sample compared to a control cell sample not contacted with the antibody or antigen-binding antibody fragment.

[0196] In one aspect, provided herein are methods of screening for an antibody or antigen-binding antibody fragment that binds to a CoV or CoV-S, the method comprising whether an antibody or antigen-binding antibody fragment comprising 1, 2, 3, 4, 5, or 6 CDRs of any of the antibodies disclosed herein may comprise one or more of the following features: (i) binds to the S protein of a CoV; (ii) binds to the SI subunit of CoV-S; (iii) binds to the RBD of CoV-S; (iv) binds to the NTD of CoV-S; (v) binds to the ACE2-binding motif of CoV-S; (vi) competes with ACE2; (vii) competes with the antibody CR3022; (viii) neutralizes one or more of SARS-CoV, SARS-CoV-2, MERS-CoV, HCoV-229E, HCoV-HKUl, HCoV-NL63, or HCoV-OK43 or variants thereof; (ix) neutralizes a pseudovirus of one or more of SARS-CoV, SARS-CoV-2, MERS-CoV, HCoV-229E, HCoV-HKUl, HCoV-NL63, or HCoV-OK43 or variants thereof; (x) results in reduced infection of cells or virus proliferation in cells in a susceptible tested cell sample compared to a control cell sample not contacted with the antibody or antigen-binding antibody fragment; or (xi) prevents or treats CoV infection in vivo. During the screening, any of the antibodies disclosed herein and/or an antibody comprising one or more of the CDRs of the antibodies disclosed herein may be used as a candidate antibody or a control antibody.

[0197] In one aspect, the present disclosure also relates to compositions comprising at least one affinity-matured first anti-CoV-S antibody or antigen-binding antibody fragment and a pharmaceutically acceptable carrier or excipient.

[0198] In some embodiments, the at least one first antibody or antigen-binding antibody fragment may comprise: a VH comprising a VH CDR1, a VH CDR2, a VH CDR3; and a VL, comprising a VL CDR1 a VL CDR2, a VL CDR3, and the amino acid sequences of said VH CDR1, said VH CDR2, said VH CDR3, said VL CDR1, said VL CDR2, and said VL CDR3 are identical to the amino acid sequences of the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3, respectively, of an anti-CoV-S antibody selected from the group consisting of ADI-58120, ADI- 58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI- 58129, ADI-58130, ADI-58131. [0199] In some embodiments, the first antibody or antigen-binding antibody fragment may comprise an Fc region, optionally wherein the Fc region may comprise an amino acid sequence of SEQ ID NOs: 411, 412, 413, 414, 415, 416, or 417.

[0200] In one embodiment, the HC and LC of the first antibody or antigen-binding antibody fragment are the HC and LC, respectively, of an anti-CoV-S antibody selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, and ADI-58131.

[0201] In certain embodiments, the composition may further comprise at least one second antibody or antigen-binding antibody fragment comprising a VH comprising a VH CDR1, a VH CDR2, a VH CDR3 and a VL, comprising a VL CDR1 a VL CDR2, a VL CDR3. In particular embodiments, the amino acid sequences of said VH CDR1, said VH CDR2, said VH CDR3, said VL CDR1, said VL CDR2, and said VL CDR3 may be identical to the amino acid sequences of the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3, respectively, of an anti-CoV-S antibody selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, and ADI-58131.

[0202] In some embodiments, the second antibody or antigen-binding antibody fragment may comprise an Lc region, optionally wherein the Lc region may comprise an amino acid sequence of SEQ ID NOs: 411, 412, 413, 414, 415, 416, or 417.

[0203] In particular embodiments, the antibody or antigen-binding antibody fragment according to the present disclosure may comprise:

(1) a HC comprising the amino acid sequence of SEQ ID NO: 10 and a LC comprising the amino acid sequence of SEQ ID NO: 210;

(2) a HC comprising the amino acid sequence of SEQ ID NO: 20 and a LC comprising the amino acid sequence of SEQ ID NO: 220;

(3) a HC comprising the amino acid sequence of SEQ ID NO: 30 and a LC comprising the amino acid sequence of SEQ ID NO: 230;

(4) a HC comprising the amino acid sequence of SEQ ID NO: 40 and a LC comprising the amino acid sequence of SEQ ID NO: 240;

(5) a HC comprising the amino acid sequence of SEQ ID NO: 50 and a LC comprising the amino acid sequence of SEQ ID NO: 250;

(6) a HC comprising the amino acid sequence of SEQ ID NO: 60 and a LC comprising the amino acid sequence of SEQ ID NO: 260;

(7) a HC comprising the amino acid sequence of SEQ ID NO: 70 and a LC comprising the amino acid sequence of SEQ ID NO: 270;

(8) a HC comprising the amino acid sequence of SEQ ID NO: 80 and a LC comprising the amino acid sequence of SEQ ID NO: 280; (9) a HC comprising the amino acid sequence of SEQ ID NO: 90 and a LC comprising the amino acid sequence of SEQ ID NO: 290;

(10) a HC comprising the amino acid sequence of SEQ ID NO: 100 and a LC comprising the amino acid sequence of SEQ ID NO: 300;

(11) a HC comprising the amino acid sequence of SEQ ID NO: 110 and a LC comprising the amino acid sequence of SEQ ID NO: 310; or

(12) a HC comprising the amino acid sequence of SEQ ID NO: 120 and a LC comprising the amino acid sequence of SEQ ID NO: 320.

[0204] In further embodiments, the composition according to the present disclosure may comprise: (A) at least one first antibody or antigen-binding antibody fragment selected from the group consisting of the antibodies or antigen-binding antibody fragments comprising the HC and LC combination as described above; and (B) a pharmaceutically acceptable carrier or excipient.

[0205] In yet further embodiments, the composition may additionally comprise at least one second antibody or antigen-binding antibody fragment selected from the group consisting of the antibodies or antigen-binding antibody fragments comprising the HC and LC combination as described above. [0206] Additionally, the present disclosure further encompasses isolated antibodies and antigen binding antibody fragments thereof, which competes for binding with any one or more of the anti- CoV antibodies or antigen-binding antibody fragments thereof as described herein.

[0207] The present disclosure also encompasses isolated antibodies or antigen-binding antibody fragments thereof, which bind the same epitope as any one or more of the anti-CoV antibodies or antigen-binding antibody fragments thereof as described herein.

[0208] The present disclosure further encompasses affinity matured variants of any one or more of the anti-CoV antibodies or antigen-binding antibody fragments thereof as described herein.

[0209] In one aspect, disclosed herein is a method of treating a coronavirus infection by SARS-CoV, SARS-CoV-2, and/or another coronavirus optionally selected from the group consisting of MERS- CoV, HCoV-HKUl, HCoV-OC43, HCoV-229E, and HCoV-NL63 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an antibody, or antigen-binding antibody fragment thereof, which binds the same epitope as ADI-58125, and/or which competes for binding with ADI-58125.

[0210] In one aspect, disclosed herein is a method of decreasing the risk of mortality, hospitalization, mechanical ventilation, or a combination thereof in a patient infected by SARS-CoV, ARS-CoV-2, and/or another coronavirus optionally selected from the group consisting of MERS-CoV, HCoV- HKU1, HCoV-OC43, HCoV-229E, and HCoV-NL63, the method comprising administering to the subject a therapeutically effective amount of an isolated antibody, or antigen-binding antibody fragment thereof, which binds the same epitope as ADI-58125, and/or which competes for binding with ADI-58125. [0211] In another aspect, disclosed herein is a method of preventing infection of a subject by SARS- CoV, SARS-CoV-2, and/or another coronavirus optionally selected from the group consisting of MERS-CoV, HCoV-HKUl, HCoV-OC43, HCoV-229E, and HCoV-NL63, the method comprising administering to the subject a therapeutically effective amount of an isolated antibody, or antigen binding antibody fragment thereof, which binds the same epitope as ADI-58125, and/or which competes for binding with ADI-58125.

[0212] In another aspect, the present invention also provides a method for treating a coronavirus infection in a subject in need thereof, the method comprising administering to the subject an isolated antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising a VH CDR1 comprising SEQ ID NO:52, a VH CDR2 comprising SEQ ID NO:54, and a VH CDR3 comprising SEQ ID NO:56, and a light chain variable region (VL) comprising a VL CDR1 comprising SEQ ID NO:252, a VL CDR2 comprising SEQ ID NO:254, and a VL CDR3 comprising SEQ ID NO:256; and wherein the antibody, or antigen-binding fragment thereof, is administered at a dosage of at least 300 mg within 5, 4, 3, 2, or 1 days of symptom onset.

[0213] In some embodiments, the antibody, or antigen-binding fragment thereof, is administered at a dosage of about 300 mg. In some embodiments, the antibody, or antigen-binding fragment thereof, is administered at a dosage of about 500 mg. In some embodiments, the antibody, or antigen-binding fragment thereof, is administered at a dosage of about 600 mg. In some embodiments, the antibody, or antigen-binding fragment thereof, is administered at a dosage of about 1200 mg. In some embodiments, the antibody, or antigen-binding fragment thereof, is administered at a dosage of about 4500 mg.

[0214] In some embodiments, the subject has at least one risk factor which renders them more prone to a poor clinical outcome. In some embodiments, the at least one risk factor is selected from the group consisting of: an old age selected from the group consisting of over 55, over 60 or over 65 years old; diabetes, a chronic respiratory condition, obesity, hypertension, a cardiac or cardiovascular condition, a chronic inflammatory or autoimmune condition, and an immune compromised status. In some embodiments, the subject is immunocompromised.

[0215] In some embodiments, the subject is at a high risk of disease progression. In some embodiments, the subject is (a) age 50 years or above with no comorbid conditions or additional risk factors for progression of COVID-19; (b) between about 18 to about 50 years old and with one or more preexisting medical conditions selected from the group consisting of obesity, diabetes, chronic kidney disease, chronic lung disease, cardiac disease, sickle cell disease or thalassemia, solid organ or blood stem cell transplant recipient, other immunodeficiency due to underlying illness or immunosuppressant medication, Down Syndrome, stroke or cerebrovascular disease, substance use disorder, and pregnancy; or (c) between about 12 to about 17 years old and with one or more preexisting medical conditions selected from the group consisting of obesity, diabetes, chronic kidney disease, sickle cell disease or thalassemia, congenital or acquired heart disease, neurodevelopmental disorder, a medically-related technological dependence, asthma or chornic respiratory disease, solid organ or blood stem cell transplant recipient, other immunodeficiency due to underlying illness or immunosuppressant medication, Down Syndrome, stroke or cerebrovascular disease, substance use disorder, and pregnancy. In some embodiments, the subject is age 50 or above with no comorbid conditions or additional risk factors for progression of COVID-19. In some embodiments, the subject has hypertension with at least one medication prescribed or recommended. In some embodiments, the subject has moderate to severe asthma requiring daily therapy.

[0216] In another aspect, the present invention provides a composition for use in inducing an immune response against CoV in a subject at high risk of COVID disease progression, wherein the composition comprises an antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising a VH CDR1 comprising SEQ ID NO:52, a VH CDR2 comprising SEQ ID NO:54, and a VH CDR3 comprising SEQ ID NO:56, and a light chain variable region (VL) comprising a VL CDR1 comprising SEQ ID NO:252, a VL CDR2 comprising SEQ ID NO:254, and a VL CDR3 comprising SEQ ID NO:256; and wherein the antibody, or antigen-binding fragment thereof, is administered within 5, 4 ,3, 2, or 1 days of symptom onset.

[0217] In another aspect, the present invention provides a composition for use in treating or preventing a coronavirus infection in a subject at high risk of COVID disease progression, wherein the composition comprises an antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising a VH CDR1 comprising SEQ ID NO:52, a VH CDR2 comprising SEQ ID NO:54, and a VH CDR3 comprising SEQ ID NO:56, and a light chain variable region (VL) comprising a VL CDR1 comprising SEQ ID NO:252, a VL CDR2 comprising SEQ ID NO:254, and a VL CDR3 comprising SEQ ID NO:256; and wherein the antibody, or antigen-binding fragment thereof, is administered within 5, 4, 3, 2, or 1 days of symptom onset.

[0218] In another aspect, the present invention provides a composition for use in treating a symptom of a coronavirus infection in a subject at high risk of COVID disease progression, wherein the composition comprises an antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising a VH CDR1 comprising SEQ ID NO:52, a VH CDR2 comprising SEQ ID NO:54, and a VH CDR3 comprising SEQ ID NO:56, and a light chain variable region (VL) comprising a VL CDR1 comprising SEQ ID NO:252, a VL CDR2 comprising SEQ ID NO:254, and a VL CDR3 comprising SEQ ID NO:256; and wherein the antibody, or antigen-binding fragment thereof, is administered within 5, 4, 3, 2, or 1 days of symptom onset.

[0219] In another aspect, the present invention provides a composition for use in decreasing the risk of mortality, hospitalization, mechanical ventilation, or a combination thereof, in a subject at high risk of COVID disease progression, wherein the composition comprises an antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising a VH CDR1 comprising SEQ ID NO:52, a VH CDR2 comprising SEQ ID NO:54, and a VH CDR3 comprising SEQ ID NO:56, and a light chain variable region (VL) comprising a VL CDR1 comprising SEQ ID NO:252, a VL CDR2 comprising SEQ ID NO:254, and a VL CDR3 comprising SEQ ID NO:256; and wherein the antibody, or antigen-binding fragment thereof, is administered within 5, 4, 3, 2, or 1 days of symptom onset.

BRIEF DESCRIPTION OF THE DRAWINGS [0220] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0221] Figure 1 depicts the mean serum concentration of ADI-58125 in 8 subjects following a single IM adminsitration of 300 mg ADI-58125 over a period of 21 days.

[0222] Figure 2 depicts the quantitative systems pharmacology/physiologically based pharmacokinetic (QSP/PBPK) model-predicted and observed ADI-58125 concentrations following a 300 mg IM dose across the 21 -day sampling interval. The line represents the mediam model -predicted ADI-58125 profile, shaded area represents the 90% prediction interval, and black circles represent observed ADI-58125 concentrations.

[0223] Figure 3 depicts the serum neutralizing titers from participants receiving a single 300 mg IM dose of ADI-58125.

[0224] Figure 4 is a schematic depicting the experimental procedure for a plaque reduction neutralization test (PRNT)

[0225] Figure 5 is a schematic depicting the experimental procedure for a post-infection assay to measure the concentration of antibody required to prevent viral replication in infected cells.

[0226] Figure 6 depicts the concentration curves of ADI-58125 for preventing replication of SARS- CoV-2 D614G and beta B.1.351 variants in infected cells.

[0227] Figure 7 depicts the neutralizing activity of ADI-58125 and ADI-58122 against authentic SARS-CoV-2 variants including the Alpha/B.1.1.7, the Beta/B.1.351, the Gamma/P.1, the Delta/B.1.617, and Omicron variants. Additional antibodies were also shown as comparators.

[0228] Figure 8A depicts the neutralizing activity of ADI-58125 and ADI-58122 against pseudoviruses encoding spike proteins of circulating SARS-CoV-2 variants. Figure 8B depicts the neutralizing activity of ADI-58125 and ADI-58122 against pseudoviruses encoding SARS-CoV-2 spike proteins with sing!e-/doubIe-spike mutations, in a pseudovirus assay. The neutralizing activity was expressed as a fold change relative to the D614G reference variant. Figure 8C depicts the neutralizing activity of ADI-58125 against SARS-CoV-2 variants associated with resistance to EUA mAbs. The points represent neutralizing activity of ADI-58125 against SARS-CoV-2 variants. [0229] Figures 9A, 9B, 9C, and 9D depict an overview of QSP/PBPK model. Figure 9A depicts a tissue-level diagram. Figure 9B depicts a cellular-level diagram specifically for the upper airway, lower airway, and alveolar spaces within the lung. Figure 9C depicts the predicted median ADI- 58125 concentration in NHP serum following a single ADI-58125 10 mg/kg IM dose with observed NHP ADI-58125 concentration data overlaid (black dots). The shaded area represents the 90% prediction interval. Figure 9D depicts the predicted median human serum and ELF PK in humans following a single ADI-58125 300 mg IM dose with observed human serum (red line) ADI-58125 concentration data overlaid (black dots), ELF upper airway (blue line), and ELF lower airway (gold). The shaded area represents the 90% prediction interval. CL_up, rate of pinocytosis of antibody entry and exit from the endosomal space; CL_up-epi, rate of pinocytosis of antibody entry and exit from the epithelial space; FR, fraction of FcRn bound antibody that recycles to the vascular space; L, lymphatic flow rate; LG, large, k_de , degradation constant; k_0ff, first-order dissociation rate constant of antibody from FcRn; k_on, second-order association rate constant for binding of antibody to FcRn; Q, blood or tissue flow rate; SM, small.

[0230] Figures 10A-10B depict a QSP/PBPK model forecast of ADI-58125 300 mg IM in adults. Figure 10A depicts the QSP/PBPK predicted median ADI-58125 concentration following a single 300 mg IM injection in different compartments overlaid by the threashold associated with 95% viral growth suppression (as indicated by the dotted line) for the SARS-CoV-2 Beta variant in a post infection assay. The shaded area represents the 90% prediction interval. Figure 10B depicts the receptor occupancy (RO) of ADI-58125 at various Delta variant virion densities (10⁷, 10^s and 10⁹) after a single 300 mg IM injection expressed as percent occupancy with the dotted line representing the threshold for 90% RO.

[0231] Figure 11 is a schematic representation for the in vivo efficacy study in hamsters. Hamsters were treated with a range of ADI-58125 doses (9.25 - 2000 μg) or control mAh 24 hours prior to challenge with SARS-2/WA-1 to evaluate prophylactic efficacy of ADI-58125.

[0232] Figures 12A-12B depict the impact of ADI-58125 on weight gain and lung pathology in SARS-CoV-2 -infected Syrian hamsters. Specifically, Figure 12A depicts the changes in weight from baseline on Day 6. Figure 12B depicts the total lung pathology score. Bars represent mean ± standard deviation. Dotted line represents no change in weight from baseline. Statistical comparison was calculated using unpaired, two-sided t-tests (A) and unpaired two-sided Mann-Whiteney tests (B): *P<0.05; **** P<0.0001 vs controls.

[0233] Figure 13 depicts the impact of ADI-58125 on viral load in SARS-CoV-2 -infected Syrian hamsters. Bars represent mean ± standard deviation. Dotted line represents limit of detection. Statistical comparison was calculated using unpaired, two-sided t-tests: **P<0.005; *** P<0.001; ****p<0.0001 vs controls. [0234] Figure 14 is a schematic representation for the in vivo efficacy study in non-human primates (NHP). Rhesus macaques were treated with ADI-58125 at 5 mg/kg or 25 mg/kg, or control mAh (25 mg/kg) 3 days prior to challenge with SARS-2/WA-1 to evaluate prophylactic efficacy of ADI-58125. [0235] Figure 15 depicts the impact of ADI-58125 on viral replication in Rhesus macaques, specifically, the impact on replication of sub-genomic viral RNA in bronchoalveolar lavage (BAL), nasopharyngeal (NP) and oropharyngeal (OP) samples.

[0236] Figure 16 depicts the impact of ADI-58125 on viral titre in Rhesus macaques.

[0237] Figure 17 depicts the mean serum concentration of ADI-58125 in 8 subjects following a single IM adminsitration of 300 mg ADI-58125 over a period of 3 months.

[0238] Figure 18 depicts the serum neutralizing titers from participants receiving a single 300 mg IM dose of ADI-58125 as compared to peak responses following AZD1222 and mRNA-1273 vaccination. Statistical analysis is by 2-tailed Mann-Whitney U test (*P<0.05; **P<0.01; ***P<0.0001).

[0239] Figure 19 depicts the mean serum concentration of ADI-58125 in subjects following a single IM adminsitration of 300 mg ADI-58125, a single IM adminsitration of 600 mg ADI-58125, and a single IV administration of 500 mg ADI-58125 over a period of 6 months.

[0240] Figure 20 depicts the relationship between ADI-58125 serum concentration and sVNA over a period of 6 months. The line represents the mean linear regression. The hading represents 95% confidence interval. Black circles represent individual time matched ADI-58125 serum concentration and MN50 sVNA titer measurements. Linear regression excluded samples that were taken following SARS-CoV-2 vaccination from participants who received vaccination during the trial.

[0241] Figures 21A, 21B, and 21C depict the simulated human body weight (A) and distribution of estimated K_D,FcRn values for other extended half-life mAbs in healthy human adults (log-normal, B) and NHPs (normal, C).

[0242] Figures 22A-22B depict the observed (dots) and model-forecasted NHP median (90% prediction interval) serum ADI-58125 PK profiles based on distribution of NHP K_D,FcRn values for other extended half-life mAbs following intravenous (IV; A) and intramuscular (IM; B) administration. Dots represent the raw observed data. Solid lines represent simulated medians. The shaded area represents the 90% prediction interval.

[0243] Figures 23A-23B depict the observed (dots) and optimized QSP model-predicted NHP median (90% prediction interval) serum ADI-58125 concentration-time profiles in NHPs following intravenous (IV; A) and intramuscular (IM; B) administration. Dots represent the raw observed data. Solid lines represent simulated medians. The shaded area represents the 90% prediction interval. [0244] Figures 24A-24D depict the observed (dots) versus QSP model-predicted median (90% prediction interval) serum ADI-58125 PK profiles in healthy adult participants predicted a priori based on the distribution of human K_D,FcRn values for other extended half-life mAbs (A, C) and after optimization (B, D). Dots represent the raw observed data. Solid lines represent simulated medians. The shaded area represents the 90% prediction interval.

[0245] Figures 25A-25C depict the QSP model-predicted median (90% prediction interval) serum ADI-58125 PK profiles following a single IM 150 mg (A), 300 mg (B), and 450 mg (C) injection in humans predicted a priori based on the distribution of human K_D,FcRn values for other extended half- life mAbs (as shown in Figures 21 A-B). Dashed line represents 100 * in vitro IC₉₀ of 0.011 μg/mL or 1.1 mg/L against the USA-WA1/2020 variant.

[0246] Figures 26A-26C depict the optimized QSP model-predicted median (90% prediction interval) serum ADI-58125 PK profiles following a single IM 150 mg (A), 300 mg (B), and 450 mg (C) injection in humans. Dashed line represents 100 * in vitro IC₉₀ of 0.011 μg/mL or 1.1 mg/L against the USA-WA1/2020 variant.

[0247] Figure 27 depicts the serum neutralizing titers (geometric mean MN80) from participants receiving a single 300 mg IM dose of ADI-58125 as compared to peak titers with 2-dose mRNA-1273 vaccination. “Statistical comparisons for Delta were based on prelilminary results. ^bPeak vaccine response timepoint: 7 to 31 days post 2nd dose; ^cExeludes samples taken following SARS-CoV-2 vaccination. Statistical comparisons of titres achieved by ADI-58125 against each variant were performed using 2-sided Mann Whitney U tests: *P<0.05; **P<0.01; ***P<0.001; ns, non-significant vs mRNA-1273 vaccination response against the corresponding variant.

[0248] Figure 28 depicts the visual predictive check plots for the base ADI-58125 pharmacokinetic model.

[0249] Figure 29A depicts the key binding residues in SARS-CoV-2 S protein for ADI-58125, and the strong conservation of these residues among global circulating SARS-CoV-2 variants.

Frequencies were calculated from 3,928,364 sequences deposited in GISAID (Global Initiative on Sharing All influenza Data) as of Oct 15, 2021. Figure 29B depicts the key binding residues in SARS-CoV-2 S protein for class 1 (e.g., LY-C0VOI6, REGN10933), class 2 (e.g., P2B-2F6, LY- CoV555, COV2-2196) and class 3 (e.g., REGN10987, COV2-2130, LY-CoV1404) antibodies.

[0250] Figure 30 depicts that the newly emerged Omicron (B.1.1.529) variant contains mutations in the epitopes of all three public classes of antibodies.

[0251] Figure 31 depicts that ADI-58125 binds to an epitope distinct from those recognized by common elicited nAbs.

[0252] Figure 32A depicts the non-overlapping epitopes between ADI-58125 and other clinical stage/EUA authorized antibodies. Figure 32B depicts the non-overlapping epitopes between ADI- 58122 and ADI-58125.

[0253] Figure 33 depicts the locally extensive area of red discoloration and consolidation (black arrows) in the hilar region of the right caudal lung lobe at 6 dpi. RM 1221. [0254] Figure 34 depicts the cut section of right caudal lung lobe showing the locally extensive region of consolidation/non-inflating (black arrow) at 6 dpi. RM 1221.

[0255] Figures 35A-35E depict the right caudal lung lobe, central section. Figure 35A. Multifocal moderate interstitial pneumonia at 6 dpi, 2x, H&E, RM 1221. Figure 35B, boxed area from Figure 35A, Moderate inflammation expanding the alveolar septa and extending into the alveolar lumina and moderate type II pneumocyte hyperplasia at 6 dpi, lOx, H&E, RM 1221. Figure 35C, boxed area from Figure 35B, alveolar septa were expanded by moderate numbers of lymphocytes, histiocytes, neutrophils and fibrin, which extended into lumen. Multifocally alveolar septa were lined by type II pneumocytes (arrows) at 6 dpi, 20x, H&E, RM 1221 Figure 35D. Rare IHC positive labeling in areas of inflammation, 2x, nucleocapsid protein for SARS-CoV-2, RM 1221. Figure 35E, boxed areas from Figure 35D, rare IHC positive labeling in areas of inflammation, 20x, nucleocapsid protein for SARS- CoV-2, RM 1221.

[0256] Figures 36A-36B depict nasal turbinate. Figure 36A. Locally extensive region of ulceration with subadjacent inflammation, hemorrhage and edema at 5 dpi, 4x, H&E, RM 7137. Figure 36B, boxed area from Figure 36A: Mucosal ulceration with mild to moderate lymphoplasmacytic and neutrophilic inflammation with necrosis, hemorrhage and edema at 5 dpi, lOx, H&E, RM 7137.

[0257] Figures 37A-37D depict right caudal lung lobe, central section. Figure 37A. Multifocal mild inflammation surrounding blood vessels, expanding alveolar septa and occasionally extending into the lumina at 5 dpi, 2x, H&E, RM 7175. Figure 37B, boxed area from Figure 37A: Mild inflammation composed predominately of histiocytes and lymphocytes with fewer neutrophils, around vessels and expanding septa at 5 dpi, lOx, H&E, RM 7175. Figure 37C. IHC labeling was not identified in areas of inflammation at 5 dpi, 2x, nucleocapsid protein for SARS-CoV-2, RM 7175. Figure 37D. IHC labeling was not identified in areas of inflammation at 5 dpi, lOx, nucleocapsid protein for SARS- CoV-2, RM 7175.

[0258] Figures 38A-38D depict lung, left caudal lobe, central section. RM 1430. Figure 38A. Multifocal mild inflammation surrounding blood vessels, expanding alveolar septa and extending into the alveolar lumina at 6 dpi, 2x, H&E, RM 1430. Figure 38B, boxed area from Figure 38A: Mild inflammation composed predominately of histiocytes and lymphocytes with fewer neutrophils, around vessels and expanding septa and within the alveolar lumina at 6 dpi, lOx, H&E, RM 1430. Figure 38C. IHC labeling was not identified in areas of inflammation at 6 dpi, 2x, nucleocapsid protein for SARS-CoV-2, RM 1430. Figure 38D. IHC labeling was not identified in areas of inflammation at 6 dpi, lOx, nucleocapsid protein for SARS-CoV-2, RM 1430.

[0259] Figure 39 depicts mild red discoloration for all lung lobes at 5 dpi. RM 1294.

[0260] Figure 40 depicts multifocal mild red discoloration throughout all lobes with locally extensive fibrinous adhesions noted from the left caudal lung lobe to the thoracic cavity at 5 dpi. RM 5240. [0261] Figure 41 depicts average fold change in IC50 for ADI-58125 relative to the D614G reference strain in a lentiviral pseudovirus assay.

[0262] Figure 42A shows the neutralization curves for ADI-58125 and ADI-58122 against Omicron BA.l variant (red) and the D614G reference strain (black) using a pseudo virus neutralization assay. [0263] Figue 42B shows the neutralization curves for ADI-58125 against D614G and Omicron sublineages (BA.l, BA.1.1 and BA.2) using a pseudovirus neutralization assay.

[0264] Figure 43 shows the neutralization curves for ADI-58125, ADI-58122, ADI-58127 and other commercial antibodies against Victoria and Omicron sublineages (BA.l, BA.1.1 and BA.2) in an authentic neutralization assay.

[0265] Figure 44 shows the neutralization data for ADI-58125, ADI-58122, ADI-58127 and other commercial antibodies against Victoria and all variants of concern, Alpha, Beta, Gamma, Delta and Omicron (BA.l., BA.1.1, BA.2) in an authentic neutralization assay.

[0266] Figure 45 depicts the correlation between serum neutralizing antibody titers induced by vaccination or mAh administration and reported vaccine or mAh efficacy against symptomatic COVID-19. Geometric mean serum neutralizing titers for samples obtained from AZD1222 and BNT162b2 vaccinees at the indicated timepoints against the indicated variants are plotted against reported vaccine efficacy at matched timepoints against the indicated variants. Red and black dotted lines indicate predicted month 3 serum neutralizing antibody titers against the Omicron variant following administration of 300 mg IM AZD7442 or 1200 mg IM ADI-58125, respectively. Predicted serum neutralizing antibody titers were calculated by dividing the estimated serum concentration of mAb(s) at the indicated time point by the mAh neutralization IC50(s) against Omicron. *Protective efficacy data shown for REGEN-COV (1200 mg SC) and AZD7442 (300 mg IM) at 8 and 6.5 months, respectively, was obtained from published reports (AstraZeneca 2021; O'Brien 2021; Regeneron 2021). Predicted serum neutralizing antibody titers shown for AZD7442 and REGEN- COV against the Delta variant were calculated by dividing the serum antibody concentration estimated from published PK data at the indicated timepoint by the mAh neutralization IC50(s) against Delta. Abbreviations: FRNT50=50% focus reduction neutralization test; 3M=month 3.

[0267] Figure 46 depicts the predicted median (10%-90% PI) ADI-58125 serum concentration-time profile following single 1200 mg IM dose. Simulation from preliminary PopPK model developed using data from the first-in-human study. Solid black line and shaded area represent median and 80% (10%-90%) prediction interval, respectively. Solid red line indicates the median serum concentration of ADI-58125 associated with the target threshold serum neutralizing titer of 1:100. Blue and green dashed/dotted lines represent the median IC90 (dashed) and IC50 (dotted) values for ADI-58125 against the Omicron variant in the ELF assuming an ELF: serum ratio of 10% (blue) or 15% (green). Abbreviations: ELF=epithelial lining fluid; sVNT=serum virus neutralizing titer. [0268] Figure 47 depicts the predicted median (10%-90% PI) ADI-58125 serum concentration-time profile following single 1200 mg IV dose. Simulation from preliminary PopPK model developed using data from the first-in-human study. Solid black line and shaded area represent median and 80% (10%-90%) prediction interval, respectively. Solid red line indicates the median serum concentration of ADI-58125 associated with the target threshold serum neutralizing titer of 1:100. Blue and green dashed/dotted lines represent the median IC90 (dashed) and IC50 (dotted) values for ADI-58125 against the Omicron variant in the ELF assuming an ELF: serum ratio of 10% (blue) or 15% (green). Abbreviations: ELF=epithelial lining fluid; sVNT=serum virus neutralizing titer.

[0269] Figure 48 depicts the neutralization curves of authentic Omicron virus by ADI-58125 and EUA mAbs. Antibody neutralization of authentic Omicron virus (B.1.1.529), as determined by a focus reduction neutralization assay. Data points and error bars represent the mean and standard deviation. Dotted lines indicate 50% and 90% neutralization.

[0270] Figure 49 depicts the goodness-of-fit plots for the ADI-58125 PK model.

[0271] Figure 50 depicts the key ADI-58125 PK parameter distributions across all doses (300mg IM, 500 mg IV, and 600 mg IM). CL: clearance. T - half-life. Vss: steady state volume of distribution.

[0272] Figure 51 depicts the population median predicted concentrations of ADI-58125 over time with IV and IM administration.

[0273] Figure 52A provides a graph comparing binding affinity of ADI-58125 and affinity maturation progenies for the SI from the Omicron BA.l varaint. Figure 52B provides a graph comparing the ability of ADI-58125 and affinity maturation progenies to neutralize the Omicron BA.l varaint.

[0274] Figure 53A provides a graph comparing binding affinity of affinity maturation ADI-58125 progenies for different variants of concern. Figure 53B provides a graph comparing the ability of affinity maturation ADI-58125 progenies to neutralize different variants of concern.

[0275] Figure 54 depicts the median (90% confidenence interval) ADI-58125 concentration-time profile following a 300 mg IM dose for phase 1 and phase 2/3 prevention and treatment studies. Shaded areas represent 90% CL Solid line represents median.

[0276] Figure 55 depicts the correlation between serum neutralizing antibody titers induced by vaccination or mAh administration and reported vaccine or mAh efficacy against symptomatic COVID-19. Geometric mean serum neutralizing titers for samples obtained from AZD1222 and BNT162b2 vaccinees at the indicated timepoints against the indicated variants are plotted against reported vaccine efficacy at matched timepoints against the indicated variants. Serum concentrations from population PK model based on Phase 2/3 data of ADI-58125 on days 55 and 76 (Omicron BA.1/BA1.1), and 90 (Delta) were used to calculate predictive nAb titers and corresponding efficacy for the Delta and Omicron variants and then compared to clinical efficacy results from the EVADE clinical trial in prevention of COVID-19. Abbreviations: FRNT50=50% focus reduction neutralization test.

DETAILED DESCRIPTION

A. Definitions

[0277] It is to be understood that this disclosure is not limited to the particular methodology, protocols, cell lines, animal species or genera, and reagents described, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present disclosure, which will be limited only by the appended claims. As used herein the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells and reference to "the protein" includes reference to one or more proteins and equivalents thereof known to those skilled in the art, and so forth. All technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs unless clearly indicated otherwise.

[0278] Spike protein (S protein ): As used herein, unless stated otherwise S protein includes any coronavirus form of S protein. The term coronavirus S protein (“CoV-S”) is used to describe the S protein of any coronaviruses. In particular, the “SARS-CoV-S” and “SARS-CoV-2-S” encompass the S protein of SARS-CoV and of SARS-CoV-2. SEQ ID NO: 401 is an exemplary polypeptide sequence of SARS-CoV-S, comprising 1288 amino acids (Accession# PDB: 6VSB_B). SEQ ID NO: 403 is an exemplary polypeptide sequence of SARS-CoV-2-S, comprising 1273 amino acids (GenBank: QHD43416.1). SEQ ID NO: 402 (3864 nucleotides) encodes the SARS-CoV-S (SEQ ID NO: 401) and SEQ ID NO: 404 (3822 nucleotides, NC_045512:21563.25384, also see the corresponding region of GenBank: MN908947) encodes SARS-CoV -2-S (SEQ ID NO: 403).

[0279] In some embodiments, the “SARS-CoV-S” and “SARS-CoV -2-S” encompass any mutants, splice variants, isoforms, orthologs, homologs, and variants of SEQ ID Nos 401 and 403. In some embodiments, the CoV-S comprises a polypeptide sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to either SEQ ID NO: 401 or SEQ ID NO: 403.

[0280] “Effective treatment or prevention of CoV infection” herein refers to eliminating CoV from the subject or preventing the expansion of CoV in the subject or eliminating or reducing the symptoms such as fever, cough, shortness of breath, runny nose, congestion, conjunctivitis, and/or gastrointestinal symptoms after administration of an effective amount of an anti-CoV-S antibody or antigen-binding fragment thereof. In some instances, effective treatment may eliminate the need for the subject to be placed on a ventilator or reduce the time the subject needs to be on a ventilator. The treatment may be effected as a monotherapy or in association with another active agent such as an antiviral agent or anti-inflammatory agent by way of example. [0281] As used herein, "treatment" is an approach for obtaining beneficial or desired clinical results. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, one or more of the following: improvement in any aspect of COV-S-related conditions such as fever or cough. For example, in the context of CoV infection treatment this includes lessening severity, alleviation of fever, cough, shortness of breath, and other associated symptoms, reducing frequency of recurrence, increasing the quality of life of those suffering from the CoV-related symptoms, and decreasing dose of other medications required to treat the CoV-related symptoms. Other associated symptoms include, but are not limited to, diarrhea, conjunctivitis, loss of smell, and loss of taste. Still other symptoms which may be alleviated or prevented include inflammation, cytokine storm and/or sepsis.

[0282] "Reducing incidence" or “prophylaxis” or “prevention” means any of reducing severity for a particular disease, condition, symptom, or disorder (the terms disease, condition, and disorder are used interchangeably throughout the application). Reduction in severity includes reducing drugs and/or therapies generally used for the condition by, for example, reducing the need for, amount of, and/or exposure to drugs or therapies. Reduction in severity also includes reducing the duration, and/or frequency of the particular condition, symptom, or disorder (including, for example, delaying or increasing time to next episodic attack in an individual). This further includes eliminating the need for the subject to be placed on a ventilator or reducing the time the subject needs to be on a ventilator. [0283] "Ameliorating" one or more symptoms of CoV infection-related conditions means a lessening or improvement of one or more symptoms of the condition, e.g., fever or cough or shortness of breath as compared to not administering an anti-CoV-S antagonist antibody. "Ameliorating" also includes shortening or reduction in duration of a symptom. Again, this may include eliminating the need for the subject to be placed on a ventilator or reducing the time the subject needs to be on a ventilator. [0284] As used herein, "controlling CoV-related symptom” or “controlling” another CoV-S-related condition refers to maintaining or reducing severity or duration of one or more symptoms of the condition (as compared to the level before treatment). For example, the duration or severity or frequency of symptoms is reduced by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% in the individual as compared to the level before treatment. The reduction in the duration or severity, or frequency of symptoms can last for any length of time, e.g., 2 weeks, 4 weeks (1 month), 8 weeks (2 months), 16 weeks (3 months), 4 months, 5 months, 6 months, 9 months, 12 months, etc.

[0285] As used therein, "delaying" the development of a CoV-S-related condition such as shortness of breath, bronchitis, or pneumonia e.g., interstitial), means to defer, hinder, slow, retard, stabilize, and/or postpone progression of the condition or disease. This delay can be of varying lengths of time, depending on the history of the condition or disease and/or individuals being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop symptoms. A method that "delays" development of the symptom is a method that reduces probability of developing the symptom in a given time frame and/or reduces extent of the symptoms in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects. [0286] "Development" or "progression" of a CoV-related condition such as cough or fever means initial manifestations and/or ensuing progression of the disorder. Development of cough or fever can be detectable and assessed using standard clinical techniques as well known in the art. However, development also refers to progression that may be undetectable. For purpose of this disclosure, development, or progression refers to the biological course of the symptoms. "Development" includes occurrence, recurrence, and onset. As used herein "onset" or "occurrence" of a condition includes initial onset and/or recurrence.

[0287] As used herein, an "effective dosage" or "effective amount" of drug, compound, or pharmaceutical composition is an amount sufficient to effect beneficial or desired results. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the outset of the disease, including biochemical, histological, and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results include clinical results such as reducing symptom intensity, duration, or frequency, and decreasing one or more symptoms resulting from CoV infection, including its complications and intermediate pathological phenotypes presenting during development of the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication, and/or delaying the progression of the disease of patients, eliminating the need for the subject to be placed on a ventilator or reducing the time the subject needs to be on a ventilator.

[0288] An effective dosage can be administered in one or more administrations. For purposes of this disclosure, an effective dosage of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective dosage of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an "effective dosage" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.

[0289] A “suitable host cell” or “host cell” generally includes any cell wherein the subject anti-CoV- S antibodies and antigen-binding fragments thereof can be produced recombinantly using techniques and materials readily available. For example, the anti-CoV-S antibodies and antigen-binding fragments thereof of the present disclosure can be produced in genetically engineered host cells according to conventional techniques. Suitable host cells are those cell types that can be transformed or transfected with exogenous DNA and grown in culture, and include bacteria, fungal cells (e.g., yeast), and cultured higher eukaryotic cells (including cultured cells of multicellular organisms), particularly cultured mammalian cells, e.g., human or non-human mammalian cells. In an exemplary embodiment these antibodies may be expressed in CHO cells. Techniques for manipulating cloned DNA molecules and introducing exogenous DNA into a variety of host cells are disclosed by Sambrook et ai, Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press (1989), and Current Protocols in Molecular Biology, Ausubel et ai, editors, New York, NY: Green and Wiley and Sons (1993).

[0290] In some exemplary embodiments the antibodies may be expressed in mating competent yeast, e.g., any haploid, diploid or tetraploid yeast that can be grown in culture. Yeast useful in fermentation expression methods may exist in a haploid, diploid, or other polyploid form.

[0291] A “selectable marker” herein refers to a gene or gene fragment that confers a growth phenotype (physical growth characteristic) on a cell receiving that gene as, for example through a transformation event. The selectable marker allows that cell to survive and grow in a selective growth medium under conditions in which cells that do not receive that selectable marker gene cannot grow. Selectable marker genes generally fall into several types, including positive selectable marker genes such as a gene that confers on a cell resistance to an antibiotic or other drug, temperature when two temperature sensitive (“ts”) mutants are crossed or a ts mutant is transformed; negative selectable marker genes such as a biosynthetic gene that confers on a cell the ability to grow in a medium without a specific nutrient needed by all cells that do not have that biosynthetic gene, or a mutagenized biosynthetic gene that confers on a cell inability to grow by cells that do not have the wild type gene; and the like.

[0292] An “expression vector” herein refers to DNA vectors containing elements that facilitate manipulation for the expression of a foreign protein within the target host cell, e.g., a bacterial, insect, yeast, plant, amphibian, reptile, avian, or mammalian cell, e.g., a CHO or HEK cell. Conveniently, manipulation of sequences and production of DNA for transformation may first performed in a bacterial host, e.g. E. coli, and usually vectors will include sequences to facilitate such manipulations, including a bacterial origin of replication and appropriate bacterial selection marker. Selection markers encode proteins necessary for the survival or growth of transformed host cells grown in a selective culture medium. Host cells not transformed with the vector containing the selection gene will not survive in the culture medium. Typical selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, (b) complement auxotrophic deficiencies, or (c) supply critical nutrients not available from complex media. Exemplary vectors and methods for transformation of yeast are described, for example, in Burke, D., Dawson, D., & Stearns, T., Methods in yeast genetics: a Cold Spring Harbor Laboratory course manual, Plainview, NY : Cold Spring Harbor Laboratory Press (2000). Expression vectors for use in the methods of the disclosure may include yeast or mammalian specific sequences, including a selectable auxotrophic or drug marker for identifying transformed host s. A drug marker may further be used to amplify copy number of the vector in a yeast host cell.

[0293] The polypeptide coding sequence of interest is operably linked to transcriptional and translational regulatory sequences that provide for expression of the polypeptide in the desired host cells, e.g., yeast or mammalian cells. These vector components may include, but are not limited to, one or more of the following: an enhancer element, a promoter, and a transcription termination sequence. Sequences for the secretion of the polypeptide may also be included, e.g. a signal sequence, and the like. An origin of replication, e.g., a yeast or mammalian origin of replication, is optional, as expression vectors may be integrated into the host cell genome.

[0294] Nucleic acids are "operably linked" when placed into a functional relationship with another nucleic acid sequence. For example, DNA for a signal sequence is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence. Generally, "operably linked" means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading frame. However, enhancers do not have to be contiguous. Linking is accomplished by ligation at convenient restriction sites or via a PCR/recombination method familiar to those skilled in the art (GATEWAY^® Technology (universal method for cloning DNA); Invitrogen, Carlsbad California). If such sites do not exist, the synthetic oligonucleotide adapters or linkers are used in accordance with conventional practice.

[0295] Promoters are untranslated sequences located upstream (5') to the start codon of a structural gene (generally within about 100 to 1000 bp) that control the transcription and translation of particular nucleic acid sequences to which they are operably linked. Such promoters fall into several classes: inducible, constitutive, and repressible promoters (that increase levels of transcription in response to absence of a repressor). Inducible promoters may initiate increased levels of transcription from DNA under their control in response to some change in culture conditions, e.g., the presence or absence of a nutrient or a change in temperature.

[0296] The promoter fragment may also serve as the site for homologous recombination and integration of the expression vector into the same site in the host cell, e.g., yeast or mammalian cell, genome; alternatively, a selectable marker may be used as the site for homologous recombination. Suitable promoters for use in different eukaryotic and prokaryotic cells are well known and commercially available.

[0297] The polypeptides of interest may be produced recombinantly not only directly, but also as a fusion polypeptide with a heterologous polypeptide, e.g. a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide. In general, the signal sequence may be a component of the vector, or it may be a part of the polypeptide coding sequence that is inserted into the vector. The heterologous signal sequence selected preferably is one that is recognized and processed through one of the standard pathways available within the host cell, e.g., a mammalian cell, an insect cell, or a yeast cell. Additionally, these signal peptide sequences may be engineered to provide for enhanced secretion in expression systems. Secretion signals of interest also include mammalian and yeast signal sequences, which may be heterologous to the protein being secreted, or may be a native sequence for the protein being secreted. Signal sequences include pre peptide sequences, and in some instances may include propeptide sequences. Many such signal sequences are known in the art, including the signal sequences found on immunoglobulin chains, e.g., K28 preprotoxin sequence, PHA-E, FACE, human MCP-1, human serum albumin signal sequences, human Ig heavy chain, human Ig light chain, and the like. For example, see Hashimoto et. al., Protein Eng., 11(2):75 (1998); and Kobayashi et. al., Therapeutic Apheresis, 2(4):257 (1998)).

[0298] Transcription may be increased by inserting a transcriptional activator sequence into the vector. These activators are cis-acting elements of DNA, usually about from 10 to 300 bp, which act on a promoter to increase its transcription. Transcriptional enhancers are relatively orientation and position independent, having been found 5' and 3' to the transcription unit, within an intron, as well as within the coding sequence itself. The enhancer may be spliced into the expression vector at a position 5' or 3' to the coding sequence, but is preferably located at a site 5' from the promoter.

[0299] Expression vectors used in eukaryotic host cells may also contain sequences necessary for the termination of transcription and for stabilizing the rnRNA. Such sequences are commonly available from 3' to the translation termination codon, in untranslated regions of eukaryotic or viral DNAs or cDNAs. These regions contain nucleotide segments transcribed as polyadenylated fragments in the untranslated portion of the rnRNA.

[0300] Construction of suitable vectors containing one or more of the above -listed components employs standard ligation techniques or PCR/recombination methods. Isolated plasmids or DNA fragments are cleaved, tailored, and re-ligated in the form desired to generate the plasmids required or via recombination methods. For analysis to confirm correct sequences in plasmids constructed, the ligation mixtures are used to transform host cells, and successful transformants selected by antibiotic resistance (e.g. ampicillin or Zeocin) where appropriate. Plasmids from the transformants are prepared, analyzed by restriction endonuclease digestion, and/or sequenced.

[0301] As an alternative to restriction and ligation of fragments, recombination methods based on specific attachment (“ att ”) sites and recombination enzymes may be used to insert DNA sequences into a vector. Such methods are described, for example, by Landy, Ann. Rev. Biochem., 58:913-949 (1989); and are known to those of skill in the art. Such methods utilize intermolecular DNA recombination that is mediated by a mixture of lambda and E. coli -encoded recombination proteins. Recombination occurs between att sites on the interacting DNA molecules. For a description of aft sites see Weisberg and Landy, Site-Specific Recombination in Phage Lambda, in Lambda II, P- 211- 250, Cold Spring Harbor, NY: Cold Spring Harbor Press (1983). The DNA segments flanking the recombination sites are switched, such that after recombination, the att sites are hybrid sequences comprised of sequences donated by each parental vector. The recombination can occur between DNAs of any topology.

[0302] Att sites may be introduced into a sequence of interest by ligating the sequence of interest into an appropriate vector; generating a PCR product containing att B sites through the use of specific primers; generating a cDNA library cloned into an appropriate vector containing att sites; and the like. [0303] Folding, as used herein, refers to the three-dimensional structure of polypeptides and proteins, where interactions between amino acid residues act to stabilize the structure. While non-covalent interactions are important in determining structure, usually the proteins of interest will have intra- and/or intermolecular covalent disulfide bonds formed by two cysteine residues. For naturally occurring proteins and polypeptides or derivatives and variants thereof, the proper folding is typically the arrangement that results in optimal biological activity, and can conveniently be monitored by assays for activity, e.g. ligand binding, enzymatic activity, etc.

[0304] In some instances, for example where the desired product is of synthetic origin, assays based on biological activity will be less meaningful. The proper folding of such molecules may be determined on the basis of physical properties, energetic considerations, modeling studies, etc.

[0305] The expression host may be further modified by the introduction of sequences encoding one or more enzymes that enhance folding and disulfide bond formation, i.e. foldases, chaperonins, etc. Such sequences may be constitutively or inducibly expressed in the host cell, using vectors, markers, etc. as known in the art. Preferably the sequences, including transcriptional regulatory elements sufficient for the desired pattern of expression, are stably integrated in the yeast genome through a targeted methodology.

[0306] For example, the eukaryotic protein disulfide isomerase (“PDI”) is not only an efficient catalyst of protein cysteine oxidation and disulfide bond isomerization, but also exhibits chaperone activity. Co-expression of PDI can facilitate the production of active proteins having multiple disulfide bonds. Also of interest is the expression of immunoglobulin heavy chain binding protein (“BIP”); cyclophilin; and the like.

[0307] Cultured mammalian cells are exemplary hosts for production of the disclosed anti-CoV-S antibodies and antigen-binding fragments thereof. As mentioned CHO cells are particularly suitable for expression of antibodies. Many procedures are known in the art for manufacturing monoclonal antibodies in mammalian cells. (See, Galfre, G. and Milstein, C., Methods Enzym., 73:3-46, 1981; Basalp et al, Turk. J. Biol., 24:189-196, 2000; Wurm, F.M., Nat. Biotechnol., 22:1393-1398, 2004; and Li et al, mAbs, 2(5):466-477, 2010). As mentioned in further detail infra, common host cell lines employed in mammalian monoclonal antibody manufacturing schemes include, but are not limited to, human embryonic retinoblast cell line PER.C6® (Crucell N.V., Leiden, The Netherlands), NSO murine myeloma cells (Medical Research Council, London, UK), CV 1 monkey kidney cell line, 293 human embryonic kidney cell line, BHK baby hamster kidney cell line, VERO African green monkey kidney cell line, human cervical carcinoma cell line HELA, MDCK canine kidney cells, BRL buffalo rat liver cells, W138 human lung cells, HepG2 human liver cells, MMT mouse mammary tumor cells, TRI cells, MRC5 cells, Fs4 cells, myeloma or lymphoma cells, or Chinese Hamster ( Cricetulus griseus ) Ovary (CHO) cells, and the like. Many different subclones or sub-cell lines of CHO cells known in the art that are useful and optimized for production of recombinant monoclonal antibodies, such as the DP12 (CHO K1 dhfr-) cell line, NSO cells are a non-Ig secreting, non-light chain- synthesizing subclone of NS-1 cells that are resistant to azaguanine. Other Chinese Hamster and CHO cells are commercially available (from ATCC, etc.), including CHO-DXB11 (CHO-DUKX), CHO- pro3, CHO-DG44, CHO 1-15, CHO DP-12, Lec2, M1WT3, Lec8, μgsA-745, and the like, ah of which are genetically altered to optimize the cell line for various parameters. Monoclonal antibodies are commonly manufactured using a batch fed method whereby the monoclonal antibody chains are expressed in a mammalian cell line and secreted into the tissue culture medium in a bioreactor. Medium (or feed) is continuously supplied to the bioreactor to maximize recombinant protein expression. Recombinant monoclonal antibody is then purified from the collected media. In some circumstances, additional steps are needed to reassemble the antibodies through reduction of disulfide bonds, etc. Such production methods can be scaled to be as large as 10,000 L in a single batch or more. It is now routine to obtain as much as 20 μg/cell/day through the use of such cell lines and methodologies, providing titers as high as 10 g/L or more, amounting to 15 to 100 kg from bioreactors of 10 kL to 25 kL. (Li et ai, 2010). Various details of this production methodology, including cloning of the polynucleotides encoding the antibodies into expression vectors, transfecting cells with these expression vectors, selecting for transfected cells, and expressing and purifying the recombinant monoclonal antibodies from these cells are provided below.

[0308] For recombinant production of an anti-CoV-S antibody or antigen-binding fragment in mammalian cells, nucleic acids encoding the antibody or fragment thereof are generally inserted into a replicable vector for further cloning (amplification of the DNA) or for expression. DNA encoding the antibody is readily isolated or synthesized using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to DNAs encoding the heavy and light chains of the antibody). The vector components generally include, but are not limited to, one or more of the following: a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence. Selection of promoters, terminators, selectable markers, vectors, and other elements is a matter of routine design within the level of ordinary skill in the art. Many such elements are known in the art and are available through commercial suppliers.

[0309] The antibodies of this disclosure may be produced recombinantly not only directly, but also as a fusion polypeptide with a heterologous polypeptide, which is preferably a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide.

The homologous or heterologous signal sequence selected preferably is one that is recognized and processed (i.e., cleaved by a signal peptidase) by the host cell. In mammalian cell expression, mammalian signal sequences as well as viral secretory leaders, for example, the herpes simplex gD signal, are available.

[0310] Such expression vectors and cloning vectors will generally contain a nucleic acid sequence that enables the vector to replicate in one or more selected host cells. Typically, in cloning vectors this sequence is one that enables the vector to replicate independently of the host chromosomal DNA, and includes origins of replication or autonomously replicating sequences. Such sequences are well known for a variety of bacteria, yeast, and viruses, e.g. , the origin of replication from the plasmid pBR322 is suitable for most Gram-negative bacteria, the 2mu plasmid origin is suitable for yeast, and various viral origins (Simian Virus 40 (“SV40”), polyoma, adenovirus, vesicular stomatitis virus (“VSV”), or bovine papillomavirus (“BPV”) are useful for cloning vectors in mammalian cells. Generally, the origin of replication component is not needed for mammalian expression vectors (the SV40 origin may typically be used only because it contains the early promoter).

[0311] These vectors will also typically contain a selection gene, also termed a selectable marker. Typical selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, e.g., ampicillin, neomycin, methotrexate, or tetracycline, (b) complement auxotrophic deficiencies, or (c) supply critical nutrients not available from complex media, e.g., the gene encoding D-alanine racemase for Bacilli.

[0312] One example of a selection scheme utilizes a drug to arrest growth of a host cell. Drug selection is generally used to select for cultured mammalian cells into which foreign DNA has been inserted. Such cells are commonly referred to as "transfectants". Cells that have been cultured in the presence of the selective agent and are able to pass the gene of interest to their progeny are referred to as "stable transfectants." Examples of such dominant selection use the drugs neomycin, mycophenolic acid, and hygromycin. An exemplary selectable marker is a gene encoding resistance to the antibiotic neomycin. Selection is carried out in the presence of a neomycin-type drug, such as G-418 or the like. Those cells that are successfully transformed with a heterologous gene produce a protein conferring drug resistance and thus survive the selection regimen.

[0313] Selection systems can also be used to increase the expression level of the gene of interest, a process referred to as "amplification." Amplification of transfectants typically occurs by culturing the cells in the presence of a low level of the selective agent and then increasing the amount of selective agent to select for cells that produce high levels of the products of the introduced genes. Exemplary suitable selectable markers for mammalian cells are those that enable the identification of cells competent to take up the antibody nucleic acid, such as dihydrofolate reductase (“DHFR”), thymidine kinase, metallothionein-I and -II, preferably primate metallothionein genes, adenosine deaminase, ornithine decarboxylase, etc.

[0314] For example, an amplifiable selectable marker for mammalian cells is dihydrofolate reductase, which confers resistance to methotrexate. Other drug resistance genes (e.g. hygromycin resistance, multi-drug resistance, puromycin acetyltransferase) can also be used. Cells transformed with the DHFR selection gene are first identified by culturing all of the transformants in a culture medium that contains methotrexate (“MTX”), a competitive antagonist of DHFR. An appropriate host cell when wild-type DHFR is employed is the Chinese hamster ovary (“CHO”) cell line deficient in DHFR activity.

[0315] Alternatively, host cells (particularly wild-type hosts that contain endogenous DHFR) transformed or co-transformed with DNA sequences encoding antibody, wild-type DHFR protein, and another selectable marker such as aminoglycoside 3'-phosphotransferase (“APH”) can be selected by cell growth in medium containing a selection agent for the selectable marker such as an aminoglycosidic antibiotic, e.g., kanamycin, neomycin, or G-418. See U.S. Patent No. 4,965,199. [0316] These vectors may comprise an enhancer sequence that facilitates transcription of a DNA encoding the antibody. Many enhancer sequences are known from mammalian genes (for example, globin, elastase, albumin, alpha-fetoprotein, and insulin). A frequently used enhancer is one derived from a eukaryotic cell virus. Examples thereof include the SV40 enhancer on the late side of the replication origin (bp 100-270), the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers (See also Yaniv, Nature, 297:17- 18 (1982) on enhancing elements for activation of eukaryotic promoters). The enhancer may be spliced into the vector at a position 5' or 3' to the antibody-encoding sequence, but is preferably located at a site 5' from the promoter.

[0317] Expression and cloning vectors will also generally comprise a promoter that is recognized by the host organism and is operably linked to the antibody nucleic acid. Promoter sequences are known for eukaryotes. Virtually all eukaryotic genes have an AT-rich region located approximately 25 to 30 bases upstream from the site where transcription is initiated. Another sequence found 70 to 80 bases upstream from the start of transcription of many genes is a CNCAAT region where N may be any nucleotide. At the 3' end of most eukaryotic genes is an AATAAA sequence that may be the signal for addition of the poly A tail to the 3' end of the coding sequence. All of these sequences are suitably inserted into eukaryotic expression vectors.

[0318] Antibody transcription from vectors in mammalian host cells may be controlled, for example, by promoters obtained from the genomes of viruses such as polyoma virus, fowlpox virus, adenovirus (such as Adenovirus 2), BPV, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus, and most preferably SV40, from heterologous mammalian promoters, e.g., the actin promoter or an immunoglobulin promoter, from heat-shock promoters, provided such promoters are compatible with the host cell systems.

[0319] The early and late promoters of the SV40 virus are conveniently obtained as an SV40 restriction fragment that also contains the SV40 viral origin of replication. The immediate early promoter of the human cytomegalovirus is conveniently obtained as a Hindlll E restriction fragment. A system for expressing DNA in mammalian hosts using the BPV as a vector is disclosed in U.S. Patent No. 4,419,446. A modification of this system is described in U.S. Patent No. 4,601,978. See also Reyes et ai, Nature, 297:598-601 (1982) on expression of human beta-interferon cDNA in mouse cells under the control of a thymidine kinase promoter from herpes simplex virus. Alternatively, the Rous sarcoma virus long terminal repeat can be used as the promoter.

[0320] Strong transcription promoters can be used, such as promoters from SV40, cytomegalovirus, or myeloproliferative sarcoma virus. See, e.g., U.S. Patent No. 4,956,288 and U.S. Patent Publication No. 20030103986. Other suitable promoters include those from metallothionein genes (U.S. Patent Nos. 4,579,821 and 4,601,978) and the adenovirus major late promoter. Expression vectors for use in mammalian cells include pZP-1, pZP-9, and pZMP21, which have been deposited with the American Type Culture Collection, 10801 University Blvd., Manassas, VA. USA under accession numbers 98669, 98668, and PTA-5266, respectively, and derivatives of these vectors.

[0321] Expression vectors used in eukaryotic host cells (yeast, fungus, insect, plant, animal, human, or a nucleated cell from other multicellular organism) will also generally contain sequences necessary for the termination of transcription and for stabilizing the rnRNA. Such sequences are commonly available from the 5' and, occasionally 3', untranslated regions of eukaryotic or viral DNAs or cDNAs. These regions contain nucleotide segments transcribed as polyadenylated fragments in the untranslated portion of the rnRNA encoding the antibody. One useful transcription termination component is the bovine growth hormone polyadenylation region. See WO 94/11026 and the expression vector disclosed therein.

[0322] Suitable host cells for cloning or expressing the subject antibodies include prokaryote, yeast, or higher eukaryote cells described above. However, interest has been greatest in vertebrate cells, and propagation of vertebrate cells in culture has become a routine procedure. Examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-1 (ATCC No. CRL 1650); and COS-7, ATCC CRL 1651); human embryonic kidney line (293 or 293 cells subcloned for growth in suspension culture, (ATCC No. CRL 1573; Graham et ai, J. Gen. Virol., 36:59-72 (1977)); baby hamster kidney cells (BHK, ATCC CCL 10, ATCC No. CRL 1632; BHK 570, ATCC No. CRL 10314); CHO cells (CHO-K1, ATCC No. CCL 61; CHO-DG44, Urlaub et ai, Proc. Natl. Acad. Sci. USA, 77:4216-4220 (1980)); mouse sertoli cells (TM4, Mather, Biol. Reprod., 23:243-251 (1980)); monkey kidney cells (CV1 ATCC CCL 70); African green monkey kidney cells (VERO-76, ATCC CRL-1587); human cervical carcinoma cells (HELA, ATCC CCL 2); canine kidney cells (MDCK, ATCC CCL 34); buffalo rat liver cells (BRL 3A, ATCC CRL 1442); human lung cells (W138, ATCC CCL 75); human liver cells (Hep G2, HB 8065); mouse mammary tumor (MMT 060562, ATCC CCL51); TRI cells (Mather et al, Annals N.Y. Acad. Sci., 383:44-68 (1982)); MRC 5 cells; LS4 cells; and a human hepatoma line (Hep G2). Additional suitable cell lines are known in the art and available from public depositories such as the American Type Culture Collection, Manassas, VA.

[0323] Host cells are transformed with the above -described expression or cloning vectors for antibody production and cultured in conventional nutrient media modified as appropriate for inducing promoters, selecting transformants, or amplifying the genes encoding the desired sequences as discussed supra.

[0324] The mammalian host cells used to produce the antibody of this disclosure may be cultured in a variety of media. Commercially available media such as Ham's L10 (Sigma-Aldrich Corporation, St. Louis, MO), Minimal Essential Medium ((“MEM” (Sigma-Aldrich Corporation, St. Louis, MO), Roswell Park Memorial Institute- 1640 medium (“RPMI-1640”, Sigma-Aldrich Corporation, St.

Louis, MO), and Dulbecco's Modified Eagle's Medium ((“DMEM” Sigma-Aldrich Corporation, St. Louis, MO) are suitable for culturing the host cells. In addition, any of the media described in Ham et al, Meth. Enz·, 58:44 (1979), Barnes et aI., AhaI. Biochem., 102:255 (1980), U.S. Patent Nos. 4,767,704; 4,657,866; 4,927,762; 4,560,655; or 5,122,469; WO 90/03430; WO 87/00195; or U.S. Patent Reexam No. 30,985 can be used as culture media for the host cells. Any of these media may be supplemented as necessary with hormones and/or other growth factors (such as insulin, transferrin, or epidermal growth factor), salts (such as sodium chloride, calcium, magnesium, and phosphate), buffers (such as HEPES), nucleotides (such as adenosine and thymidine), antibiotics (such as Gentamycin drug), trace elements (defined as inorganic compounds usually present at final concentrations in the micromolar range), and glucose or an equivalent energy source. Any other necessary supplements may also be included at appropriate concentrations that would be known to those skilled in the art. The culture conditions, such as temperature, pH, and the like, are those previously used with the host cell selected for expression, and will be apparent to the ordinarily skilled artisan. Methods of development and optimization of media and culture conditions are known in the art (See, Gronemeyer et al., Bioengineering, 1(4): 188-212, 2014).

[0325] After culture conditions are optimized and a preferred cell line clone is selected, these cells are cultured (either adherent cells or suspension cultures) most typically in a batch-fed process in a bioreactor (many models are commercially available) that involves continuously feeding the cell culture with medium and feed, optimized for the particular cell line chosen and selected for this purpose. (See, Butler, M., Appl. Microbiol. BiotechnoL, 68:283-291, 2005; and Kelley, B., mAb, l(5):443-452, 2009). Perfusion systems are also available in which media and feed are continuously supplied to the culture while the same volume of media is being withdrawn from the bioreactor. (Wurm, 2004). Synthetic media, also commercially available, are available for growing cells in a batch-fed culture, avoiding the possibility of contamination from outside sources, such as with the use of animal components, such as bovine serum albumin, etc. However, animal-component-free hydrolysates are commercially available to help boost cell density, culture viability and productivity. (Li et al, 2010). Many studies have been performed in an effort to optimize cell culture media, including careful attention to head space available in roller bottles, redox potentials during growth and expression phases, presence of reducing agents to maintain disulfide bonds during production, etc. (See, for instance, Hutterer et al, mAbs, 5(4):608-613, 2013; and Mullan et ai, BMC Proceed., 5(Suppl 8):P110, 2011). Various methodologies have been developed to address the possibility of harmful oxidation during recombinant monoclonal antibody production. (See, for example, U.S.

Patent No. 8,574,869). Cultured cells may be grown by feeding nutrients continuously or as separately administered amounts. Often various process parameters such as cell concentration, pH, temperature, CO2, d0₂, osmolality, amount of metabolites such as glucose, lactate, glutamine and glutamate, and the like, are monitored by the use of probes during the cell growth either on-line by direct connection to calibrated analyzers or off-line by intervention of operators. The culturing step also typically involves ensuring that the cells growing in culture maintain the transfected recombinant genes by any means known in the art for cell selection.

[0326] Following fermentation, i.e. , upon reaching maximum cell growth and recombinant protein expression, the culturing step is typically followed by a harvesting step, whereby the cells are separated from the medium and a harvested cell culture media is thereby obtained. (See, Liu et al. , mAbs, 2(5):480-499, 2010). Typically, various purification steps, involving column chromatography and the like, follow culturing to separate the recombinant monoclonal antibody from cell components and cell culture media components. The exact purification steps needed for this phase of the production of recombinant monoclonal antibodies depends on the site of expression of the proteins, i.e., in the cytosol of the cells themselves, or the more commonly preferred route of protein excreted into the cell culture medium. Various cell components may be separated using techniques known in the art such as differential centrifugation techniques, gravity-based cell settling, and/or size exclusion chromatograph/filtration techniques that can include tangential flow micro-filtration or depth filtration. (See, Pollock et al. , Biotechnol. Bioeng. , 110:206-219, 2013, and Liu et al. , 2010). Centrifugation of cell components may be achieved on a large scale by use of continuous disk stack centrifuges followed by clarification using depth and membrane filters. (See, Kelley, 2009). Most often, after clarification, the recombinant protein is further purified by Protein A chromatography due to the high affinity of Protein A for the Fc domain of antibodies, and typically occurs using a low pH/acidification elution step (typically the acidification step is combined with a precautionary virus inactivation step). Flocculation and/or precipitation steps using acidic or cationic polyelectrolytes may also be employed to separate animal cells in suspension cultures from soluble proteins. (Liu et al, 2010). Lastly, anion- and cation-exchange chromatography, hydrophobic interaction chromatograph (“HIC”), hydrophobic charge induction chromatograph (HCIC), hydroxyapatite chromatography using ceramic hydroxyapatite (Cas(P04)30H)2, and combinations of these techniques are typically used to polish the solution of recombinant monoclonal antibody. Final formulation and concentration of the desired monoclonal antibody may be achieved by use of ultracentrifugation techniques. Purification yields are typically 70 to 80%. (Kelley, 2009).

[0327] The terms "desired protein" or "desired antibody" herein are used interchangeably and refer generally to a parent antibody specific to a target, i.e., CoV-S or a chimeric or humanized antibody or a binding portion thereof derived therefrom as described herein. The term “antibody” is intended to include any polypeptide chain-containing molecular structure with a specific shape that fits to and recognizes an epitope, where one or more non-covalent binding interactions stabilize the complex between the molecular structure and the epitope. The archetypal antibody molecule is the immunoglobulin, and ah types of immunoglobulins, IgG, IgM, IgA, IgE, IgD, etc., from ah sources, e.g. human, rodent, rabbit, cow, sheep, pig, dog, other mammals, chicken, other avians, etc., are considered to be “antibodies.” Examples thereof include chimeric antibodies, human antibodies and other non-human mammalian antibodies, humanized antibodies, single chain antibodies (such as scFvs), camelbodies, nanobodies, IgNAR (single-chain antibodies which may be derived from sharks, for example), small-modular immunopharmaceuticals (“SMIPs”), and antibody fragments such as Fabs, Fab', F(ab')2, and the like ( See Streltsov et ai, Protein ScL, 14(11) :2901 -9 (2005); Greenberg et al, Nature, 374(6518):168-73 (1995); Nuttall et al, Mol. Immunol., 38(4):313-26 (2001); Flamers- Casterman et al., Nature, 363(6428):446-8 (1993); Gill et al., Curr. Opin. Biotechnol., (6):653-8 (2006)).

[0328] For example, antibodies or antigen-binding fragments thereof may be produced by genetic engineering. In this technique, as with other methods, antibody-producing cells are sensitized to the desired antigen or immunogen. The messenger RNA isolated from antibody producing cells is used as a template to make cDNA using PCR amplification. A library of vectors, each containing one heavy chain gene and one light chain gene retaining the initial antigen specificity, is produced by insertion of appropriate sections of the amplified immunoglobulin cDNA into the expression vectors. A combinatorial library is constructed by combining the heavy chain gene library with the light chain gene library. This results in a library of clones that co-express a heavy and light chain (resembling the Fab fragment or antigen-binding fragment of an antibody molecule). The vectors that carry these genes are co-transfected into a host cell. When antibody gene synthesis is induced in the transfected host, the heavy and light chain proteins self-assemble to produce active antibodies that can be detected by screening with the antigen or immunogen. [0329] Antibody coding sequences of interest include those encoded by native sequences, as well as nucleic acids that, by virtue of the degeneracy of the genetic code, are not identical in sequence to the disclosed nucleic acids, and variants thereof. Variant polypeptides can include amino acid (“aa”) substitutions, additions, or deletions. The amino acid substitutions can be conservative amino acid substitutions or substitutions to eliminate non-essential amino acids, such as to alter a glycosylation site, or to minimize misfolding by substitution or deletion of one or more cysteine residues that are not necessary for function. Variants can be designed so as to retain or have enhanced biological activity of a particular region of the protein (e.g., a functional domain, catalytic amino acid residues, etc). Variants also include fragments of the polypeptides disclosed herein, particularly biologically active fragments and/or fragments corresponding to functional domains. Techniques for in vitro mutagenesis of cloned genes are known. Also included in the subject disclosure are polypeptides that have been modified using ordinary molecular biological techniques so as to improve their resistance to proteolytic degradation or to optimize solubility properties or to render them more suitable as a therapeutic agent.

[0330] Chimeric antibodies may be made by recombinant means by combining the V_L and V_H regions, obtained from antibody producing cells of one species with the constant light and heavy chain regions from another. Typically, chimeric antibodies utilize rodent or rabbit variable regions and human constant regions, in order to produce an antibody with predominantly human domains.

The production of such chimeric antibodies is well known in the art, and may be achieved by standard means (as described, e.g., in U.S. Patent No. 5,624,659, incorporated herein by reference in its entirety). It is further contemplated that the human constant regions of chimeric antibodies of the disclosure may be selected from IgGl, IgG2, IgG3, and IgG4 constant regions.

[0331] Humanized antibodies are engineered to contain even more human-like mmunoglobulin domains, and incorporate only the complementarity determining regions of the animal -derived antibody. This is accomplished by carefully examining the sequence of the hyper- variable loops of the variable regions of the monoclonal antibody and fitting them to the structure of the human antibody chains. Although facially complex, the process is straightforward in practice. See, e.g., U.S. Patent No. 6,187,287, incorporated fully herein by reference.

[0332] In addition to entire immunoglobulins (or their recombinant counterparts), immunoglobulin fragments comprising the epitope binding site (e.g., Fab’, F(ab’)2, or other fragments) may be synthesized. “Fragment” or minimal immunoglobulins may be designed utilizing recombinant immunoglobulin techniques. For instance, “Fv” immunoglobulins for use in the present disclosure may be produced by synthesizing a fused variable light chain region and a variable heavy chain region. Combinations of antibodies are also of interest, e.g. diabodies, which comprise two distinct Fv specificities. In another embodiment, small molecule immunopharmaceuticals (“SMIPs”), camelbodies, nanobodies, and IgNAR are encompassed by immunoglobulin fragments. [0333] Immunoglobulins and fragments thereof may be modified post-translationally, e.g. to add effector moieties such as chemical linkers, detectable moieties, such as fluorescent dyes, enzymes, toxins, substrates, bioluminescent materials, radioactive materials, chemiluminescent moieties, and the like, or specific binding moieties, such as streptavidin, avidin, or biotin, and the like may be utilized in the methods and compositions of the present disclosure. Examples of additional effector molecules are provided infra.

[0334] A polynucleotide sequence "corresponds" to a polypeptide sequence if translation of the polynucleotide sequence in accordance with the genetic code yields the polypeptide sequence (i.e., the polynucleotide sequence "encodes" the polypeptide sequence), one polynucleotide sequence "corresponds" to another polynucleotide sequence if the two sequences encode the same polypeptide sequence.

[0335] A "heterologous" region or domain of a DNA construct is an identifiable segment of DNA within a larger DNA molecule that is not found in association with the larger molecule in nature.

Thus, when the heterologous region encodes a mammalian gene, the DNA flanking the gene usually does not flank the mammalian genomic DNA in the genome of the source organism. Another example of a heterologous region is a construct where the coding sequence itself is not found in nature (e.g., a cDNA where the genomic coding sequence contains introns or synthetic sequences having codons different than the native gene). Allelic variations or naturally-occurring mutational events do not give rise to a heterologous region of DNA as defined herein.

[0336] A "coding sequence" is an in-frame sequence of codons that correspond to or encode a protein or peptide sequence. Two coding sequences correspond to each other if the sequences or their complementary sequences encode the same amino acid sequences. A coding sequence in association with appropriate regulatory sequences may be transcribed and translated into a polypeptide. A polyadenylation signal and transcription termination sequence will usually be located 3' to the coding sequence. A "promoter sequence" is a DNA regulatory region capable of initiating transcription of a downstream (3' direction) coding sequence, and typically contain additional sites for binding of regulatory molecules, e.g., transcription factors, that affect the transcription of the coding sequence. A coding sequence is "under the control" of the promoter sequence or "operatively linked" to the promoter when RNA polymerase binds the promoter sequence in a cell and transcribes the coding sequence into mRNA, which is then in turn translated into the protein encoded by the coding sequence.

[0337] The general structure of antibodies in vertebrates now is well understood. See Edelman, G. M., Ann. N.Y. Acad. Sci., 190:5 (1971). Antibodies consist of two identical light polypeptide chains of molecular weight approximately 23,000 daltons (the “light chain”), and two identical heavy chains of molecular weight 53,000-70,000 (the “heavy chain”). The four chains are joined by disulfide bonds in a “Y” configuration wherein the light chains bracket the heavy chains starting at the mouth of the “Y” configuration. The “branch” portion of the “Y” configuration is designated the F_ab region; the stem portion of the “Y” configuration is designated the Fc region. The amino acid sequence orientation runs from the N-terminal end at the top of the “Y” configuration to the C-terminal end at the bottom of each chain. The N-terminal end possesses the variable region having specificity for the antigen that elicited it, and is approximately 100 amino acids in length, there being slight variations between light and heavy chain and from antibody to antibody.

[0338] The variable region is linked in each chain to a constant region that extends the remaining length of the chain and that within a particular class of antibody does not vary with the specificity of the antibody (i.e., the antigen eliciting it). There are five known major classes of constant regions that determine the class of the immunoglobulin molecule (IgG, IgM, IgA, IgD, and IgE corresponding to g, m, a, d, and e (gamma, mu, alpha, delta, or epsilon) heavy chain constant regions). The constant region or class determines subsequent effector function of the antibody, including activation of complement ( see Kabat, E. A., Structural Concepts in Immunology and Immunochemistry, 2nd Ed., p. 413-436, New York, NY: Flolt, Rinehart, Winston (1976)), and other cellular responses ( see Andrews et ai, Clinical Immunology, pp. 1-18, W. B. Sanders, Philadelphia, PA (1980); Kohl et ai, Immunology, 48:187 (1983)); while the variable region determines the antigen with which it will react. Light chains are classified as either k (kappa) or l (lambda). Each heavy chain class can be prepared with either kappa or lambda light chain. The light and heavy chains are covalently bonded to each other, and the “tail” portions of the two heavy chains are bonded to each other by covalent disulfide linkages when the immunoglobulins are generated either by hybridomas or by B -cells.

[0339] The expression “variable region” or “VR” refers to the domains within each pair of light and heavy chains in an antibody that are involved directly in binding the antibody to the antigen. Each heavy chain has at one end a variable region (VFI) followed by a number of constant domains. Each light chain has a variable region (VL) at one end and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain.

[0340] The expressions “complementarity-determining region,” “hypervariable region,” or “CDR” refer to one or more of the hyper-variable or complementarity-determining regions (“CDRs”) found in the variable regions of light or heavy chains of an antibody ( See Kabat et ai, Sequences of Proteins of Immunological Interest, 4^th ed., Bethesda, MD: U.S. Dept of Flealth and Human Services, Public Health Service, National Institutes of Health (1987)). These expressions include the hypervariable regions as defined by Kabat et ai, ( Sequences of Proteins of Immunological Interest, NIH Publication No. 91-3242, Bethesda, MD: U.S. Dept of Health and Human Services, National Institutes of Health (1983)) or the hypervariable loops in 3-dimensional structures of antibodies (Chothia and Lesk, J.

Mol. Biol., 196:901-917 (1987)). The CDRs in each chain are held in close proximity by framework regions (“FRs”) and, with the CDRs from the other chain, contribute to the formation of the antigen binding site. Within the CDRs there are select amino acids that have been described as the selectivity determining regions (“SDRs”) that represent the critical contact residues used by the CDR in the antibody-antigen interaction ( see Kashmiri et al, Methods, 36(l):25-34 (2005)).

[0341] An "epitope" or "binding site" is an area or region on an antigen to which an antigen-binding peptide (such as an antibody) specifically binds. A protein epitope may comprise amino acid residues directly involved in the binding (also called immunodominant component of the epitope) and other amino acid residues, which are not directly involved in the binding, such as amino acid residues that are effectively blocked by the specifically antigen binding peptide (in other words, the amino acid residue is within the "footprint" of the specifically antigen binding peptide). The term epitope herein includes both types of amino acid binding sites in any particular region of CoV-S, e.g., SARS-CoV-S or SARS-CoV-2-S, that specifically binds to an anti-CoV-S antibody. CoV-S may comprise a number of different epitopes, which may include, without limitation, (1) linear peptide antigenic determinants, (2) conformational antigenic determinants that consist of one or more non-contiguous amino acids located near each other in a mature CoV-S conformation; and (3) post-translational antigenic determinants that consist, either in whole or part, of molecular structures covalently attached to a CoV-S protein such as carbohydrate groups. In particular, the term “epitope” includes the specific residues in a protein or peptide, e.g., CoV-S, which are involved in the binding of an antibody to such protein or peptide as determined by known and accepted methods such as alanine scanning techniques or the use of various S protein portions with varying lengths.

[0342] The phrase that an antibody (e.g., first antibody) binds "substantially" or "at least partially" the same epitope as another antibody (e.g., second antibody) means that the epitope binding site for the first antibody comprises at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more of the amino acid residues on the antigen that constitutes the epitope binding site of the second antibody. Also, that a first antibody binds substantially or partially the same or overlapping epitope as a second antibody means that the first and second antibodies compete in binding to the antigen, as described above. Thus, the term "binds to substantially the same epitope or determinant as" a monoclonal antibody means that an antibody "competes" with the antibody.

[0343] The phrase "binds to the same or overlapping epitope or determinant as" an antibody of interest means that an antibody "competes" with said antibody of interest for at least one, (e.g., at least 2, at least 3, at least 4, at least 5) or all residues on CoV-S to which said antibody of interest specifically binds. The identification of one or more antibodies that bind(s) to substantially or essentially the same epitope as the monoclonal antibodies described herein can be readily determined using alanine scanning. Additionally, any one of variety of immunological screening assays in which antibody competition can be assessed. A number of such assays are routinely practiced and well known in the art (see, e.g., U.S. Patent No. 5,660,827, issued Aug. 26, 1997, which is specifically incorporated herein by reference). It will be understood that actually determining the epitope to which an antibody described herein binds is not in any way required to identify an antibody that binds to the same or substantially the same or overlapping epitope as the monoclonal antibody described herein. [0344] For example, where the test antibodies to be examined are obtained from different source animals, or are even of a different Ig isotype, a simple competition assay may be employed in which the control antibody is mixed with the test antibody and then applied to a sample containing CoV-S. Protocols based upon ELISAs, radioimmunoassays, Western blotting, and the use of BIACORE®

(GE Healthcare Life Sciences, Marlborough, MA) analysis are suitable for use in such simple competition studies.

[0345] In certain embodiments, the control anti-CoV-S antibody is pre-mixed with varying amounts of the test antibody (e.g., in ratios of about 1:1, 1:2, 1:10, or about 1:100) for a period of time prior to applying to the CoV-S (e.g., SARS-CoV-S or SARS-CoV-2-S) antigen sample. In other embodiments, the control and varying amounts of test antibody can simply be added separately and admixed during exposure to the SARS-CoV-S or SARS-CoV-2-S antigen sample. As long as bound antibodies can be distinguished from free antibodies (e.g., by using separation or washing techniques to eliminate unbound antibodies) and control antibody from the test antibody (e.g., by using species specific or isotype specific secondary antibodies or by specifically labeling the control antibody with a detectable label) it can be determined if the test antibody reduces the binding of the control antibody to the SARS-CoV-S or SARS-CoV-2-S antigens, indicating that the test antibody recognizes substantially the same epitope as the control anti-CoV-S antibody. The binding of the (labeled) control antibody in the presence of a completely irrelevant antibody (that does not bind CoV-S) can serve as the control high value. The control low value can be obtained by incubating the labeled control antibody with the same but unlabeled control antibody, where competition would occur and reduce binding of the labeled antibody. In a test assay, a significant reduction in labeled antibody reactivity in the presence of a test antibody is indicative of a test antibody that recognizes substantially the same epitope, i.e., one that competes with the labeled control antibody. For example, any test antibody that reduces the binding of the control antibody to SARS-CoV-S or SARS-CoV-2-S by at least about 50%, such as at least about 60%, or more preferably at least about 70% (e.g., about 65-100%), at any ratio of test antibody between about 1:1 or 1:10 and about 1:100 is considered to be an antibody that binds to substantially the same or overlapping epitope or determinant as the control antibody.

[0346] Preferably, such test antibody will reduce the binding of the control antibody to SARS-CoV-S or SARS-CoV-2-S (or another CoV-S) antigen preferably at least about 50%, at least about 60%, at least about 80%, or at least about 90% (e.g., about 95%) of the binding of the control antibody observed in the absence of the test antibody.

[0347] A simple competition assay in which a test antibody is applied at saturating concentration to a surface onto which SARS-CoV-S or SARS-CoV-2-S (or another CoV-S) is immobilized also may be advantageously employed. The surface in the simple competition assay is preferably a BIACORE® (GE Healthcare Life Sciences, Marlborough, MA) chip (or other media suitable for surface plasmon resonance (“SPR”) analysis). The binding of a control antibody that binds SARS-CoV-S or SARS- CoV-2-S to the COV-S-coated surface is measured. This binding to the SARS-CoV-S- or SARS- CoV -2 -S -containing surface of the control antibody alone is compared with the binding of the control antibody in the presence of a test antibody. A significant reduction in binding to the SARS-CoV-S- or S ARS -Co V -2 -S -containing surface by the control antibody in the presence of a test antibody indicates that the test antibody recognizes substantially the same epitope as the control antibody such that the test antibody "competes" with the control antibody. Any test antibody that reduces the binding of control antibody by at least about 20% or more, at least about 40%, at least about 50%, at least about 70%, or more, can be considered to be an antibody that binds to substantially the same epitope or determinant as the control antibody. Preferably, such test antibody will reduce the binding of the control antibody to SARS-CoV-S or SARS-CoV-2-S by at least about 50% (e.g., at least about 60%, at least about 70%, or more). It will be appreciated that the order of control and test antibodies can be reversed; i.e. the control antibody can be first bound to the surface and then the test antibody is brought into contact with the surface thereafter in a competition assay. Preferably, the “sandwich- style” binding assay infra is used. Alternatively, the antibody having greater affinity for SARS-CoV-S or SARS-CoV-2-S antigen is bound to the SARS-CoV-S- or SARS-CoV-2-S-containing surface first, as it will be expected that the decrease in binding seen for the second antibody (assuming the antibodies are competing) will be of greater magnitude. Further examples of such assays are provided in e.g., Saunal and Regenmortel, J. Immunol. Methods, 183:33-41 (1995), the disclosure of which is incorporated herein by reference.

[0348] In addition, whether an antibody binds the same or overlapping epitope(s) on COV-S as another antibody or the epitope bound by a test antibody may in particular be determined using a Western-blot based assay. In this assay a library of peptides corresponding to the antigen bound by the antibody, the CoV-S protein, is made, that comprise overlapping portions of the protein, typically 10- 25, 10-20, or 10-15 amino acids long. These different overlapping amino acid peptides encompassing the CoV-S sequence are synthesized and covalently bound to a PEPSPOTS™ nitrocellulose membrane (JPT Peptide Technologies, Berlin, Germany). Blots are then prepared and probed according to the manufacturer's recommendations.

[0349] Essentially, the immunoblot assay then detects by fluorometric means what peptides in the library bind to the test antibody and thereby can identify what residues on the antigen, i.e., COV-S, interact with the test antibody. (See U.S. Patent No. 7,935,340, incorporated by reference herein). [0350] Various epitope mapping techniques are known in the art. By way of example, X-ray co- crystallography of the antigen and antibody; NMR; SPR (e.g., at 25° or 37°C); array-based oligo peptide scanning (or “pepscan analysis”); site -directed mutagenesis (e.g., alanine scanning); mutagenesis mapping; hydrogen-deuterium exchange; phage display; and limited proteolysis are all epitope mapping techniques that are well known in the art (See, e.g., Epitope Mapping Protocols: Second Edition, Methods in Molecular Biology, , editors Mike Schutkowski and Ulrich Reineke, 2^nd Ed., New York, NY: Humana Press (2009), and Epitope Mapping Protocols, Methods in Molecular Biology, editor Glenn Morris, 1^st Ed., New York, NY: Humana Press (1996), both of which are herein incorporated by referenced in their entirety).

[0351] The identification of one or more antibodies that bind(s) to substantially or essentially the same epitope as the monoclonal antibodies described herein, e.g., any one of antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, ADI-58131, can be readily determined using any one of variety of immunological screening assays in which antibody competition can be assessed. A number of such assays are routinely practiced and well known in the art (see, e.g., U.S. Patent No. 5,660,827, issued Aug. 26, 1997, which is incorporated herein by reference). It will be understood that determining the epitope to which an antibody described herein binds is not in any way required to identify an antibody that binds to the same or substantially the same epitope as the monoclonal antibody described herein.

[0352] For example, where the test antibodies to be examined are obtained from different source animals, or are even of a different Ig isotype, a simple competition assay may be employed in which the control antibody (one of antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, ADI-58131, for example) is mixed with the test antibody and then applied to a sample containing either or both SARS-CoV-S or SARS-CoV-2-S, each of which is known to be bound by antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, ADI-58131. Protocols based upon ELISAs, radioimmunoassays, Western blotting, and BIACORE® (GE Healthcare Life Sciences, Marlborough, MA) analysis (as described in the Examples section herein) are suitable for use in such simple competition studies.

[0353] In certain embodiments, the method comprises pre-mixing the control antibody with varying amounts of the test antibody (e.g., in ratios of about 1:1, 1:2, 1:10, or about 1:100) for a period of time prior to applying to the CoV-S antigen sample. In other embodiments, the control and varying amounts of test antibody can be added separately and admixed during exposure to the CoV-S antigen sample. As long as bound antibodies can be distinguished from free antibodies (e.g., by using separation or washing techniques to eliminate unbound antibodies) and control antibody from the test antibody (e.g., by using species specific or isotype specific secondary antibodies or by specifically labelling the control antibody with a detectable label), the method can be used to determine that the test antibody reduces the binding of the control antibody to the COV-S antigen, indicating that the test antibody recognizes substantially the same epitope as the control antibody (e.g., antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI- 58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, ADI-58131). The binding of the (labeled) control antibody in the presence of a completely irrelevant antibody (that does not bind CoV-S) can serve as the control high value. The control low value can be obtained by incubating the labeled control antibody with the same but unlabeled control antibody, where competition would occur and reduce binding of the labeled antibody. In a test assay, a significant reduction in labeled antibody reactivity in the presence of a test antibody is indicative of a test antibody that recognizes substantially the same epitope, i.e., one that competes with the labeled control antibody. For example, any test antibody that reduces the binding of any one of antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI- 58127, ADI-58128, ADI-58129, ADI-58130, ADI-58131, to both of SARS-CoV-S or SARS-CoV-2-S antigens by at least about 50%, such as at least about 60%, or more preferably at least about 70%

(e.g., about 65-100%), at any ratio of control antibody selected from the group consisting of ADI- 58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI- 58128, ADI-58129, ADI-58130, ADI-58131, test antibody between about 1:1 or 1:10 and about 1:100 is considered to be an antibody that binds to substantially the same epitope or determinant as any one of antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, ADI-58131, respectively. Preferably, such test antibody will reduce the binding of any one of antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI- 58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, ADI-58131, to at least one, preferably each, of the SARS-CoV-S or SARS-CoV-2-S antigens preferably at least about 50%, at least about 60%, at least about 80% or at least about 90% (e.g., about 95%) of the binding of any one of antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, ADI-58131, observed in the absence of the test antibody. These methods can be adapted to identify and/or evaluate antibodies that compete with other control antibodies.

[0354] A simple competition assay in which a test antibody is applied at saturating concentration to a surface onto which either SARS-CoV-S or SARS-CoV-2-S, or both, are immobilized also may be advantageously employed. The surface in the simple competition assay is preferably of a media suitable for OCTET® and/or PROTEON®. The binding of a control antibody (e.g., any one of antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, ADI-58131) to the CoV-S-coated surface is measured. This binding to the CoV-S-containing surface of the control antibody alone is compared with the binding of the control antibody in the presence of a test antibody. A significant reduction in binding to the CoV-S-containing surface by the control antibody in the presence of a test antibody indicates that the test antibody recognizes substantially the same epitope as the control antibody such that the test antibody "competes" with the control antibody. Any test antibody that reduces the binding of control antibody (such as anyone of antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI- 58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, ADI-58131) to both of SARS-CoV-S and SARS-CoV-2-S antigens by at least about 20% or more, at least about 40%, at least about 50%, at least about 70%, or more, can be considered to be an antibody that binds to substantially the same epitope or determinant as the control antibody (e.g., any one of antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, ADI-58131). Preferably, such test antibody will reduce the binding of the control antibody (e.g., any one of antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, ADI-58131) to the CoV-S antigen by at least about 50% (e.g., at least about 60%, at least about 70%, or more). It will be appreciated that the order of control and test antibodies can be reversed; i.e. the control antibody can be first bound to the surface and then the test antibody is brought into contact with the surface thereafter in a competition assay. Preferably, the antibody having higher affinity for SARS-CoV-S and SARS-CoV-2-S is bound to the CoV-S-containing surface first, as it will be expected that the decrease in binding seen for the second antibody (assuming the antibodies are competing) will be of greater magnitude. Further examples of such assays are provided in, e.g., Saunal and Regenmortel, J. Immunol. Methods, 183:33-41 (1989), the disclosure of which is incorporated herein by reference.

[0355] Determination of whether an antibody, antigen-binding fragment thereof, or antibody derivative, e.g., an affinity-matured antibody or antigen binding fragment of any of the anti-CoV-S antibodies exemplified herein, binds within one of the epitope regions defined above can be carried out in ways known to the person skilled in the art. In another example of such mapping/characterization methods, an epitope region for an anti-CoV-S antibody may be determined by epitope "footprinting" using chemical modification of the exposed amines/carboxyls in the SARS- CoV-S and SARS-CoV-2-S protein. One specific example of such a foot-printing technique is the use of hydrogen-deuterium exchange detected by mass spectrometry (“HXMS”), wherein a hydrogen/deuterium exchange of receptor and ligand protein amide protons, binding, and back exchange occurs, wherein the backbone amide groups participating in protein binding are protected from back exchange and therefore will remain deuterated. Relevant regions can be identified at this point by peptic proteolysis, fast microbore high-performance liquid chromatography separation, and/or electrospray ionization mass spectrometry (See, e.g., Ehring H., Analytical Biochemistry, 267(2):252-259 (1999) and Engen, J. R. & Smith, D. L., Anal. Chem., 73:256A-265A (2001)). Another example of a suitable epitope identification technique is nuclear magnetic resonance epitope mapping (“NMR”), where typically the position of the signals in two-dimensional NMR spectras of the free antigen and the antigen complexed with the antigen binding peptide, such as an antibody, are compared. The antigen typically is selectively isotopically labeled with ¹⁵N so that only signals corresponding to the antigen and no signals from the antigen binding peptide are seen in the NMR- spectrum. Antigen signals originating from amino acids involved in the interaction with the antigen binding peptide typically will shift position in the spectras of the complex compared to the spectras of the free antigen, and the amino acids involved in the binding can be identified that way. See, e.g., Ernst Sobering Res. Found. Workshop, (44):149-67 (2004); Huang etal., J. Mol. Biol., 281(1):61 -67 (1998); and Saito and Patterson, Methods, 9(3):516-24 (1996). Epitope mapping/characterization also can be performed using mass spectrometry (“MS”) methods {See, e.g., Downard, J. Mass Spectrom., 35(4):493-503 (2000) and Kiselar and Downard, Anal. Chem., 71(9):1792-801 (1999)).

[0356] Protease digestion techniques also can be useful in the context of epitope mapping and identification. Antigenic determinant-relevant regions/sequences can be determined by protease digestion, e.g. by using trypsin in a ratio of about 1:50 to SARS-CoV-S or SARS-CoV-2-S overnight (“o/n”) digestion at 37°C and pH 7-8, followed by mass spectrometry (“MS”) analysis for peptide identification. The peptides protected from trypsin cleavage by the anti-CoV-S antibody can subsequently be identified by comparison of samples subjected to trypsin digestion and samples incubated with antibody and then subjected to digestion by e.g. trypsin (thereby revealing a footprint for the antibody). Other enzymes like chymotrypsin or pepsin can be used in similar epitope characterization methods. Moreover, enzymatic digestion can provide a quick method for analyzing whether a potential antigenic determinant sequence is within a region of CoV-S in the context of a CoV-S-binding polypeptide. If the polypeptide is not surface exposed, it is most likely not relevant in terms of immunogenicity/antigenicity {See, e.g., Manca, Ann. 1st. Super. Sanita., 27(1): 15-9 (1991) for a discussion of similar techniques).

[0357] Site -directed mutagenesis is another technique useful for characterization of a binding epitope. For example, in "alanine-scanning" site -directed mutagenesis (also known as alanine scanning, alanine scanning mutagenesis, alanine scanning mutations, combinatorial alanine scanning, or creation of alanine point mutations, for example), each residue within a protein segment is replaced with an alanine residue (or another residue such as valine where alanine is present in the wild-type sequence) through such methodologies as direct peptide or protein synthesis, site-directed mutagenesis, the GENEART™ Mutagenesis Service (Thermo Fisher Scientific, Waltham, MA U.S.A.) or shotgun mutagenesis, for example. A series of single point mutants of the molecule is thereby generated using this technique; the number of mutants generated is equivalent to the number of residues in the molecule, each residue being replaced, one at a time, by a single alanine residue. Alanine is generally used to replace native (wild-type) residues because of its non-bulky, chemically inert, methyl functional group that can mimic the secondary structure preferences that many other amino acids may possess. Subsequently, the effects replacing a native residue with an alanine has on binding affinity of an alanine scanning mutant and its binding partner can be measured using such methods as, but not limited to, SPR binding experiments. If a mutation leads to a significant reduction in binding affinity, it is most likely that the mutated residue is involved in binding. Monoclonal antibodies specific for structural epitopes (i.e., antibodies that do not bind the unfolded protein) can be used as a positive control for binding affinity experiments to verify that the alanine -replacement does not influence the overall tertiary structure of the protein (as changes to the overall fold of the protein may indirectly affect binding and thereby produce a false positive result). See, e.g., Clackson and Wells, Science, 267:383-386 (1995); Weiss et al, Proc. Natl. Acad. Sci. USA, 97(16):8950-8954 (2000); and Wells, Proc. Natl. Acad. Sci. USA, 93:1-6 (1996). Example 5 identifies the specific epitope or residues of CoV-S which specifically interact with the anti-CoV-S antibodies disclosed herein.

[0358] Electron microscopy can also be used for epitope "footprinting". For example, Wang et al. , Nature, 355:275-278 (1992) used coordinated application of cryoelectron microscopy, three- dimensional image reconstruction, and X-ray crystallography to determine the physical footprint of a Fab-fragment on the capsid surface of native cowpea mosaic virus.

[0359] Other forms of "label-free" assay for epitope evaluation include SPR (sold commercially as the BIACORE® system, GE Healthcare Life Sciences, Marlborough, MA) and reflectometric interference spectroscopy (“RifS”) (See, e.g., Fagerstam et al, Journal of Molecular Recognition, 3:208-14 (1990); Nice et al, J. Chromatogr., 646:159-168 (1993); Leipert et al, Angew. Chem. Int. Ed., 37:3308-3311 (1998); Kroger et al, Biosensors and Bioelectronics, 17:937-944 (2002)).

[0360] The expressions “framework region” or “FR” refer to one or more of the framework regions within the variable regions of the light and heavy chains of an antibody ( See Rabat et al. , Sequences of Proteins of Immunological Interest, 4^th edition, Bethesda, MD: U.S. Dept of Health and Human Services, Public Health Service, National Institutes of Health (1987)). These expressions include those amino acid sequence regions interposed between the CDRs within the variable regions of the light and heavy chains of an antibody.

[0361] The term "Fc region" is used to define a C-terminal region of an immunoglobulin heavy chain. The "Fc region" may be a native sequence Fc region or a variant Fc region. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof. The numbering of the residues in the Fc region is that of the EU index as in Rabat. Rabat et al, Sequences of Proteins of Immunological Interest, 5th edition, Bethesda, MD: U.S. Dept of Health and Human Services, Public Health Service, National Institutes of Health (1991). The Fc region of an immunoglobulin generally comprises two constant domains, Cm and CH3.

[0362] The terms "Fc receptor" and "FcR" describe a receptor that binds to the Fc region of an antibody. The preferred FcR is a native sequence human FcR. Moreover, a preferred FcR is one that binds an IgG antibody (a gamma receptor) and includes receptors of the FcyRI, FcyRII, and FcyRIII subclasses, including allelic variants and alternatively spliced forms of these receptors. FcyRII receptors include FcyRIIA (an "activating receptor") and FcyRIIB (an "inhibiting receptor"), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. FcRs are reviewed in Ravetch and Kinet, Ann. Rev. Immunol., 9:457-92 (1991); Capel et al, Immunomethods, 4:25-34 (1994); and de Haas et al, J. Lab. Clin. Med., 126:330-41 (1995). "FcR" also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al, J. Immunol., 117:587 (1976); and Kim et al, J. Immunol., 24:249 (1994)), and which primarily functions to modulate and/or extend the half-life of antibodies in circulation. To the extent that the disclosed anti-CoV-S antibodies are aglycosylated, as a result of the expression system and/or sequence, the subject antibodies are expected to bind FcRn receptors, but not to bind (or to minimally bind) Fey receptors.

[0363] A "functional Fc region" possesses at least one effector function of a native sequence Fc region. Exemplary "effector functions" include Clq binding; complement dependent cytotoxicity (“CDC”); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (“ADCC”); phagocytosis; down-regulation of cell surface receptors (e.g. B cell receptor (“BCR”)), etc. Such effector functions generally require the Fc region to be combined with a binding domain (e.g. an antibody variable domain) and can be assessed using various assays known in the art for evaluating such antibody effector functions.

[0364] A "native sequence Fc region" comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature. A "variant Fc region" comprises an amino acid sequence that differs from that of a native sequence Fc region by virtue of at least one amino acid modification, yet retains at least one effector function of the native sequence Fc region. Preferably, the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or to the Fc region of a parent polypeptide, e.g. from about one to about ten amino acid substitutions, and preferably from about one to about five amino acid substitutions in a native sequence Fc region or in the Fc region of the parent polypeptide. The variant Fc region herein will preferably possess at least about 80% sequence identity with a native sequence Fc region and/or with an Fc region of a parent polypeptide, and most preferably at least about 90% sequence identity therewith, more preferably at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity therewith. [0365] In some embodiments, the Fc region of an antibody or antigen-binding antibody fragment of the present disclosure may bind to an Fc receptor (FcR). The FcR may be, but is not limited to, Fc gamma receptor (FcgR), FcgRI, FcgRIIA, FcgRIIBl, FcgRIIB2, FcgRIIIA, FcgRIIIB, Fc epsilon receptor (FceR), FceRI, FceRII, Fc alpha receptor (FcaR), FcaRI, Fc alpha/mu receptor (Fca/mR), or neonatal Fc receptor (FcRn). The Fc may be an IgM, IgD, IgG, IgE, or IgA isotype. An IgG isotype may be an IgGl, IgG2, IgG3, or IgG4.

[0366] Certain amino acid modifications in the Fc region are known to modulate Ab effector functions and properties, such as, but not limited to, antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement dependent cytotoxicity (CDC), and half -life (Wang X. et ah, Protein Cell. 2018 Jan; 9(1): 63-73; DalFAcqua W. F. et ah, J Biol Chem. 2006 Aug 18;281(33):23514-24. Epub 2006 Jun 21; Monnet C. et al, Front Immunol. 2015 Feb 4;6:39. doi: 10.3389/fimmu.2015.00039. eCollection 2015). The mutation may be symmetrical or asymmetrical. In certain cases, antibodies with Fc regions that have asymmetrical mutation(s) (i.e., two Fc regions are not identical) may provide better functions such as ADCC (Fiu Z. et al. J Biol Chem. 2014 Feb 7; 289(6): 3571-3590).

[0367] Any of the antibody variable region sequences disclosed herein may be used in combination with a wild-type (WT) Fc or a variant Fc. In particular embodiments, an Fc selected from the Fc sequences described in Table 9 may be used. Any of the variable region sequences disclosed herein may be used in combination with any appropriate Fc including any of the Fc variants provided in Table 9 to form an antibody or an antigen-binding antibody fragment of the present disclosure. The lysine (K) at the C-terminus of each Fc may be present or absent.

[0368] An IgGl -type Fc optionally may comprise one or more amino acid substitutions. Such substitutions may include, for example, N297A, N297Q, D265A, F234A, F235A, C226S, C229S, P238S, E233P, F234V, G236-deleted, P238A, A327Q, A327G, P329A, K322A, F234F, F235E, P331S, T394D, A330F, P331S, F243F, R292P, Y300F, V305I, P396F, S239D, I332E, S298A, E333A, K334A, F234Y, F235Q, G236W, S239M, H268D, D270E, K326D, A330M, K334E, G236A, K326W, S239D, E333S, S267E, H268F, S324T, E345R, E430G, S440Y, M428F, N434S, F328F, M252Y, S254T, T256E, and/or any combination thereof (the residue numbering is according to the EU index as in Rabat) (DalFAcqua W. F. et ah, J Biol Chem. 2006 Aug 18;281(33):23514-24. Epub 2006 Jun 21; Wang X. et al, Protein Cell. 2018 Jan; 9(1): 63-73), or for example, N434A, Q438R, S440E, F432D, N434F, and/or any combination thereof (the residue numbering according to EU numbering). The Fc region may further comprise one or more additional amino acid substitutions. Such substitutions may include but are not limited to A330F, F234F, F235E, P3318, and/or any combination thereof (the residue numbering is according to the EU index as in Rabat). Specific exemplary substitution combinations for an IgGl -type Fc include, but not limited to: M252Y, S254T, and T256E (“YTE” variant); M428F and N434A (“FA” variant), M428F and N434S (“LS” variant); M428L, N434A, Q438R, and S440E (“LA-RE” variant); L432D and N434L (“DEL” variant); and L234A, L235A, L432D, and N434L (“LALA-DEL” variant) (the residue numbering is according to the EU index as in Rabat). In particular embodiments, an IgGl-type Fc variant may comprise the amino acid sequence of SEQ ID NOS: 411, 412, 413, 414, 415, 416, or 417. In one embodiment, the Fc variant is an LA variant and comprises the amino acid sequence of SEQ ID NO: 413.

[0369] When the Ab is an IgG2, the Fc region optionally may comprise one or more amino acid substitutions. Such substitutions may include but are not limited to P238S, V234A, G237A, H268A, H268Q, H268E, V309L, N297A, N297Q, A330S, P331S, C232S, C233S, M252Y, S254T, T256E, and/or any combination thereof (the residue numbering is according to the EU index as in Rabat). The Fc region optionally may further comprise one or more additional amino acid substitutions. Such substitutions may include but are not limited to M252Y, S254T, T256E, and/or any combination thereof (the residue numbering is according to the EU index as in Rabat).

[0370] An IgG3-type Fc region optionally may comprise one or more amino acid substitutions. Such substitutions may include but are not limited to E235Y (the residue numbering is according to the EU index as in Rabat).

[0371] An IgG4-type Fc region optionally may comprise one or more amino acid substitutions. Such substitutions may include but are not limited to, E233P, F234V, L235A, G237A, E318A, S228P, L236E, S241P, L248E, T394D, M252Y, S254T, T256E, N297A, N297Q, and/or any combination thereof (the residue numbering is according to the EU index as in Rabat). The substitution may be, for example, S228P (the residue numbering is according to the EU index as in Rabat).

[0372] In some cases, the glycan of the hum an -like Fc region may be engineered to modify the effector function (for example, see Li T. et al, Proc Natl Acad Sci USA. 2017 Mar 28; 114(13):3485- 3490. doi: 10.1073/pnas.l702173114. Epub 2017 Mar 13).

[0373] An “isolated” antibody, as used herein, refers to an antibody that is substantially free of other antibodies having different antigenic specificities. In some embodiments, an isolated antibody is substantially free of other unintended cellular material and/or chemicals.

[0374] As used herein, “specific binding” or “specifically binds” means that the interaction of the antibody, or antigen-binding portion thereof, with an antigen is dependent upon the presence of a particular structure (e.g., antigenic determinant or epitope). For example, the antibody, or antigen binding portion thereof, binds to a specific protein, rather than proteins generally. In some embodiments, an antibody, or antigen-binding portion thereof, specifically binds a target, e.g., SARS- CoV-S and/or SARS-CoV-S-2. In some embodoiments, an antibody, or antigen-binding portion thereof, specifically binds to more than one coronavirus spike protein, e.g., the spike protein of SARS-CoV-S and the spike protein of SARS-CoV-2-S, for example. In some embodiments, the antibody, or antigen-binding portion thereof, specifically binds to two different, but related, antigens, e.g., the spike protein of SARS-CoVl-S and the spike protein of SARS-CoV2-S, e.g., via a conserved epitope.

B. Anti-CoV-S Antibodies and Binding Fragments Thereof Having Binding Activity for CoV-S [0375] CoV-S refers to the S protein of a coronavirus which is expressed on the surface of virions as a structural protein. As mentioned previously, the S protein plays an essential role for coronaviruses in binding to receptors on the host cell and determines host tropism (Zhu Z. et al. , Infect Genet Evol. 2018 Jul;61 : 183-184). SARS-CoV and SARS-CoV-2 bind to angiotensin-converting enzyme 2 (ACE2) of the host cell via the S protein’s receptor-binding domains (RBDs) and uses ACE2 as a receptor to enter the host cells (Ge X.Y. et al, Nature. 2013 Nov 28;503(7477):535-8. doi:

10.1038/nature 12711. Epub 2013 Oct 30.; Hoffmann M. et al., Cell. 2020 Mar 4. pii: S0092- 8674(20)30229-4). SARS-CoV can also use CD209L (also known as L-SIGN) as an alternative receptor (Jeffers S. A. et al, Proc Natl Acad Sci USA. 2004 Nov 2;101(44):15748-53. Epub 2004 Oct 20). MERS-CoV binds dipeptidyl peptidase 4 (“DPP4”, also known as CD26) of the host cells via a different RBD of the S protein. Cell entry of coronaviruses depends on not only binding of the S protein to a host cell receptor but often also priming of the S protein by host cell proteases, and recently SARS-CoV-2 was found to use the serine protease TMPRSS2 for S protein priming and then ACE2 for entry (Wu A. et al, Cell Host Microbe. 2020 Mar ll;27(3):325-328; Hoffmann M. et al, Cell. 2020 Mar 4. pii: S0092-8674(20)30229-4).

[0376] The S protein of SARS-CoV is referred to as SARS-CoV-S and may for example comprise the amino acid sequence of SEQ ID NO: 401 (1288 amino acids). The S protein of SARS-CoV-2 is referred to as SARS-CoV -2-S and may for example comprise the amino acid sequence of SEQ ID NO: 403 (1273 amino acids).

[0377] The present disclosure provides exemplary antibodies and antigen-binding antibody fragments that specifically bind to CoV, wherein at least some of these antibodies and antigen-binding antibody fragments specifically bind to SARS-CoV -2-S and/or SARS-CoV-2-S. Due to the sequence similarity among different CoV species, such antibodies or antigen-binding antibody fragments of the present disclosure may also cross react with the S protein of other CoV species.

[0378] The exemplary S proteins of CoV that the antibodies or antigen-binding antibody fragments of the present disclosure may specifically bind include by way of example, Bat SARS CoV (GenBank Accession No. FJ211859), SARS CoV (GenBank Accession No. FJ211860), BtSARS.HKU3.1 (GenBank Accession No. DQ022305), BtSARS.HKU3.2 (GenBank Accession No. DQ084199), BtSARS.HKU3.3 (GenBank Accession No. DQ084200), BtSARS.Rml (GenBank Accession No. DQ412043), BtCoV.279.2005 (GenBank Accession No. DQ648857), BtSARS.Rfl (GenBank Accession No. DQ412042), BtCoV.273.2005 (GenBank Accession No. DQ648856), BtSARS.Rp3 (GenBank Accession No. DQ071615), SARS CoV.A022 (GenBank Accession No. AY686863), SARSCoV.CUHK-W 1 (GenBank Accession No. AY278554), SARSCoV.GDOl (GenBank Accession No. AY278489), SARSCoV.HC.SZ.61.03 (GenBank Accession No. AY515512), SARSC0V.SZI6 (GenBank Accession No. AY304488), SARSCoV.Urbani (GenBank Accession No. AY278741), SARSCoV.civetOlO (GenBank Accession No. AY572035), or SARSCoV.MA.15 (GenBank Accession No. DQ497008), Rs SHC014 (GenBank® Accession No. KC881005), Rs3367 (GenBank® Accession No. KC881006), WiVl S (GenBank® Accession No. KC881007).

[0379] In some embodiments, the antibodies and antigen-binding antibody fragments provided herein may also bind to and neutralize existing bat CoV or pre-emergent bat CoVs. Antibodies and antigen binding antibody fragments with such binding and/or neutralization abilities would be particularly useful in a future pandemic that may be caused by a spillover from an animal reservoir, like a bat. In fact, ADI-55688, ADI-55689, ADI-55993, ADI-5600, ADI-56046, ADI-55690, ADI-56010, and ADI-55951 were shown to neutralize authentic bat coronavirus, WIV1 (see Figure 3E of Wee A. et al, Science. 2020 Jun 15;eabc7424. doi: 10.1126/science.abc7424).

[0380] Alternatively, the S proteins of CoV to which the antibodies or antigen-binding antibody fragments of the present disclosure may specifically bind to and neutralize pre-emergent coronaviruses from other species, e.g., bats.

[0381] Still alternatively, the S proteins of CoV to which the antibodies or antigen-binding antibody fragments of the present disclosure may specifically bind to may include, for example, Middle East respiratory syndrome coronavirus isolate Riyadh_2_2012 (GenBank Accession No. KF600652.1), Middle East respiratory syndrome coronavirus isolate Al-Hasa_18_2013 (GenBank Accession No. KF600651.1), Middle East respiratory syndrome coronavirus isolate Al-Hasa_17_2013 (GenBank Accession No. KF600647.1), Middle East respiratory syndrome coronavirus isolate Al-Hasa_15_2013 (GenBank Accession No. KF600645.1), Middle East respiratory syndrome coronavirus isolate Al- Hasa_16_2013 (GenBank Accession No. KF600644.1), Middle East respiratory syndrome coronavirus isolate Al-Hasa_21_2013 (GenBank Accession No. KF600634), Middle East respiratory syndrome coronavirus isolate Al-Hasa_19_2013 (GenBank Accession No. KF600632), Middle East respiratory syndrome coronavirus isolate Buraidah_l_2013 (GenBank Accession No. KF600630.1), Middle East respiratory syndrome coronavirus isolate Hafr-Al-Batin_l_2013 (GenBank Accession No. KF600628.1), Middle East respiratory syndrome coronavirus isolate Al-Hasa_12_2013 (GenBank Accession No. KF600627.1), Middle East respiratory syndrome coronavirus isolate Bisha_l_2012 (GenBank Accession No. KF600620.1), Middle East respiratory syndrome coronavirus isolate Riyadh_3_2013 (GenBank Accession No. KF600613.1), Middle East respiratory syndrome coronavirus isolate Riyadh_l_2012 (GenBank Accession No. KF600612.1), Middle East respiratory syndrome coronavirus isolate Al-Hasa_3_2013 (GenBank Accession No. KF186565.1), Middle East respiratory syndrome coronavirus isolate Al-Hasa_l_2013 (GenBank Accession No. KF186567.1), Middle East respiratory syndrome coronavirus isolate Al-Hasa_2_2013 (GenBank Accession No. KF186566.1), Middle East respiratory syndrome coronavirus isolate Al-Hasa_4_2013 (GenBank Accession No. KF186564.1), Middle East respiratory syndrome coronavirus (GenBank Accession No. KF192507.1), Betacoronavirus England 1-Nl (GenBank Accession No. NC_019843), MERS- CoV_SA-Nl (GenBank Accession No. KC667074), following isolates of Middle East Respiratory Syndrome Coronavirus (GenBank Accession No: KF600656.1, GenBank Accession No: KF600655.1, GenBank Accession No: KF600654.1, GenBank Accession No: KF600649.1, GenBank Accession No: KF600648.1, GenBank Accession No: KF600646.1, GenBank Accession No: KF600643.1, GenBank Accession No: KF600642.1, GenBank Accession No: KF600640.1, GenBank Accession No: KF600639.1, GenBank Accession No: KF600638.1, GenBank Accession No: KF600637.1, GenBank Accession No: KF600636.1, GenBank Accession No: KF600635.1, GenBank Accession No: KF600631.1, GenBank Accession No: KF600626.1, GenBank Accession No: KF600625.1, GenBank Accession No: KF600624.1, GenBank Accession No: KF600623.1, GenBank Accession No: KF600622.1, GenBank Accession No: KF600621.1, GenBank Accession No: KF600619.1, GenBank Accession No: KF600618.1, GenBank Accession No: KF600616.1, GenBank Accession No: KF600615.1, GenBank Accession No: KF600614.1, GenBank Accession No: KF600641.1, GenBank Accession No: KF600633.1, GenBank Accession No: KF600629.1, GenBank Accession No: KF600617.1), Coronavirus Neoromicia/PML-PHEl/RSA/2011 GenBank Accession: KC869678.2, Bat Coronavirus Taper/CII_KSA_287/Bisha/Saudi Arabia/GenBank Accession No: KF493885.1, Bat coronavirus Rhhar/CII_KSA_003/Bisha/Saudi Arabia/2013 GenBank Accession No: KF493888.1, Bat coronavirus Pikuh/CII_KSA_001/Riyadh/Saudi Arabia/2013 GenBank Accession No: KF493887.1, Bat coronavirus Rhhar/CII_KSA_002/Bisha/Saudi Arabia/2013 GenBank Accession No: KF493886.1, Bat Coronavirus Rhhar/CII_KSA_004/Bisha/Saudi Arabia/2013 GenBank Accession No: KF493884.1, BtCoV.HKU4.2 (GenBank Accession No. EF065506), BtCoV.HKU4.1 (GenBank Accession No. NC_009019), BtCoV.HKU4.3 (GenBank Accession No. EF065507), BtCoV.HKU4.4 (GenBank Accession No. EF065508), BtCoV 133.2005 (GenBank Accession No. NC 008315), BtCoV.HKU5.5 (GenBank Accession No. EF065512); BtCoV.HKU5.1 (GenBank Accession No. NC_009020), BtCoV.HKU5.2 (GenBank Accession No. EF065510), BtCoV.HKU5.3 (GenBank Accession No. EF065511), human betacoronavirus 2c Jordan- N3/2012 (GenBank Accession No. KC776174.1; human betacoronavirus 2c EMC/2012 (GenBank Accession No. JX869059.2), Pipistrellus bat coronavirus HKU5 isolates (GenBank Accession No:KC522089.1, GenBank Accession No:KC522088.1, GenBank Accession No:KC522087.1, GenBank Accession No:KC522086.1, GenBank Accession No:KC522085.1, GenBank Accession No: KC522084.1, GenBank Accession No:KC522083.1, GenBank Accession No:KC522082.1, GenBank Accession No:KC522081.1, GenBank Accession No:KC522080.1, GenBank Accession No:KC522079.1, GenBank Accession No:KC522078.1, GenBank Accession No: KC522077.1, GenBank Accession No:KC522076.1, GenBank Accession No:KC522075.1, GenBank Accession No:KC522104.1, GenBank Accession No:KC522104.1, GenBank Accession No:KC522103.1, GenBank Accession No:KC522102.1, GenBank Accession No: KC522101.1, GenBank Accession No:KC522100.1, GenBank Accession No:KC522099.1, GenBank Accession No:KC522098.1, GenBank Accession No:KC522097.1, GenBank Accession No:KC522096.1, GenBank Accession No:KC522095.1, GenBank Accession No: KC522094.1, GenBank Accession No:KC522093.1, GenBank Accession No:KC522092.1, GenBank Accession No:KC522091.1, GenBank Accession No:KC522090.1, GenBank Accession No:KC522119.1 GenBank Accession No:KC522118.1 GenBank Accession No: KC522117.1 GenBank Accession No:KC522116.1 GenBank Accession No:KC522115.1 GenBank Accession No:KC522114.1 GenBank Accession No:KC522113.1 GenBank Accession No:KC522112.1 GenBank Accession No:KC522111.1 GenBank Accession No: KC522110.1 GenBank Accession No:KC522109.1 GenBank Accession No:KC522108.1, GenBank Accession No:KC522107.1, GenBank Accession No:KC522106.1, GenBank Accession No:KC522105.1) Pipistrellus bat coronavirus HKU4 isolates (GenBank Accession No:KC522048.1, GenBank Accession No:KC522047.1, GenBank Accession No:KC522046.1, GenBank Accession No:KC522045.1, GenBank Accession No: KC522044.1, GenBank Accession No:KC522043.1, GenBank Accession No:KC522042.1, GenBank Accession No:KC522041.1, GenBank Accession No:KC522040.1 GenBank Accession No:KC522039.1, GenBank Accession No:KC522038.1, GenBank Accession No:KC522037.1, GenBank Accession No:KC522036.1, GenBank Accession No:KC522048.1 GenBank Accession No:KC522047.1 GenBank Accession No:KC522046.1 GenBank Accession No:KC522045.1 GenBank Accession No:KC522044.1 GenBank Accession No:KC522043.1 GenBank Accession No:KC522042.1 GenBank Accession No:KC522041.1 GenBank Accession No:KC522040.1, GenBank Accession No:KC522039.1 GenBank Accession No:KC522038.1 GenBank Accession No:KC522037.1 GenBank Accession No:KC522036.1, GenBank Accession No:KC522061.1 GenBank Accession No:KC522060.1 GenBank Accession No:KC522059.1 GenBank Accession No:KC522058.1 GenBank Accession No:KC522057.1 GenBank Accession No:KC522056.1 GenBank Accession No:KC522055.1 GenBank Accession No:KC522054.1 GenBank Accession No:KC522053.1 GenBank Accession No:KC522052.1 GenBank Accession No:KC522051.1 GenBank Accession No:KC522050.1 GenBank Accession No:KC522049.1 GenBank Accession No:KC522074.1, GenBank Accession No:KC522073.1 GenBank Accession No:KC522072.1 GenBank Accession No:KC522071.1 GenBank Accession No:KC522070.1 GenBank Accession No:KC522069.1 GenBank Accession No:KC522068.1 GenBank Accession No:KC522067.1, GenBank Accession No:KC522066.1 GenBank Accession No:KC522065.1 GenBank Accession No:KC522064.1, GenBank Accession No:KC522063.1, or GenBank Accession No:KC522062.1.

[0382] Alternatively, the S proteins of CoV to which the antibodies or antigen-binding antibody fragments of the present disclosure may specifically bind may include for example, FCov.FIPV.79.1146.VR.2202 (GenBank Accession No. NV_007025), transmissible gastroenteritis virus (TGEV) (GenBank Accession No. NC_002306; GenBank Accession No. Q811789.2; GenBank Accession No. DQ811786.2; GenBank Accession No. DQ811788.1; GenBank Accession No. DQ811785.1; GenBank Accession No. X52157.1; GenBank Accession No. AJ011482.1; GenBank Accession No. KC962433.1; GenBank Accession No. AJ271965.2; GenBank Accession No. JQ693060.1; GenBank Accession No. KC609371.1; GenBank Accession No. JQ693060.1; GenBank Accession No. JQ693059.1; GenBank Accession No. JQ693058.1; GenBank Accession No. JQ693057.1; GenBank Accession No. JQ693052.1; GenBank Accession No. JQ693051.1; GenBank Accession No. JQ693050.1), or porcine reproductive and respiratory syndrome virus (PRRSV) (GenBank Accession No. NC_001961.1; GenBank Accession No. DQ811787).

[0383] Alternatively, the S proteins of CoV to which the antibodies or antigen-binding antibody fragments of the present disclosure may specifically bind may include, for example,

BtCoV.1 A.AFCD62 (GenBank Accession No. NC_010437), BtCoV.lB.AFCD307 (GenBank Accession No. NC_010436), BtCov.FlKU8.AFCD77 (GenBank Accession No. NC_010438), BtCoV.512.2005 (GenBank Accession No. DQ648858), porcine epidemic diarrhea virus PEDV.CV777 (GenBank Accession No. NC_003436, GenBank Accession No. DQ355224.1, GenBank Accession No. DQ355223.1, GenBank Accession No. DQ355221.1, GenBank Accession No. JN601062.1, GenBank Accession No. N601061.1, GenBank Accession No. JN601060.1, GenBank Accession No. JN601059.1, GenBank Accession No. JN601058.1, GenBank Accession No. JN601057.1, GenBank Accession No. JN601056.1, GenBank Accession No. JN601055.1, GenBank Accession No. JN601054.1, GenBank Accession No. JN601053.1, GenBank Accession No. JN601052.1, GenBank Accession No. JN400902.1, GenBank Accession No. JN547395.1, GenBank Accession No. FJ687473.1, GenBank Accession No. FJ687472.1, GenBank Accession No. FJ687471.1, GenBank Accession No. FJ687470.1, GenBank Accession No. FJ687469.1, GenBank Accession No. FJ687468.1, GenBank Accession No. FJ687467.1, GenBank Accession No. FJ687466.1, GenBank Accession No. FJ687465.1, GenBank Accession No. FJ687464.1, GenBank Accession No. FJ687463.1, GenBank Accession No. FJ687462.1, GenBank Accession No. FJ687461.1, GenBank Accession No. FJ687460.1, GenBank Accession No. FJ687459.1, GenBank Accession No. FJ687458.1, GenBank Accession No. FJ687457.1, GenBank Accession No. FJ687456.1, GenBank Accession No. FJ687455.1, GenBank Accession No. FJ687454.1, GenBank Accession No. FJ687453 GenBank Accession No. FJ687452.1, GenBank Accession No. FJ687451.1, GenBank Accession No. FJ687450.1, GenBank Accession No. FJ687449.1, GenBank Accession No. AF500215.1, GenBank Accession No. KF476061.1, GenBank Accession No. KF476060.1, GenBank Accession No. KF476059.1, GenBank Accession No. KF476058.1, GenBank Accession No. KF476057.1, GenBank Accession No. KF476056.1, GenBank Accession No. KF476055.1, GenBank Accession No. KF476054.1, GenBank Accession No. KF476053.1, GenBank Accession No. KF476052.1, GenBank Accession No. KF476051.1, GenBank Accession No. KF476050.1, GenBank Accession No. KF476049.1, GenBank Accession No. KF476048.1, GenBank Accession No. KF177258.1, GenBank Accession No. KF177257.1, GenBank Accession No. KF177256.1, GenBank Accession No. KF177255.1), HCoV.229E (GenBank Accession No. NC_002645), HCoV.NL63.Amsterdam.I (GenBank Accession No. NC_005831), BtCoV.FIKU2.FIK.298.2006 (GenBank Accession No. EF203066), BtCoV.FIKU2.FIK.33.2006 (GenBank Accession No. EF203067), BtCoV.HKU2.HK.46.2006 (GenBank Accession No. EF203065), or BtCoV.FIKU2.GD.430.2006 (GenBank Accession No. EF203064).

[0384] Alternatively, the S proteins of CoV to which the antibodies or antigen-binding antibody fragments of the present disclosure may specifically bind may include, for example, FtCoV.FlKUl.C.N5 (GenBank Accession No. DQ339101), MFFV.A59 (GenBank Accession No. NC 001846), PHEV.VW572 (GenBank Accession No. NC 007732), HCoV.OC43.ATCC.VR.759 (GenBank Accession No. NC_005147), or bovine enteric coronavirus (BCoV.ENT) (GenBank Accession No. NC_003045).

[0385] Alternatively, the S proteins of CoV to which the antibodies or antigen-binding antibody fragments of the present disclosure may specifically bind may include, for example, BtCoV.HKU9.2 (GenBank Accession No. EF065514), BtCoV.HKU9.1 (GenBank Accession No. NC_009021), BtCoV.HkU9.3 (GenBank Accession No. EF065515), or BtCoV.HKU9.4 (GenBank Accession No. EF065516).

[0386] In some instances, an anti-CoV-S antibody or antigen-binding fragment thereof according to the disclosure binds to CoV-S (e.g., SARS-CoV-S and/or SARS-CoV-2-S, and/or any of the CoV S proteins listed above) with a dissociation constant (KD) of (i) 100 nM or lower; (ii) about 10 nM or lower; (iii) about 1 nM or lower; (iv) about 100 pM or lower; (v) about 10 pM or lower; (vi) about 1 pM or lower; or (vii) about 0.1 pM or lower.

[0387] The present disclosure provides exemplary antibodies or antigen-binding fragments thereof that bind CoV-S, including human CoV-S, which optionally may be affinity-matured. Other antibodies or antigen-binding fragments thereof that bind CoV-S, including those having different CDRs, and epitopic specificity may be obtained using the disclosure of the present specification, and using methods that are generally known in the art. Such antibodies and antigen-binding fragments thereof antagonize the biological effects of CoV-S in vivo and therefore are useful in treating or preventing COV-S-related conditions including, particularly coronavirus infection. In preferred embodiments, the antibody or antigen-binding fragment thereof according to the disclosure comprises one or more CDRs, a V_L chain and/or V_H chain of the anti-CoV-S antibodies and antigen-binding fragments thereof described herein.

[0388] In some embodiments, an anti-CoV-S antibody or antigen-binding fragment thereof according to the disclosure will interfere with, block, reduce, or modulate the interaction between COV-S and its receptor(s) (e.g., ACE2, CD209L, L-SIGN, DPP4, or CD26) on host cells or a S protein-priming protein on host cells (e.g., TMPRSS2). If binding of the S protein to its receptor is blocked or reduced, CoV virions may be prohibited from entering the cells, i.e., infection to further cells is prevented.

Also, if the S protein is prevented from binding to a S protein-priming protein, the S protein would not be activated and therefore the host cell entry via the receptor may be reduced, i.e., infection to further cells is prevented.

[0389] In some instance, an anti-CoV-S antibody or antigen-binding fragment thereof according to the disclosure is “neutralizing”, e.g., it substantially or totally prevents the specific interaction of CoV-S with the host receptors or priming protein. As a result, CoV virions may be substantially or totally cleared by immune cells of the host, such as phagocytes via, for example, Fc receptor mediated phagocytosis or mere phagocytosis due to increased time of virions outside the cells. In some embodiments, the antibody or antigen-binding fragment thereof neutralizes CoV-S, e.g., by remaining bound to CoV-S in a location and/or manner that prevents CoV-S from specifically binding to its receptor or priming protein on host cells. As a result, CoV virions may be substantially or totally prevented from entering the cells, i.e. infection to further cells is prevented. In certain embodiments, an anti-CoV-S antibody or antigen-binding fragment thereof according to the disclosure neutralizes CoV (e.g., SARS-CoV and/or SARS-CoV-2) at an IC50 of about 100 nM or lower, of about 50 nM or lower, of about 20 nM or lower, of about 10 nM or lower, of about 5 nM or lower, of about 2 nM or lower, of about 1 nM or lower, of about 500 pM or lower, of about 200 pM or lower, of about 100 pM or lower, of about 50 pM or lower, of about 20 pM or lower, of about 10 pM or lower, of about 5 pM or lower, of about 2 pM or lower, or of about 1 pM or lower, or at an IC50 of about 5 μg/mL or lower, of about 4.5 μg/mL, of about 4 μg/mL, of about 3.5 μg/mL, of about 3 μg/mL, of about 2.5 μg/mL, of about 2 μg/mL or lower, of about 1.5 μg/mL or lower, of about 1 μg/mL or lower, of about about 500 ng/mL or lower, about 500 ng/mL or lower, of about 400 ng/mL or lower, of about 200 ng/mL or lower, of about 100 ng/mL or lower, of about 50 ng/mL or lower, at about 20 ng/mL or lower, at about 10 ng/mL or lower, at about 5 ng/mL or lower, at about 2 ng/mL or lower, or at about 1 ng/mL or lower, or about 0.6 ng/mL or lower, or of about 0.1 ng/mL to about 5 μg/mL, of about 0.5 ng/mL to about 4.5 μg/mL, of about 0.5 ng/mL to about 4 μg/mL, of about 0.5 ng/mL to about 3.5 μg/mL, of about 0.5 ng/mL to about 3 μg/mL, of about 0.5 ng/mL to about 2.5 μg/mL, of about 0.5 ng/mL to about 2 μg/mL, of about 1 ng/mL to about 2 μg/mL, of about 1 ng/mL to about 1.5 μg/mL, of about 100 ng/mL to about 1.1 μg/mL, of about 100 ng/mL to about 1 μg/mL, of about 100 ng/mL to about 500 ng/mL, of about 400 ng/mL to about 1.1 μg/mL, of about 300 ng/mL to about 1.1 μg/mL, of about 250 ng/mL to about 1.1 μg/mL, of about 200 ng/mL to about 1.1 μg/mL, in vitro, as measured by any of the neutralization assays described in Examples herein. In another embodiment, the isolated antibody or antigen-binding antibody fragment may neutralize SARS-CoV and/or SARS- CoV-2 at an IC90 of about 10 μg/mL or less, an IC90 of about 1 to about 10 μg/mL, an IC90 of about 2 to about 10 mg/mL, an IC90 of about 3 to about 10 mg/mL, an IC90 of about 5 to 10 mg/mL, an IC90 of about 7 to 10 mg/mL, an IC90 of about 8 to 10 mg/mL, an IC90 of about 9 to 10 mg/mL, an IC90 of about 10 mg/mL, 9 mg/mL, 8 mg/mL, 7, mg/mL, 6 mg/mL, or 5 mg/mL.

[0390] In some instances, an anti-CoV-S antibody or antigen-binding fragment thereof according to the disclosure or cocktail thereof, when administered to a coronavirus infected host or one susceptible to coronavirus infection such as a health care worker may promote a neutralization response in the host against the coronavirus which is sufficient to permit the host to be able to mount an effective cell-mediated immune response against the virus, e.g., T cell-mediated or cytokine-mediated immune response against the coronavirus and/or to be more responsive to other treatment methods such as drugs, antivirals or other biologies.

[0391] As mentioned, the anti-CoV-S antibodies or antigen-binding fragments thereof according to the disclosure have a variety of uses. For example, the subject antibodies and fragments can be useful in prophylactic or therapeutic applications, as well as diagnostically in binding assays. The subject anti-CoV-S antibodies or antigen-binding fragments thereof are useful for affinity purification of CoV-S, in particular human CoV-S or its ligands and in screening assays to identify other antagonists of CoV-S activity. Some of the antibodies or antigen-binding fragments thereof are useful for inhibiting binding of CoV-S to its receptor(s) (e.g., ACE2, CD209L, L-SIGN, DPP4, or CD26) on host cells or a S protein-priming protein on host cells (e.g., TMPRSS2) or inhibiting COV-S-mediated activities and/or biological effects.

[0392] As used herein, the term “one or more biological effects associated with COV-S refers to any biological effect mediated, induced, or otherwise attributable to COV-S, e.g., binding properties, functional properties, and other properties of biological significance. Non-limiting exemplary biological effects of COV-S include COV-S binding to its receptor(s) (e.g., ACE2, CD209L, L-SIGN, DPP4, or CD26) on host cells or a S protein-priming protein on host cells (e.g., TMPRSS2), activation of host cells for allowing virus entry, activation of immune cells as a result of the entry of CoV into the cell, e.g., via presentation of CoV antigen(s) on the host cells’ MHC molecule, and resulting inflammation. The subject anti-CoV-S antibodies are capable of inhibiting one, a combination of, or all of these exemplary CoV-S biological activities. For example, the anti-CoV-S antibodies and antigen-binding fragments thereof provided herein may neutralize CoV virions or reduce the infectivity of CoV virions.

[0393] The antibody or antigen-binding fragment thereof according to the disclosure can be used in a variety of therapeutic applications. For example, in some embodiments the anti-CoV-S antibody or antigen-binding fragment thereof are useful for treating conditions associated with CoV-S, such as, but not limited to, symptoms associated with CoV infection. The CoV may be any CoV, including SARS-CoV, SARS-CoV-2, MERS-CoV, HCoV-HKUl, HCoV-OC43, HCoV-229E, and HCoV- NL63, and also may be any of the CoV species listed above herein. [0394] Specific examples of CoV infection-associated symptoms are fever, cough, dry cough, shortness of breath or difficulty of breath, fatigue, aches, runny nose, congestion, sore throat, conjunctivitis, chest pain, headache, muscle ache, chills, loss of smell, and loss of taste, and gastrointestinal symptoms including diarrhea. Complications and/or diseases/disorders associated with coronavirus infection may include, for example, bronchitis, pneumonia, respiratory failure, acute respiratory failure, organ failure, multi-organ system failure, pediatric inflammatory multisystem syndrome, acute respiratory distress syndrome (a severe lung condition that causes low oxygen in the blood and organs), blood clots, cardiac conditions, myocardial injury, myocarditis, heart failure, cardiac arrest, acute myocardial infarction, dysrhythmias, venous thromboembolism, post-intensive care syndrome, shock, anaphylactic shock, cytokine release syndrome, septic shock, disseminated intravascular coagulation, ischemic stroke, intracerebral hemorrhage, microangiopathic thrombosis, psychosis, seizure, nonconvulsive status epilepticus, traumatic brain injury, stroke, anoxic brain injury, encephalitis, posterior reversible leukoencephalopathy, necrotizing encephalopathy, post- infectious encephalitis, autoimmune mediated encephalitis, acute disseminated encephalomyelitis, acute kidney injury, acute liver injury, pancreatic injury, immune thrombocytopenia, subacute thyroiditis, gastrointestinal complications, aspergillosis, increased susceptibility to infection with another virus or bacteria, and/or pregnancy-related complications. Certain diseases and conditions, such as high blood pressure, type 1 diabetes, liver disease, overweight, chronic lung diseases including cystic fibrosis, pulmonary fibrosis, and asthma, compromised immune system due to transplant, use of an immunosuppressant, or HIV infection, and brain and nervous sustem condition, may increase the risk of CoV infection-associated complications and diseases.

[0395] The subject anti-CoV-S antibodies and antigen-binding fragments thereof may be used alone or in association with other active agents or drugs, including other biologies, to treat any subject in which blocking, inhibiting, or neutralizing the in vivo effect of CoV-S or blocking or inhibiting the interaction of CoV-S and its receptor(s) (e.g., ACE2, CD209L, L-SIGN, DPP4, or CD26) on host cells or a S protein-priming protein on host cells (e.g., TMPRSS2), is therapeutically desirable. In some embodiment, the subject anti-CoV-S antibody and antigen-binding fragment thereof, e.g., ADI- 58125, may be used in combination with a second antibody, or antigen-binding fragment thereof, wherein the second antibody, or antigen-binding fragment thereof, is selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, ADI-58131, or a combination thereof. In some embodiment, the second antibody, or antigen-binding fragment thereof, is ADI-58122. In one embodiment, the second antibody, or antigen-binding fragment thereof, is ADI-58127. In one embodiment, the second antibody, or antigen-binding fragment thereof, is ADI-58129. In one embodiment, the second antibody, or antigen-binding fragment thereof, is ADI-58131. [0396] Exemplary anti-CoV antibodies and antigen-binding fragments thereof according to the disclosure, and the specific CDRs thereof are identified in this section.

[0397] The anti-CoV-S antibodies and antigen-binding fragments thereof comprising the disclosure have binding affinity for CoV-S, such as SARS-CoV-S or SARS-CoV-S2. Some antibodies of the present disclosure bind to SARS-CoV-S or SARS-CoV-S2 with a similar K_D (M), while some antibodies of the present disclosure bind to SARS-CoV-S with a lower K_D (M) ( /^'. e. , higher affinity) than to SARS-CoV-S2, and some antibodies of the present disclosure bind to SARS-CoV-S-2 with a lower K_D (M) (i.e., higher affinity) than to SARS-CoV-S.

C. Anti-CoV-S Antibody Polypeptide Sequences and Nucleic Acid Sequences Encoding Thereof Antibodies disclosed herein

[0398] Anti-CoV-S antibodies, and antigen-binding fragments thereof, specifically provided herein include: antibodies ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI- 58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, ADI-58131, and antigen-binding fragments thereof. Any Fc variant including but not limited to those specifically disclosed in Table 9 may be used in combination with any of the variable sequences disclosed herein. In some embodiments, the Fc variant is an FA variant and comprises the amino acid sequence of SEQ ID NO: 413. In one embodiment, the antibody ADI-58125 comprises an Fc variant of SEQ ID NO:413.

[0399] Tables 1-8 show the SEQ ID NOs assigned to individual amino acid sequences of the HC, VH, VH FR1, VH CDR1, VH FR2, VH CDR2, VH FR3, VH CDR3, VH FR4, EC, VL, VL FR1, VL CDR1, VL FR2, VL CDR2, VL FR3, VL CDR3, and VL FR4 for individual antibodies, and the SEQ ID NOs assigned to the nucleic acid sequences of the VH and VL of individual antibodies.

Variations of the Disclosed Antibodies and Polynucleotide Sequences Encoding Such Variations [0400] In one embodiment, disclosed herein are anti-CoV-S antibodies or antigen-binding antibody fragments comprising (i) a VH CDR that is same as the VH CDR3 of, (ii) a VH CDR3 and VL CDR3, both of which as same as both of the VH CDR3 and the VL CDR3 of, (iii) at least 1, 2, 3, 4, 5, or 6 CDRs that are same as the corresponding CDR(s) of, or (iv) 6 CDRs that are all the same as the 6 CDRs of any one of the disclosed antibodies selected from the group consisting of ADI-58120, ADI- 58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI- 58129, ADI-58130, and ADI-58131.

[0401] In further embodiments, disclosed herein are anti-CoV-S antibodies or antigen-binding antibody fragments which optionally may be affinity-matured, comprising one of the CDR requirements (i)-(iv) of the immediately above paragraph, further wherein (a) the VH comprises an amino acid sequence with at least 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of the VH of, and (b) the VL comprises an amino acid sequence with at least 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of the VL of any one of the disclosed antibodies selected from the group consisting of ADI- 58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI- 58128, ADI-58129, ADI-58130, and ADI-58131.

[0402] In further embodiments, the disclosure contemplates anti-CoV-S antibodies or antigen binding antibody fragments which optionally may be affinity-matured, comprising one of the VH and VL requirements (i)-(iv) of the immediately above paragraph, further wherein (a) the heavy chain comprises an amino acid sequence with at least 80, 85, 90, 91, 92, 93, 9495, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of the heavy chain of, and (b) the light chain comprises an amino acid sequence with at least 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to the amino acid sequence of the light chain of any one of the disclosed antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI- 58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, and ADI-58131.

[0403] In further embodiments, the disclosure contemplates anti-CoV-S antibodies or antigen binding antibody fragments which optionally may be affinity-matured, comprising one of the CDR requirements (i)-(iv) of the immediately above paragraph, further wherein (a) the VH is identical to the VH of, and (b) the VL is identical to the VL of any one of the disclosed antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, and ADI-58131.

[0404] In other embodiments, the disclosure includes antibodies and antigen-binding fragments which optionally may be affinity-matured, having binding specificity to COV-S that bind the same epitope as one of antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI- 58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI- 58130, and ADI-58131.

[0405] In other embodiments, the disclosure includes antibodies and antigen-binding fragments having binding specificity to COV-S, which optionally may be affinity-matured, that bind the same epitope as any one of antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI- 58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI- 58130, and ADI-58131.

[0406] In other embodiments, the anti-CoV-S antibodies and antigen-binding fragments optionally may be affinity-matured, comprise, or alternatively consist of, combinations of one or more of the FRs, CDRs, the VH and VL sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto.

[0407] In a further embodiment, antigen-binding fragments comprise, or alternatively consist of, Fab fragments having binding specificity for CoV-S. The Fab fragment preferably includes the VH and the VL sequence of any one of antibodies selected from the group consisting of ADI-58120, ADI- 58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI- 58129, ADI-58130, and ADI-58131, or sequences that are at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto. This embodiment further includes Fabs containing additions, deletions, and variants of such VH and VL sequence while retaining binding specificity for CoV-S.

[0408] In some embodiments, Fab fragments may be produced by enzymatic digestion (e.g., papain) of the parent full antibody. In another embodiment, anti-CoV-S antibodies, such as anyone of antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, and ADI- 58131, and Fab fragments thereof may be produced via expression in mammalian cells, such as CHO, NSO, or HEK 293 cells, fungal, insect, or microbial systems, such as yeast cells.

[0409] In additional embodiments, disclosed herein are polynucleotides encoding antibody polypeptides having binding specificity to COV-S, including the VH and VL of any one of antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, and ADI-58131, as well as fragments, variants, optionally affinity-matured variants, and combinations of one or more of the FRs, CDRs, the VH and VL sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,

98%, or 99% identical thereto.

[0410] In other embodiments, the disclosure contemplates isolated anti-CoV-S antibodies and antigen binding fragments comprising (i) a VH which is same as the VH of any one of antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, and ADI-58131; and (ii) a VL which is same as the VL of another antibody selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, and ADI-58131, or a variant thereof, wherein optionally one or more of the framework region residues (“LR residues”) and/or CDR residues in said V_H or V_L polypeptide has been substituted with another amino acid residue resulting in an anti-CoV -S antibody that specifically binds COV-S.

[0411] The disclosure also includes humanized, primatized and other chimeric forms of these antibodies. The chimeric and humanized antibodies may include an Lc derived from IgGl, IgG2,

IgG3, or IgG4 constant regions.

[0412] In some embodiments, the chimeric or humanized antibodies or fragments or VH or VL polypeptides originate or are derived from one or more human antibodies, e.g., a human antibody identified from a clonal human B cell population. [0413] In some aspects, the disclosure provides vectors comprising a nucleic acid molecule encoding an anti-CoV-S antibody or fragment thereof as disclosed herein. In some embodiments, the disclosure provides host cells comprising a nucleic acid molecule encoding an anti-CoV-S antibody or fragment thereof as disclosed herein.

[0414] In some aspects, the disclosure provides isolated antibodies or antigen binding fragments thereof that competes for binding to CoV-S with an antibody or antigen binding fragment thereof disclosed herein.

[0415] In some aspects, the disclosure provides a nucleic acid molecule encoding any of the antibodies or antigen binding fragments disclosed herein.

[0416] In some aspects, the disclosure provides a pharmaceutical or diagnostic composition comprising at least one antibody or antigen binding fragment thereof as disclosed herein.

[0417] In some aspects, the disclosure provides a method for treating or preventing a condition associated with elevated CoV-S levels in a subject, comprising administering to a subject in need thereof an effective amount of at least one isolated antibody or antigen binding fragment thereof as disclosed herein.

[0418] In some aspects, the disclosure provides a method of inhibiting binding of COV-S to its receptor (e.g., ACE2, L-SIGN, CD209L, DPP4, CD26) or an S protein-priming protein (e.g., TMPRSS2) in a subject comprising administering an effective amount of at least one antibody or antigen binding fragment thereof as disclosed herein. For example, administering one or more of antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, and ADI- 58131 may inhibit binding of COV-S to its receptor, e.g., ACE2.

[0419] In some aspects, the disclosure provides an antibody or antigen binding fragment thereof that selectively binds to CoV-S, wherein the antibody or antigen binding fragment thereof binds to CoV-S with a K_D of less than or equal to 5x10⁵ M, 10⁵ M, 5x10⁶ M, 10⁶ M, 5x10⁷ M, 10⁷ M, 5x10⁸ M,

10⁸ M, 5x10⁹ M, 10⁹ M, 5x10¹⁰ M, 10¹⁰ M, 5x10¹¹ M, 10¹¹ M, 5x10¹² M, 10¹² M, 5x10¹³ M, or 10¹³ M; preferably, with a K_D of less than or equal to 5x10¹⁰ M, 10¹⁰ M, 5x10¹¹ M, 10¹¹ M, 5x10¹² M, or 10¹² M; more preferably, with a K_D that is less than about 100 pM, less than about 50 pM, less than about 40 pM, less than about 25 pM, less than about 1 pM, between about 10 pM and about 100 pM, between about 1 pM and about 100 pM, or between about 1 pM and about 10 pM. Preferably, the anti-CoV-S antibody or antigen binding fragment has cross-reactivity to the S protein of CoV other than SARS-CoV-S or SARS-CoV-2-S.

[0420] The inventive antibodies and antigen binding fragments thereof may be modified post- translationally to add effector moieties such as chemical linkers, detectable moieties such as for example fluorescent dyes, enzymes, substrates, bioluminescent materials, radioactive materials, and chemiluminescent moieties, or functional moieties such as for example streptavidin, avidin, biotin, a cytotoxin, a cytotoxic agent, and radioactive materials.

[0421] Antibodies and antigen binding fragments thereof may also be chemically modified to provide additional advantages such as increased solubility, stability and circulating time (in vivo half- life) of the polypeptide, or decreased immunogenicity ( See U.S. Patent No. 4,179,337). The chemical moieties for derivatization may be selected from water soluble polymers such as polyethylene glycol, ethylene glycol/propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol, and the like. The antibodies and fragments thereof may be modified at random positions within the molecule, or at predetermined positions within the molecule and may include one, two, three, or more attached chemical moieties.

[0422] The polymer may be of any molecular weight, and may be branched or unbranched. For polyethylene glycol, the preferred molecular weight is between about 1 kDa and about 100 kDa (the term "about" indicating that in preparations of polyethylene glycol, some molecules will weigh more, some less, than the stated molecular weight) for ease in handling and manufacturing. Other sizes may be used, depending on the desired therapeutic profile (e.g., the duration of sustained release desired, the effects, if any on biological activity, the ease in handling, the degree or lack of antigenicity and other known effects of the polyethylene glycol to a therapeutic protein or analog). For example, the polyethylene glycol may have an average molecular weight of about 200, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10,000,

10.500, 11,000, 11,500, 12,000, 12,500, 13,000, 13,500, 14,000, 14,500, 15,000, 15,500, 16,000,

16.500, 17,000, 17,500, 18,000, 18,500, 19,000, 19,500, 20,000, 25,000, 30,000, 35,000, 40,000,

50,000, 55,000, 60,000, 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, 95,000, or 100,000 kDa.

Branched polyethylene glycols are described, for example, in U.S. Patent No. 5,643,575; Morpurgo et al., Appl. Biochem. Biotechnol., 56:59-72 (1996); Vorobjev et al, Nucleosides and Nucleotides, 18:2745-2750 (1999); and Caliceti et al, Bioconjug. Chem., 10:638-646 (1999), the disclosures of each of which are incorporated herein by reference.

[0423] There are a number of attachment methods available to those skilled in the art ( See e.g., EP 0 401 384, herein incorporated by reference, disclosing a method of coupling PEG to G-CSF; and Malik et al, Exp. Hematol, 20:1028-1035 (1992) (reporting pegylation of GM-CSF using tresyl chloride)). For example, polyethylene glycol may be covalently bound through amino acid residues via a reactive group, such as, a free amino or carboxyl group. Reactive groups are those to which an activated polyethylene glycol molecule may be bound. The amino acid residues having a free amino group may include lysine residues and the N-terminal amino acid residues; those having a free carboxyl group may include aspartic acid residues glutamic acid residues and the C-terminal amino acid residue. Sulfhydryl groups may also be used as a reactive group for attaching the polyethylene glycol molecules. Preferred for therapeutic purposes is attachment at an amino group, such as attachment at the N-terminus or lysine group.

[0424] As described above, polyethylene glycol may be attached to proteins via linkage to any of a number of amino acid residues. For example, polyethylene glycol can be linked to polypeptides via covalent bonds to lysine, histidine, aspartic acid, glutamic acid, or cysteine residues. One or more reaction chemistries may be employed to attach polyethylene glycol to specific amino acid residues (e.g., lysine, histidine, aspartic acid, glutamic acid, or cysteine) or to more than one type of amino acid residue (e.g., lysine, histidine, aspartic acid, glutamic acid, cysteine and combinations thereof). [0425] Alternatively, antibodies or antigen binding fragments thereof having increased in vivo half- lives may be produced via fusion with albumin (including but not limited to recombinant human serum albumin or fragments or variants thereof (See, e.g., U.S. Patent No. 5,876,969, EP 0413 622, and U.S. Patent No. 5,766,883, herein incorporated by reference in their entirety)), or other circulating blood proteins such as transferrin or ferritin. In a preferred embodiment, polypeptides and/or antibodies of the present disclosure (including fragments or variants thereof) are fused with the mature form of human serum albumin (i.e., amino acids 1-585 of human serum albumin as shown in FIGS. 1 and 2 of EP 0 322094) which is herein incorporated by reference in its entirety. Polynucleotides encoding fusion proteins of the disclosure are also encompassed by the disclosure. [0426] Regarding detectable moieties, further exemplary enzymes include, but are not limited to, horseradish peroxidase, acetylcholinesterase, alkaline phosphatase, Z¾Za-galactosidase, and luciferase. Further exemplary fluorescent materials include, but are not limited to, rhodamine, fluorescein, fluorescein isothiocyanate, umbelliferone, dichlorotriazinylamine, phycoerythrin, and dansyl chloride. Further exemplary chemiluminescent moieties include, but are not limited to, luminol. Further exemplary bioluminescent materials include, but are not limited to, luciferin and aequorin. Further exemplary radioactive materials include, but are not limited to, Iodine 125 (¹²⁵I), Carbon 14 (¹⁴C), Sulfur 35 (³⁵S), Tritium (³H) and Phosphorus 32 (³²P).

[0427] Methods are known in the art for conjugating an antibody or antigen binding fragment thereof to a detectable moiety and the like, such as for example those methods described by Hunter et al, Nature, 144:945 (1962); David et al, Biochemistry, 13:1014 (1974); Pain et al, J. Immunol. Meth., 40:219 (1981); and Nygren, J., Histochem. and Cytochem., 30:407 (1982).

[0428] Embodiments described herein further include variants and equivalents that are substantially homologous to the antibodies, antibody fragments, diabodies, SMIPs, camelbodies, nanobodies, IgNAR, polypeptides, variable regions, and CDRs set forth herein. These may contain, e.g., conservative substitution mutations, (i.e., the substitution of one or more amino acids by similar amino acids). For example, conservative substitution refers to the substitution of an amino acid with another within the same general class, e.g., one acidic amino acid with another acidic amino acid, one basic amino acid with another basic amino acid, or one neutral amino acid by another neutral amino acid. The intent of a conservative amino acid substitution is well known in the art.

[0429] In other embodiments, the disclosure contemplates polypeptide sequences having at least 90% or greater sequence homology to any one or more of the polypeptide sequences of antigen binding fragments, variable regions and CDRs set forth herein. More preferably, the disclosure contemplates polypeptide sequences having at least 95% or greater sequence homology, even more preferably at least 98% or greater sequence homology, and still more preferably at least 99% or greater sequence homology to any one or more of the polypeptide sequences of antigen binding fragments, variable regions, and CDRs set forth herein.

[0430] Methods for determining homology between nucleic acid and amino acid sequences are well known to those of ordinary skill in the art.

[0431] In other embodiments, the disclosure further contemplates the above-recited polypeptide homologs of the antigen binding fragments, variable regions and CDRs set forth herein further having anti-CoV-S activity. Non-limiting examples of anti-CoV-S activity are set forth herein, e.g., ability to inhibit CoV-S binding to its receptor such as ACE2 or L-SIGN or an S protein-priming protein, thereby resulting in the reduced entry of CoV into cells.

[0432] In other embodiments, the disclosure further contemplates the generation and use of antibodies that bind any of the foregoing sequences, including, but not limited to, anti-idiotypic antibodies. In an exemplary embodiment, such an anti-idiotypic antibody could be administered to a subject who has received an anti-CoV-S antibody to modulate, reduce, or neutralize, the effect of the anti-CoV-S antibody. Such antibodies could also be useful for treatment of an autoimmune disease characterized by the presence of anti-CoV-S antibodies. A further exemplary use of such antibodies, e.g., anti-idiotypic antibodies, is for detection of the anti-CoV-S antibodies of the present disclosure, for example to monitor the levels of the anti-CoV-S antibodies present in a subject’s blood or other bodily fluids. For example, in one embodiment, the disclosure provides a method of using the anti- idiotypic antibody to monitor the in vivo levels of said anti-CoV-S antibody or antigen binding fragment thereof in a subject or to neutralize said anti-CoV-S antibody in a subject being administered said anti-CoV-S antibody or antigen binding fragment thereof.

[0433] The present disclosure also contemplates anti-CoV-S antibodies comprising any of the polypeptide or polynucleotide sequences described herein substituted for any of the other polynucleotide sequences described herein. For example, without limitation thereto, the present disclosure contemplates antibodies comprising the combination of any of the VF and VH sequences described herein, and further contemplates antibodies resulting from substitution of any of the CDR sequences described herein for any of the other CDR sequences described herein.

[0434] Another embodiment of the disclosure contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO, or HEK-293 cells, or in fungal, insect, or microbial systems such as yeast cells. In one embodiment of the disclosure described herein, Fab fragments can be produced by enzymatic digestion (e.g., papain) of any one of antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, and ADI-58131, following expression of the full-length polynucleotides in a suitable host. In another embodiment, anti-Co V-S antibodies, such as anyone of antibodies selected from the group consisting of ADI- 58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI- 58128, ADI-58129, ADI-58130, and ADI-58131, or Fab fragments thereof, can be produced via expression of the polynucleotides encoding any one of antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI- 58127, ADI-58128, ADI-58129, ADI-58130, and ADI-58131, in mammalian cells such as CFIO,

NSO, or F1EK 293 cells, fungal, insect, or microbial systems such as yeast cells.

[0435] Flost cells and vectors comprising said polynucleotides are also contemplated.

[0436] The disclosure further contemplates vectors comprising the polynucleotide sequences encoding the variable heavy and light chain polypeptide sequences, as well as the individual CDRs (hypervariable regions), as set forth herein, as well as host cells comprising said vector sequences. In one embodiment, the host cells are mammalian cells, such as CFIO cells. In one embodiment, the host cells are yeast cells.

D. Antibody -drug Conjugate Comprising Anti-CoV-S Antibody

[0437] In some aspects, the disclosure is further directed to antibody-drug conjugates (ADCs) comprising (a) any antibody or antigen-binding antibody fragment described herein; and (b) a drug conjugated to the antibody or antigen-binding antibody fragment, either directly or indirectly (e.g., via a linker).

[0438] In some aspects, the drug may be, but not limited to, a cytotoxic drug, an apoptotic drug, an immunostimulatory drug, an anti-microbial drug, an antibacterial drug or vaccine, an antiviral drug, antihelminth drug, antiparasitic drug, an anti-inflammatory drug, antihistamine, an anti-fibrotic drug, an immunosuppressive drug, a steroid, a bronchodilator, a beta blocker, an ACE inhibitor, an enzyme, a serine protease inhibitor, a toxin, a radioisotope, a compound, a small molecule, a small molecule inhibitor, a protein, a peptide, a vector, a plasmid, a viral particle, a nanoparticle, a DNA molecule, an RNA molecule, an siRNA, an shRNA, a micro RNA, an oligonucleotide, and an imaging drug.

[0439] An antiviral drug may be remdesivir, favipiravir, darunavir, nelfinavir, saquinavir, lopinavir or ritonavir; an antihelminth drug may be ivermectin; an antiparasite drug may be hydroxychloroquine, chloroquine, or atovaquone; antibacterial drug or vaccine may be the tuberculosis vaccine BCG; an anti-inflammatory drug, may be ciclesonide, a TNF inhibitor (e.g., adalimumab), a TNF receptor inhibitor (e.g., etanercept), an IL-6 inhibitor (e.g., clazakizumab), an IL-6 receptor inhibitor (e.g., toclizumab), or metamizole; an antihistamine drug may be bepotastine; an ACE inhibitor may be moexipril; and a drug that inhibits priming of CoV-S may be a serine protease inhibitor such as nafamostat.

[0440] The toxin may be a bacterial, fungal, plant, or animal toxin, or a fragment thereof. Examples include, but are not limited to, diphtheria A chain, diphtheria toxin, exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha sarcin, Aleurites fordii protein, a dianthin protein, or a Phytolacca Americana protein.

[0441] The cytotoxic drug or anti-proliferative drug may be, for example, but is not limited to, doxorubicin, daunorubicin, cucurbitacin, chaetocin, chaetoglobosin, chlamydocin, calicheamicin, nemorubicin, cryptophyscin, mensacarcin, ansamitocin, mitomycin C, geldanamycin, mechercharmycin, rebeccamycin, safracin, okilactomycin, oligomycin, actinomycin, sandramycin, hypothemycin, polyketomycin, hydroxyellipticine, thiocolchicine, methotrexate, triptolide, taltobulin, lactacystin, dolastatin, auristatin, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), telomestatin, tubastatin A, combretastatin, maytansinoid, MMAD, MMAF, DM1, DM4, DTT, 16-GMB -APA-GA, 17-DMAP-GA, JW 55, pyrrolobenzodiazepine, SN-38, Ro 5-3335, puwainaphycin, duocarmycin, bafilomycin, taxoid, tubulysin, ferulenol, lusiol A, fumagillin, hygrolidin, glucopiericidin, amanitin, ansatrienin, cinerubin, phallacidin, phalloidin, phytosphongosine, piericidin, poronetin, phodophyllotoxin, gramicidin A, sanguinarine, sinefungin, herboxidiene, microcolin B, microcystin, muscotoxin A, tolytoxin, tripolin A, myoseverin, mytoxin B, nocuolin A, psuedolaric acid B, pseurotin A, cyclopamine, curvulin, colchicine, aphidicolin, englerin, cordycepin, apoptolidin, epothilone A, limaquinone, isatropolone, isofistularin, quinaldopeptin, ixabepilone, aeroplysinin, arruginosin, agrochelin, epothilone, or a derivative thereof (for example, see Polakis P. et ai, Pharmacol Rev. 2016 Jan;68(l):3-19. doi: 10.1124/pr.114.009373) (the drugs may be obtained from many vendors, including Creative Biolabs ®).

[0442] The radioisotope may be for example, but is not limited to, At²¹¹, 1¹³¹, In¹³¹, 1¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹² and radioactive isotopes of Lu.

[0443] In certain embodiments, the drug may be, but is not limited to, MMAE or MMAF.

[0444] In some embodiments, the Ab or antigen-binding Ab fragment is directly conjugated to the drug to form an ADC.

[0445] In some embodiments, the antibody or antigen-binding antibody fragment is indirectly conjugated to the drug to form an ADC.

[0446] Any appropriate conjugation method may be used to generate an ADC (for example, Nolting B. Methods Mol Biol. 2013;1045:71-100; Jain N. etal., Pharm Res. 2015 Nov;32(ll):3526-40; Tsuchikama K. et al, Protein Cell. 2018 Jan;9(l):33-46; Polakis P. et ai, Pharmacol Rev . 2016 Jan;68(l):3-19). Examples of methods that may be used to perform conjugation include, but are not limited to, chemical conjugation and enzymatic conjugation. [0447] Chemical conjugation may utilize, for example, but is not limited to, lysine amide coupling, cysteine coupling, and/or non-natural amino acid incorporation by genetic engineering. Enzymatic conjugation may utilize, for example, but is not limited to, transpeptidation using sortase, transpeptidation using microbial transglutaminase, and/or N-Glycan engineering.

[0448] In certain aspects, one or more of cleavable linkers may be used for conjugation. The cleavable linker may enable cleavage of the drug upon responding to, for example, but not limited to, an environmental difference between the extracellular and intracellular environments (pH, redox potential, etc.) or by specific lysosomal enzymes.

[0449] Examples of the cleavable linker include, but are not limited to, hydrazone linkers, peptide linkers including cathepsin B-responsive linkers, such as valine -citrulline (vc) linker, disulfide linkers such as N-succinimidyl-4-(2-pyridyldithio) (SPP) linker or N-succinimidyl-4-(2- pyridyldithiojbutanoate (SPDB) linker, and pyrophosphate diester linkers.

[0450] Alternatively or simultaneously, one or more of non-cleavable linkers may be used. Examples of non-cleavable linkers include thioether linkers, such as N-succinimidyl 4-(N-maleimidomethyl) cyclohexane- 1-carboxylate (SMCC), and maleimidocaproyl (me) linkers. Generally, non-cleavable linkers are more resistant to proteolytic degradation and more stable compared to cleavable linkers.

E. Chimeric Antisen Receptor Comprising Anti-CoV-S Antigen-Binding Antibody Frasment [0451] In some embodiments, a compound specific to CoV-S according to the present disclosure may be a chimeric antigen receptor (CAR). In particular, the CARs of the present disclosure comprise an antigen binding (AB) domain that binds to CoV-S, a transmembrane (TM) domain, and an intracellular signaling (ICS) domain. In some embodiments, a CAR may comprise a hinge that joins the AB domain and said TM domain. In some embodiments, the CAR may comprise one or more costimulatory (CS) domains.

AB domain

[0452] A CAR according to the disclosure will comprise an antigen-binding (AB) domain which binds to COV-S. In some embodiments, the AB domain of the CAR may comprise any of the anti- COV-S antigen-binding antibody fragments disclosed herein.

[0453] In some embodiments, the AB domain of the CAR may comprise any of the antigen-binding domain of any of the anti-COV-S antibodies disclosed herein.

[0454] In some embodiments, the AB domain of the CAR may comprise any of the anti-COV-S antibodies, anti-COV-S antigen-binding antibody fragments, anti-COV-S multi-specific Abs, anti- COV-S multi-specific antigen-binding antibody fragments, and anti-COV-S ADCs disclosed herein, or the ABD thereof.

[0455] In some embodiments, the AB domain of the CAR may comprise an anti-COV-S scFv. [0456] In some embodiments, the AB domain may comprise an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an scFv comprising the VH and VL of any one of antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI- 58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI- 58130, and ADI-58131.

[0457] In some aspects, the AB domain may compete for binding to COV-S with any one of antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, and ADI- 58131.

Hinge

[0458] In some embodiments, the CAR may comprise a hinge sequence between the AB domain and the TM domain. One of the ordinary skill in the art will appreciate that a hinge sequence is a short sequence of amino acids that facilitates flexibility (see, e.g. Woof J.M. et al, Nat. Rev. Immunol.,

4(2): 89-99 (2004)). The hinge sequence can be any suitable sequence derived or obtained from any suitable molecule.

[0459] In some embodiments, the length of the hinge sequence may be optimized based on the desired length of the extracellular portion of the CAR, which may be based on the location of the epitope within the target molecule. For example, if the epitope is in the membrane proximal region within the target molecule, longer hinges may be optimal.

[0460] In some embodiments, the hinge may be derived from or include at least a portion of an immunoglobulin Fc region, for example, an IgGl Fc region, an IgG2 Fc region, an IgG3 Fc region, an IgG4 Fc region, an IgE Fc region, an IgM Fc region, or an IgA Fc region. In certain embodiments, the hinge includes at least a portion of an IgGl, an IgG2, an IgG3, an IgG4, an IgE, an IgM, or an IgA immunoglobulin Fc region that falls within its CH2 and CH3 domains. In some embodiments, the hinge may also include at least a portion of a corresponding immunoglobulin hinge region. In some embodiments, the hinge is derived from or includes at least a portion of a modified immunoglobulin Fc region, for example, a modified IgGl Fc region, a modified IgG2 Fc region, a modified IgG3 Fc region, a modified IgG4 Fc region, a modified IgE Fc region, a modified IgM Fc region, or a modified IgA Fc region. The modified immunoglobulin Fc region may have one or more mutations (e.g., point mutations, insertions, deletions, duplications) resulting in one or more amino acid substitutions, modifications, or deletions that cause impaired binding of the hinge to an Fc receptor (FcR). In some aspects, the modified immunoglobulin Fc region may be designed with one or more mutations which result in one or more amino acid substitutions, modifications, or deletions that cause impaired binding of the hinge to one or more FcR including, but not limited to, FcyRI, FcyR2A, FcyR2Bl, Fcy2B2, Fey 3A, Fey 3B, FceRI, FcsR2, FcaRI, Fca/pR, or FcRn. [0461] In some aspects, a portion of the immunoglobulin constant region may serve as a hinge between the AB domain, for example scFv or nanobody, and the TM domain. The hinge can be of a length that provides for increased responsiveness of the CAR-expressing cell following antigen binding, as compared to in the absence of the hinge. In some examples, the hinge is at or about 12 amino acids in length or is no more than 12 amino acids in length. Exemplary hinges include those having at least about 10 to 229 amino acids, about 10 to 200 amino acids, about 10 to 175 amino acids, about 10 to 150 amino acids, about 10 to 125 amino acids, about 10 to 100 amino acids, about 10 to 75 amino acids, about 10 to 50 amino acids, about 10 to 40 amino acids, about 10 to 30 amino acids, about 10 to 20 amino acids, or about 10 to 15 amino acids, and including any integer between the endpoints of any of the listed ranges. In some embodiments, a hinge has about 12 amino acids or less, about 119 amino acids or less, or about 229 amino acids or less. Exemplary hinges include a CD28 hinge, IgG4 hinge alone, IgG4 hinge linked to CH2 and CH3 domains, or IgG4 hinge linked to the CH3 domain. Exemplary hinges include, but are not limited to, those described in Hudecek M. et al. (2013) Clin. Cancer Res., 19:3153, international patent application publication number WO2014031687, U.S. Pat. No. 8,822,647 or published App. No. US2014/0271635.

[0462] Known hinge sequences include those derived from CD8 a molecule or a CD28 molecule.

Transmembrane (TM) domain

[0463] With respect to the TM domain, the CAR can be designed to comprise a TM domain that is fused to the AB domain of the CAR. A hinge sequence may be inserted between the AB domain and the TM domain. TM domains may be derived from a natural or from synthetic sources. Where the source is natural, the domain may be derived from any membrane-bound or transmembrane protein. Typically, a TM domain denotes a single transmembrane a helix of a transmembrane protein, also known as an integral protein. TM domains e.g., may be derived from (i.e. comprise at least the transmembrane region(s) of) CD28, CD3 e, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD45, CD64, CD80, CD86, CD134, CD137, CD154, TCR a, TCR b, or CD3 zeta and/or TM domains containing functional variants thereof such as those retaining a substantial portion of the structural, e.g., transmembrane, properties thereof.

[0464] Alternatively, the TM domain may be synthetic, in which case the TM domain will comprise predominantly hydrophobic residues such as leucine and valine. Preferably a triplet of phenylalanine, tryptophan and valine will be found at each end of a synthetic TM domain. A TM domain is generally thermodynamically stable in a membrane. It may be a single a helix, a transmembrane b barrel, a b- helix of gramicidin A, or any other structure. Transmembrane helices are usually about 20 amino acids in length.

[0465] A well-used TM domain comprises the TM region of CD28, e.g., human CD28. Often, a short oligo- or polypeptide spacer, e.g., between 2 and 10 amino acids in length is used to form the linkage between the TM domain and the ICS domain(s) of the CAR. Intracellular signaling ) domain and costimulatorv (CS ) domain [0466] The ICS domain or the cytoplasmic domain of a CAR generally triggers or elicits activation of at least one of the normal effector functions of the cell in which the CAR has been placed. The term "effector function" refers to a specialized function of a cell. Effector function of a T cell, for example, may be cytolytic activity or helper activity including the secretion of cytokines. Thus, the term "intracellular signaling domain" or “ICS domain” refers to the portion of a protein which transduces the effector function signal and directs the cell to perform a specialized function. While usually the entire ICS domain can be employed, in many cases it is not necessary to use the entire chain. To the extent that a truncated portion of the intracellular signaling domain is used, such truncated portion may be used in place of the intact chain as long as it transduces the effector function signal. The term "intracellular signaling domain" or “ICS domain” is thus meant to include any truncated portion of the ICS domain sufficient to transduce the effector function signal.

[0467] Examples of known ICS domains include the cytoplasmic sequences of the T cell receptor (TCR) and co-receptors that act in concert to initiate signal transduction following antigen receptor engagement, as well as any derivative or variant of these sequences and any synthetic sequence that has the same functional capability.

[0468] Signals generated through one ICS domain alone may be insufficient for full activation of a cell, and a secondary or costimulatory signal may also be required. In such cases, a costimulatory domain (CS domain) may be included in the cytoplasmic portion of a CAR. A CS domain is a domain that transduces such a secondary or costimulatory signal. In some instances, a CAR of the present disclosure may comprise two or more CS domains. The CS domain(s) may be placed upstream of the ICS domain or downstream of the ICS domain.

[0469] T cell activation can be mediated by two distinct classes of cytoplasmic signaling sequence: those that initiate antigen-dependent primary activation through the TCR (primary cytoplasmic signaling sequences) and those that act in an antigen-independent manner to provide a secondary or costimulatory signal (secondary cytoplasmic signaling sequences). Primary cytoplasmic signaling sequences regulate primary activation of the TCR complex either in a stimulatory way, or in an inhibitory way. Primary cytoplasmic signaling sequences that act in a stimulatory manner may contain signaling motifs which are known as immunoreceptor tyrosine-based activation motifs or IT AMs. Such a cytoplasmic signaling sequence may be contained in the ICS or the CS domain of a CAR. [0470] Examples of ITAM-containing primary cytoplasmic signaling sequences include those derived from an ICS domain of a lymphocyte receptor chain, a TCR/CD3 complex protein, an Fc receptor subunit, an IL-2 receptor subunit, CD3z, FcR g, FcR , CD3y, CD35, CD3e, CD5, CD22, CD66d, CD79a, CD79b, CD278 (ICOS), Fee RI, DAP10, and DAP12. A well-used ICS domain comprises a cytoplasmic signaling sequence derived from CD3 zeta. In some instances, the CD3z ICS domain may be combined with one or more of other cytoplasmic domain(s). For example, the cytoplasmic domain of the CAR can comprise a CD3 z ICS domain and a CS domain wherein a CS region refers to a portion of the CAR comprising the intracellular domain of a costimulatory molecule. A costimulatory molecule is a cell surface molecule other than an antigen receptor or their ligands that is required for an efficient response of lymphocytes to an antigen.

[0471] Examples of co-stimulatory molecules include an MHC class I molecule, TNF receptor proteins, Immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocytic activation molecules (SLAM proteins), activating NK cell receptors, a Toll ligand receptor, B7-H3, BAFFR, BTLA, BLAME (SLAMF8), CD2, CD4, CD5, CD7, CD 8 a, CD 8 b, CDlla, LFA-1 (CDlla/CD18), CDllb, CDllc, CDlld, CD18, CD19, CD19a, CD27, CD28, CD29, CD30, CD40, CD49a, CD49D, CD49f, CD69, CD84, CD96 (Tactile), CD100 (SEMA4D), CD103, CRTAM, 0X40 (CD 134), 4-1BB (CD137), SLAM (SLAMF1, CD150, IPO-3), CD160 (BY55), SELPLG (CD162), DNAM1 (CD226), Ly9 (CD229), SLAMF4 (CD244, 2B4), ICOS (CD278), CEACAM1, CDS, CRTAM, DAP 10, GADS, GITR, HVEM (LIGHTR), IA4, ICAM-1, IL2R b, IL2R g, IL7R a, ITGA4, ITGA6, ITGAD, ITGAE, ITGAL, ITGAM, ITGAX, ITGB1, ITGB2, ITGB7, KIRDS2, LAT, LFA-1, LIGHT, LTBR, NKG2C, NKG2D, NKp30, NKp44, NKp46, NKp80 (KLRF1), PAG/Cbp, PD-1, PSGL1, SLAMF6 (NTB-A, Lyl08), SLAMF7, SLP-76, TNFR2, TRANCE/RANKL, VLA1, VLA-6, a ligand that specifically binds with CD83, and the like. The ICS domain and the CS domain(s) of the CAR may be linked to each other in a random or specified order, optionally via a short oligo- or polypeptide linker, e.g., between 2 and 10 amino acids in length.

Exemplary CAR constructs

[0472] A CAR construct may comprise the following format: “AB domain - hinge - TM domain - CS domain - ICS domain.”

[0473] CARs may comprise an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any of the exemplary constructs below. In the exemplary constructs below, the “anti-CoV-S scFv” may be an scFv generated by linking the VH and VL (in the order of VH-linker-VL or VL-linker-VH) of any one of anti-CoV-S antibodies selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, and ADI-58131.

[0474] In some embodiments, a leader sequence (LS) may be placed upstream of the polynucleotide sequences encoding the CAR. The leader sequence facilitates the expression of the CAR on the cell surface.

Further modification

[0475] CARs according to the present disclosure, nucleotide sequences encoding the same, vectors encoding the same, and cells comprising nucleotide sequences encoding said CARs may be further modified, engineered, optimized, or appended in order to provide or select for various features. These features may include, but are not limited to, efficacy, persistence, target specificity, reduced immunogenicity, multi-targeting, enhanced immune response, expansion, growth, reduced off-target effect, reduced subject toxicity, improved target cytotoxicity, improved attraction of disease alleviating immune cells, detection, selection, targeting, and the like. For example, the cells may be engineered to express another CAR, or to have a suicide mechanism, and may be modified to remove or modify expression of an endogenous receptor or molecule such as a TCR and/or MHC molecule. [0476] In some embodiments, the vector or nucleic acid sequence encoding the CAR further encodes other genes. The vector or nucleic acid sequence may be constructed to allow for the co-expression of multiple genes using a multitude of techniques including co-transfection of two or more plasmids, the use of multiple or bidirectional promoters, or the creation of bicistronic or multicistronic vectors. The construction of multicistronic vectors may include the encoding of IRES elements or 2 A peptides, such as T2A, P2A, E2A, or F2A (for example, see Kim, J.H., et ai, “High cleavage efficiency of a 2A peptide derived from porcine teschovirus-1 in human cell lines, zebrafish and mice”, PLoS One.

2011 ;6(4)). The CAR expressing cell may further comprise a disruption to one or more endogenous genes.

Efficacy

[0477] The CARs of the present disclosure and cells expressing these CARs may be further modified to improve efficacy against cells expressing the target molecule. The cells may be cells expressing COV-S. The cells expressing COV-S may be cancer cells, vascular cells, or any other target disease- associated cells. In some embodiments, the improved efficacy may be measured by increased cytotoxicity against cells expressing the target molecule, for example cytotoxicity against cancer cells. In some embodiments, the improved efficacy may also be measured by increased production of cytotoxic mediators such as, but not limited to, IFN g, perforin, and granzyme B. In some embodiments, the improved efficacy may be shown by reduction in the signature cytokines of the diseases, or alleviated symptoms of the disease when the CAR expressing cells are administered to a subject. Other cytokines that may be reduced include TGF-beta, IL-6, IL-4, IL-10, and/or IL-13. the improved efficacy may be shown by COV-S-specific immune cell responses, such as T cell cytotoxicity. In case of cancer, improved efficacy may be shown by better tumor cytotoxicity, better infiltration into the tumor, reduction of immunosuppressive mediators, reduction in weight decrease, reduction in ascites, reduction in tumor burden, and/or increased lifespan. In case of autoimmune diseases, reduced responsiveness of autoreactive cells or decrease in autoreactive T cells, B cells, or Abs may represent improved efficacy. In some embodiments, gene expression profiles may be also investigated to evaluate the efficacy of the CAR.

[0478] In one aspect, the CAR expressing cells are further modified to evade or neutralize the activity of immunosuppressive mediators, including, but not limited to prostaglandin E2 (PGE2) and adenosine. In some embodiments, this evasion or neutralization is direct. In other embodiments, this evasion or neutralization is mediated via the inhibition of protein kinase A (PKA) with one or more binding partners, for example ezrin. In a specific embodiment, the CAR-expressing cells further express the peptide “regulatory subunit I anchoring disruptor” (RIAD). RIAD is thought to inhibit the association of protein kinase A (PKA) with ezrin, which thus prevents PKA’s inhibition of TCR activation (Newick K. et al. Cancer Immunol Res. 2016 Jun;4(6):541-51).

[0479] In some embodiments, the CAR expressing cells may induce a broad immune response, consistent with epitope spreading.

[0480] In some embodiments, the CAR expressing cells further comprise a homing mechanism. For example, the cell may transgenically express one or more stimulatory chemokines or cytokines or receptors thereof. In particular embodiments, the cells are genetically modified to express one or more stimulatory cytokines. In certain embodiments, one or more homing mechanisms are used to assist the inventive cells to accumulate more effectively to the disease site. In some embodiments, the CAR expressing cells are further modified to release inducible cytokines upon CAR activation, e.g., to attract or activate innate immune cells to a targeted cell (so-called fourth generation CARs or TRUCKS). In some embodiments, CARs may co-express homing molecules, e.g., CCR4 or CCR2b, to increase trafficking to the disease site.

Controlling CAR expression

[0481] In some instances, it may be advantageous to regulate the activity of the CAR or CAR expressing cells CAR. For example, inducing apoptosis using, e.g., a caspase fused to a dimerization domain (see, e.g., Di et al, N Engl. J. Med. 2011 Nov. 3; 365(18): 1673-1683), can be used as a safety switch in the CAR therapy of the instant disclosure. In another example, CAR-expressing cells can also express an inducible Caspase-9 (iCaspase-9) molecule that, upon administration of a dimerizer drug (e.g., rimiducid (also called AP1903 (Bellicum Pharmaceuticals) or AP20187 (Ariad)) leads to activation of the Caspase-9 and apoptosis of the cells. The iCaspase-9 molecule contains a chemical inducer of dimerization (CID) binding domain that mediates dimerization in the presence of a CID. This results in inducible and selective depletion of CAR-expressing cells. In some cases, the iCaspase-9 molecule is encoded by a nucleic acid molecule separate from the CAR-encoding vector(s). In some cases, the iCaspase-9 molecule is encoded by the same nucleic acid molecule as the CAR-encoding vector. The iCaspase-9 can provide a safety switch to avoid any toxicity of CAR- expressing cells. See, e.g., Song et al. Cancer Gene Ther. 2008; 15(10):667-75; Clinical Trial Id. No. NCT02107963; and Di et al. N. Engl. J. Med. 2011; 365:1673-83.

[0482] Alternative strategies for regulating the CAR therapy include utilizing small molecules or antibodies that deactivate or turn off CAR activity, e.g., by deleting CAR-expressing cells, e.g., by inducing antibody dependent cell-mediated cytotoxicity (ADCC). For example, CAR-expressing cells described herein may also express an antigen that is recognized by molecules capable of inducing cell death, e.g., ADCC or compliment-induced cell death. For example, CAR expressing cells described herein may also express a receptor capable of being targeted by an antibody or antibody fragment. Examples of such receptors include EpCAM, VEGFR, integrins (e.g., integrins anb3, a4, aI3/4b3, a4b7, a5b1, anb3, an), members of the TNF receptor superfamily (e.g., TRAIL-R1, TRAIL -R2), PDGF Receptor, interferon receptor, folate receptor, GPNMB, ICAM-1, HLA-DR, CEA, CA-125, MUC1, TAG-72, IL-6 receptor, 5T4, GD2, GD3, CD2, CD3, CD4, CD5, CD11, CDlla/LFA-1, CD15, CD18/ITGB2, CD19, CD20, CD22, CD23/lgE Receptor, CD25, CD28, CD30, CD33, CD38, CD40, CD41, CD44, CD51, CD52, CD62L, CD74, CD80, CD125, CD147/basigin, CD152/CTLA-4, CD154/CD40L, CD195/CCR5, CD319/SLAMF7, and EGFR, and truncated versions thereof (e.g., versions preserving one or more extracellular epitopes but lacking one or more regions within the cytoplasmic domain). For example, CAR-expressing cells described herein may also express a truncated epidermal growth factor receptor (EGFR) which lacks signaling capacity but retains the epitope that is recognized by molecules capable of inducing ADCC, e.g., cetuximab (ERBITUX®), such that administration of cetuximab induces ADCC and subsequent depletion of the CAR- expressing cells (see, e.g., WO2011/056894, and Jonnalagadda et al, “ Gene Ther. 2013; 20(8)853- 860).

[0483] In some embodiments, the CAR cell comprises a polynucleotide encoding a suicide polypeptide, such as for example RQR8. See, e.g., WO2013153391A, which is hereby incorporated by reference in its entirety. In CAR cells comprising the polynucleotide, the suicide polypeptide may be expressed at the surface of a CAR cell. The suicide polypeptide may also comprise a signal peptide at the amino terminus. Another strategy includes expressing a highly compact marker/suicide gene that combines target epitopes from both CD32 and CD20 antigens in the CAR-expressing cells described herein, which binds rituximab, resulting in selective depletion of the CAR-expressing cells, e.g., by ADCC (see, e.g., Philip et al, Blood 2014; 124(8)1277-1287). Other methods for depleting CAR-expressing cells include administration of CAMPATH®, a monoclonal anti-CD52 antibody that selectively binds and targets mature lymphocytes, e.g., CAR-expressing cells, for destruction, e.g., by inducing ADCC. In other embodiments, the CAR-expressing cell can be selectively targeted using a CAR ligand, e.g., an anti-idiotypic antibody. In some embodiments, the anti-idiotypic antibody can cause effector cell activity, e.g., ADCC or ADC activities, thereby reducing the number of CAR- expressing cells. In other embodiments, the CAR ligand, e.g., the anti-idiotypic antibody, can be coupled to an agent that induces cell killing, e.g., a toxin, thereby reducing the number of CAR- expressing cells. Alternatively, the CAR molecules themselves can be configured such that the activity can be regulated, e.g., turned on and off, as described below.

[0484] In some embodiments, a regulatable CAR (RCAR) where the CAR activity can be controlled is desirable to optimize the safety and efficacy of a CAR therapy. In some embodiments, a RCAR comprises a set of polypeptides, typically two in the simplest embodiments, in which the components of a standard CAR described herein, e.g., an AB domain and an ICS domain, are partitioned on separate polypeptides or members. In some embodiments, the set of polypeptides include a dimerization switch that, upon the presence of a dimerization molecule, can couple the polypeptides to one another, e.g., can couple an AB domain to an ICS domain. Additional description and exemplary configurations of such regulatable CARs are provided herein and in International Publication No. WO 2015/090229, hereby incorporated by reference in its entirety.

[0485] In an aspect, an RCAR comprises two polypeptides or members: 1) an intracellular signaling member comprising an ICS domain, e.g., a primary ICS domain described herein, and a first switch domain; 2) an antigen binding member comprising an AB domain, e.g., that specifically binds a target molecule described herein, as described herein and a second switch domain. Optionally, the RCAR comprises a TM domain described herein. In an embodiment, a TM domain can be disposed on the intracellular signaling member, on the antigen binding member, or on both. Unless otherwise indicated, when members or elements of an RCAR are described herein, the order can be as provided, but other orders are included as well. In other words, in an embodiment, the order is as set out in the text, but in other embodiments, the order can be different. E.g., the order of elements on one side of a transmembrane region can be different from the example, e.g., the placement of a switch domain relative to an ICS domain can be different, e.g., reversed.

[0486] In some embodiments, the CAR expressing immune cell may only transiently express a CAR. For example, the cells may be transduced with mRNA comprising a nucleic acid sequence encoding an inventive CAR. In this vein, the present disclosure also includes an RNA construct that can be directly transfected into a cell. A method for generating mRNA for use in transfection involves in vitro transcription (IVT) of a template with specially designed primers, followed by polyA addition, to produce a construct containing 3' and 5' untranslated sequences ("UTRs"), a 5' cap and/or Internal Ribosome Entry Site (IRES), the nucleic acid to be expressed, and a polyA tail, typically 50-2000 bases in length (SEQ ID NO: 405). RNA so produced can efficiently transfect different kinds of cells. In one embodiment, the template includes sequences for the CAR. In an embodiment, an RNA CAR vector is transduced into a cell by electroporation.

Target specificity

[0487] The CAR expressing cells may further comprise one or more CARs, in addition to the first CAR. These additional CARs may or may not be specific for the target molecule of the first CAR. In some embodiments, the one or more additional CARs may act as inhibitory or activating CARs. In some aspects, the CAR of some embodiments is the stimulatory or activating CAR; in other aspects, it is the costimulatory CAR. In some embodiments, the cells further include inhibitory CARs (iCARs, see Fedorov et al, Sci. Transl. Medicine, 2013 Dec;5(215): 215ral72), such as a CAR recognizing an antigen other than the target molecule of the first CAR, whereby an activating signal delivered through the first CAR is diminished or inhibited by binding of the inhibitory CAR to its ligand, e.g., to reduce off-target effects. [0488] In some embodiments, the AB domain of the CAR is or is part of an immunoconjugate, in which the AB domain is conjugated to one or more heterologous molecule(s), such as, but not limited to, a cytotoxic agent, an imaging agent, a detectable moiety, a multimerization domain, or other heterologous molecule. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At211, 1131, 1125, Y90, Rel86, Rel88, Sml53, Bi212, P32, Pb212 and radioactive isotopes of Lu); chemotherapeutic agents; growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; antibiotics; toxins such as small molecule toxins or enzymatically active toxins. In some embodiments, the AB domain is conjugated to one or more cytotoxic agents, such as chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof), or radioactive isotopes.

[0489] In some embodiments, to enhance persistence, the cells may be further modified to overexpress pro-survival signals, reverse anti-survival signals, overexpress Bcl-xL, overexpress hTERT, lack Fas, or express a TGF-b dominant negative receptor. Persistence may also be facilitated by the administration of cytokines, e.g., IF-2, IF-7, and IF-15.

F. B-cell Screening and Isolation

[0490] In one embodiment, the present disclosure contemplates the preparation and isolation of a clonal population of antigen-specific B-cells that may be used for isolating at least one CoV-S antigen-specific cell, which can be used to produce a monoclonal antibody against CoV-S, which is specific to a desired CoV-S antigen, or a nucleic acid sequence corresponding to such an antibody. Methods of preparing and isolating said clonal population of antigen-specific B-cells are taught, for example, in U.S. Patent Publication No. US2007/0269868 to Carvalho-Jensen et al, the disclosure of which is herein incorporated by reference in its entirety. Methods of preparing and isolating said clonal population of antigen-specific B-cells are also taught herein in the examples. Methods of “enriching” a cell population by size or density are known in the art. See, e.g., U.S. Patent No. 5,627,052. These steps can be used in addition to enriching the cell population by antigen-specificity.

G. Methods of Producing Antibodies and Fragments Thereof

[0491] In another embodiment, the present disclosure contemplates methods for producing anti-CoV- S antibodies and fragments thereof. Methods of producing antibodies are well known to those of ordinary skill in the art. For example, methods of producing chimeric antibodies are now well known in the art (See, for example, U.S. Patent No. 4,816,567 to Cabilly et al.·, Morrison et al, Proc. Natl. Acad. Sci. U.S.A., 81:8651-55 (1984); Neuberger et al., Nature, 314:268-270 (1985); Boulianne, G.F. et al, Nature, 312:643-46 (1984), the disclosures of each of which are herein incorporated by reference in their entireties). [0492] As mentioned above, methods of producing humanized antibodies are now well known in the art (See, for example, U.S. Patent Nos. 5,530,101, 5,585,089, 5,693,762, and 6,180,370 to Queen et al U.S. Patent Nos. 5,225,539 and 6,548,640 to Winter; U.S. Patent Nos. 6,054,297, 6,407,213 and 6,639,055 to Carter et al U.S. Patent No. 6,632,927 to Adair; Jones, P.T. et al, Nature, 321:522-525 (1986); Reichmann, L. et al., Nature, 332:323-327 (1988); Verhoeyen, M. etal., Science, 239:1534- 36 (1988), the disclosures of each of which are herein incorporated by reference in their entireties). [0493] Antibody polypeptides of the disclosure having CoV-S binding specificity may also be produced by constructing, using conventional techniques well known to those of ordinary skill in the art, an expression vector containing a promoter (optionally as a component of a eukaryotic or prokaryotic operon) and a DNA sequence encoding an antibody heavy chain in which the DNA sequence encoding the CDRs required for antibody specificity is derived from a non-human cell source, e.g., a rabbit or rodent B-cell source, while the DNA sequence encoding the remaining parts of the antibody chain is derived from a human cell source.

[0494] A second expression vector is produced using the same conventional means well known to those of ordinary skill in the art, said expression vector containing a promoter (optionally as a component of a eukaryotic or prokaryotic operon) and a DNA sequence encoding an antibody light chain in which the DNA sequence encoding the CDRs required for antibody specificity is derived from a non-human cell source, e.g., a rabbit or rodent B-cell source, while the DNA sequence encoding the remaining parts of the antibody chain is derived from a human cell source.

[0495] The expression vectors are transfected into a host cell by convention techniques well known to those of ordinary skill in the art to produce a transfected host cell, said transfected host cell cultured by conventional techniques well known to those of ordinary skill in the art to produce said antibody polypeptides.

[0496] The host cell may be co-transfected with the two expression vectors described above, the first expression vector containing DNA encoding a promoter (optionally as a component of a eukaryotic or prokaryotic operon) and a light chain-derived polypeptide and the second vector containing DNA encoding a promoter (optionally as a component of a eukaryotic or prokaryotic operon) and a heavy chain-derived polypeptide. The two vectors contain different selectable markers, but preferably achieve substantially equal expression of the heavy and light chain polypeptides. Alternatively, a single vector may be used, the vector including DNA encoding both the heavy and light chain polypeptides. The coding sequences for the heavy and light chains may comprise cDNA, genomic DNA, or both.

[0497] The host cells used to express the antibody polypeptides may be either a bacterial cell such as E. coli, or a eukaryotic cell such as P. pastoris. In one embodiment, a mammalian cell of a well- defined type for this purpose, such as a myeloma cell, a CHO cell line, a NSO cell line, or a HEK293 cell line may be used. [0498] The general methods by which the vectors may be constructed, transfection methods required to produce the host cell and culturing methods required to produce the antibody polypeptides from said host cells all include conventional techniques. Although preferably the cell line used to produce the antibody is a mammalian cell line, any other suitable cell line, such as a bacterial cell line such as an E. coli- derived bacterial strain, or a yeast cell line, may alternatively be used.

[0499] Similarly, once produced the antibody polypeptides may be purified according to standard procedures in the art, such as for example cross-flow filtration, ammonium sulphate precipitation, affinity column chromatography, hydrophobic interaction chromatography (“HIC”), and the like. [0500] The antibody polypeptides described herein may also be used for the design and synthesis of either peptide or non-peptide mimetics that would be useful for the same therapeutic applications as the antibody polypeptides of the disclosure (See, for example, Saragobi et ai, Science, 253:792-795 (1991), the contents of which are herein incorporated by reference in its entirety).

[0501] In another embodiment, the present disclosure contemplates methods for humanizing antibody heavy and light chains which bind to CoV-S. Exemplary methods for humanizing antibody heavy and light chains that may be applied to anti-CoV-S antibodies are identified herein and are conventional in the art.

H. Screening Assays

[0502] The screening assays described here may be used to identify high affinity anti-CoV-S Abs which may be useful in the treatment of diseases and disorders associated with CoV-S in subjects exhibiting symptoms of a CoV-S associated disease or disorder.

[0503] In some embodiments, the antibody is used as a diagnostic tool. The antibody can be used to assay the amount of CoV-S present in a sample and/or subject. As will be appreciated by one of skill in the art, such antibodies need not be neutralizing antibodies. In some embodiments, the diagnostic antibody is not a neutralizing antibody. In some embodiments, the diagnostic antibody binds to a different epitope than the neutralizing antibody binds to. In some embodiments, the two antibodies do not compete with one another.

[0504] In some embodiments, the antibodies disclosed herein are used or provided in an assay kit and/or method for the detection of CoV-S in mammalian tissues or cells in order to screen/diagnose for a disease or disorder associated with changes in levels of CoV-S. The kit comprises an antibody that binds CoV-S and means for indicating the binding of the antibody with CoV-S, if present, and optionally CoV-S protein levels. Various means for indicating the presence of an antibody can be used. For example, fluorophores, other molecular probes, or enzymes can be linked to the antibody and the presence of the antibody can be observed in a variety of ways. The method for screening for such disorders can involve the use of the kit, or simply the use of one of the disclosed antibodies and the determination of whether the antibody binds to CoV-S in a sample. As will be appreciated by one of skill in the art, high or elevated levels of CoV-S will result in larger amounts of the antibody binding to CoV-S in the sample. Thus, degree of antibody binding can be used to determine how much CoV-S is in a sample. Subjects or samples with an amount of CoV-S that is greater than a predetermined amount (e.g., an amount or range that a person without a CoV-S -related disorder would have) can be characterized as having a CoV-S-mediated disorder.

[0505] The present disclosure further provides for a kit for detecting binding of an anti-CoV-S antibody of the disclosure to CoV-S. In particular, the kit may be used to detect the presence of CoV- S specifically reactive with an anti-CoV-S antibody or an immunoreactive fragment thereof. The kit may also include an antibody bound to a substrate, a secondary antibody reactive with the antigen and a reagent for detecting a reaction of the secondary antibody with the antigen. Such a kit may be an ELISA kit and can comprise the substrate, primary and secondary antibodies when appropriate, and any other necessary reagents such as detectable moieties, enzyme substrates, and color reagents, for example as described herein. The diagnostic kit may also be in the form of an immunoblot kit. The diagnostic kit may also be in the form of a chemiluminescent kit (Meso Scale Discovery,

Gaithersburg, MD). The diagnostic kit may also be a lanthanide -based detection kit (PerkinElmer, San Jose, CA).

[0506] A skilled clinician would understand that a biological sample includes, but is not limited to, sera, plasma, urine, fecal sample, saliva, mucous, pleural fluid, synovial fluid, and spinal fluid.

7. Methods of Ameliorating or Reducing Symptoms of, or Treating, or Preventing, Diseases and Disorders Associated with CoV

[0507] In another embodiment, anti-CoV-S antibodies described herein, or antigen-binding fragments thereof, are useful for ameliorating or reducing the symptoms of, or treating, or preventing, diseases and disorders associated with CoV-S. Anti-CoV-S antibodies described herein, or antigen binding fragments thereof, as well as combinations, can also be administered in a therapeutically effective amount to patients in need of treatment of diseases and disorders associated with CoV-S in the form of a pharmaceutical composition as described in greater detail below.

[0508] Symptoms of CoV infection may include fever, cough, runny nose, congestion, sore throat, bronchitis, pneumonia, shortness of breath, chest pain, headache, muscle ache, chills, fatigue, conjunctivitis, diarrhea, loss of smell, and loss of taste. Complications and/or diseases/disorders associated with coronavirus infection may include, for example, bronchitis, pneumonia, respiratory failure, acute respiratory failure, organ failure, multi-organ system failure, pediatric inflammatory multisystem syndrome, acute respiratory distress syndrome (a severe lung condition that causes low oxygen in the blood and organs), blood clots, cardiac conditions, myocardial injury, myocarditis, heart failure, cardiac arrest, acute myocardial infarction, dysrhythmias, venous thromboembolism, post intensive care syndrome, shock, anaphylactic shock, cytokine release syndrome, septic shock, disseminated intravascular coagulation, ischemic stroke, intracerebral hemorrhage, microangiopathic thrombosis, psychosis, seizure, nonconvulsive status epilepticus, traumatic brain injury, stroke, anoxic brain injury, encephalitis, posterior reversible leukoencephalopathy, necrotizing encephalopathy, post- infectious encephalitis, autoimmune mediated encephalitis, acute disseminated encephalomyelitis, acute kidney injury, acute liver injury, pancreatic injury, immune thrombocytopenia, subacute thyroiditis, gastrointestinal complications, aspergillosis, increased susceptibility to infection with another virus or bacteria, and/or pregnancy-related complications. Certain diseases and conditions, such as high blood pressure, type 1 diabetes, liver disease, overweight, chronic lung diseases including cystic fibrosis, pulmonary fibrosis, and asthma, compromised immune system due to transplant, use of an immunosuppressant, or HIV infection, and brain and nervous system condition, may increase the risk of CoV infection-associated complications and diseases.

[0509] Also, the subject anti-CoV-S antibodies and antigen-binding fragments may be used alone or in conjunction with other active agents, e.g., opioids and non-opioid analgesics such as NSAIDs to elicit analgesia. In some embodiments, aspirin and/or acetaminophen may be taken in conjunction with the subject anti-CoV-S antibody or antigen-binding fragment. Aspirin is another type of non steroidal anti-inflammatory compound.

[0510] The subject antibodies potentially optionally may be combined with one or more of the following: (i) an antiviral drug, optionally, remdesivir, favipiravir, darunavir, nelfinavir, saquinavir, lopinavir, or ritonavir; (ii) an antihelminth drug, optionally ivermectin; (iii) an antiparasitic drug, optionally hydroxychloroquine, chloroquine, or atovaquone; (iv) antibacterial vaccine, optionally the tuberculosis vaccine BCG; or (v) an anti-inflammatory drug, optionally a steroid such as ciclesonide, a TNF inhibitor (e.g., adalimumab), a TNF receptor inhibitor (e.g., etanercept), an IL-6 inhibitor (e.g., clazakizumab), an IL-6 receptor inhibitor (e.g., toclizumab), or metamizole; (vi) an antihistamine drug, optionally bepotastine; (vii) an ACE inhibitor, which is optionally moexipril; or (viii) a drug that inhibits priming of CoV-S, optionally a serine protease inhibitor, further optionally nafamostat. in order to increase or enhance pain management. This may allow for such analgesic compounds to be administered for longer duration or at reduced dosages thereby potentially alleviating adverse side effects associated therewith.

[0511] The subject to which the pharmaceutical formulation is administered can be, e.g., any human or non-human animal needing such treatment, prevention and/or amelioration, or who would otherwise benefit from the inhibition or attenuation of CoV-S-mediated activity. For example, the subject can be an individual that is diagnosed with, or who is deemed to be at risk of being afflicted by any of the aforementioned diseases or disorders. In some instances the subject may be in an advanced state of CoV infection, e.g., a subject who is on a ventilator. In some instances, the subject can be one having one or more risk factors (such as advanced age, obesity, diabetes, etc, and others previously identified) which correlate to a poor CoV treatment or recovery prognosis. The present disclosure further includes the use of any of the pharmaceutical formulations disclosed herein in the manufacture of a medicament for the treatment, prevention and/or amelioration of any disease or disorder associated with CoV or CoV-S activity (including any of the above-mentioned exemplary diseases, disorders and conditions).

[0512] The present invention also provides a method for treating a coronavirus infection in a subject in need thereof, the method comprising administering to the subject an isolated antibody, or antigen binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising a VH CDR1 comprising SEQ ID NO:52, a VH CDR2 comprising SEQ ID NO:54, and a VH CDR3 comprising SEQ ID NO:56, and a light chain variable region (VL) comprising a VL CDR1 comprising SEQ ID NO:252, a VL CDR2 comprising SEQ ID NO:254, and a VL CDR3 comprising SEQ ID NO:256; and wherein the antibody, or antigen-binding fragment thereof, is administered at a dosage of at least 300 mg within 5, 4, 3, 2, or 1 days of symptom onset. In some embodiments, the antibody, or antigen-binding fragment thereof, is administered at a dosage of about 300 mg. In some embodiments, the antibody, or antigen-binding fragment thereof, is administered at a dosage of about 500 mg. In some embodiments, the antibody, or antigen-binding fragment thereof, is administered at a dosage of about 600 mg. In some embodiments, the antibody, or antigen-binding fragment thereof, is administered at a dosage of about 1200 mg. In some embodiments, the antibody, or antigen-binding fragment thereof, is administered at a dosage of about 4500 mg.

[0513] In some embodiments, the subject has at least one risk factor which renders them more prone to a poor clinical outcome. In some embodiments, the at least one risk factor is selected from the group consisting of: an old age selected from the group consisting of over 55, over 60 or over 65 years old; diabetes, a chronic respiratory condition, obesity, hypertension, a cardiac or cardiovascular condition, a chronic inflammatory or autoimmune condition, and an immune compromised status. In some embodiments, the subject is immunocompromised. In some embodiments, the subject is at a high risk of disease progression. In some embodiments, the subject is (a) age 50 years or above with no comorbid conditions or additional risk factors for progression of COVID-19; (b) between about 18 to about 50 years old and with one or more preexisting medical conditions selected from the group consisting of obesity, diabetes, chronic kidney disease, chronic lung disease, cardiac disease, sickle cell disease or thalassemia, solid organ or blood stem cell transplant recipient, other immunodeficiency due to underlying illness or immunosuppressant medication, Down Syndrome, stroke or cerebrovascular disease, substance use disorder, and pregnancy; or (c) between about 12 to about 17 years old and with one or more preexisting medical conditions selected from the group consisting of obesity, diabetes, chronic kidney disease, sickle cell disease or thalassemia, congenital or acquired heart disease, neurodevelopmental disorder, a medically-related technological dependence, asthma or chornic respiratory disease, solid organ or blood stem cell transplant recipient, other immunodeficiency due to underlying illness or immunosuppressant medication, Down Syndrome, stroke or cerebrovascular disease, substance use disorder, and pregnancy. In some embodiments, the subject is age 50 or above with no comorbid conditions or additional risk factors for progression of COVID-19. In some embodiments, the subject has hypertension with at least one medication prescribed or recommended. In some embodiments, the subject has moderate to severe asthma requiring daily therapy.

J. Administration

[0514] In one embodiment, the anti-CoV-S antibodies described herein, or CoV-S binding fragments thereof, as well as combinations of said antibodies or antigen-binding fragments thereof, are administered to a subject at a concentration of between 0.1 mg/ml and about any one of 0.5, 1, 5, 10, 15 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170,

180, 190, or 200 mg/ml, +/-10% error.

[0515] In another embodiment, the anti-CoV-S antibodies and fragments thereof described herein are administered to a subject at a dose of between about 0.01 and 100.0 or 200.0 mg/kg of body weight of the recipient subject. In certain embodiments, depending on the type and severity of the CoV-S- related disease, about 1 μg/kg to 50 mg/kg (e.g., 0.1-20 mg/kg) of antibody is an initial candidate dosage for administration to the patient, whether, for example, by one or more separate administrations, or by continuous infusion. In another embodiment, about 1 μg/kg to 15 mg/kg (e.g., 0.1 mg/kg- 10 mg/kg) of antibody is an initial candidate dosage for administration to the patient. A typical daily dosage might range from about 1 μg/kg to 100 mg/kg or more, depending on several factors, e.g., the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. However, other dosage regimens may be useful.

[0516] For example, in addition to the relative dosages (mg/kg) discussed herein, the subject anti- CoV-S antibodies and antigen-binding fragments thereof can be administered to a subject at an absolute dose (mg). Accordingly, in one embodiment, the anti-CoV-S antibodies and antigen-binding fragments thereof described herein are administered to a subject at a dose of between about 1 microgram and about 2000 milligrams regardless of the route of administration.

[0517] In some embodiments, the antibody, or antigen-binding fragment thereof, is administered at a dose of about 100 mg to about 5000 mg, about 100 mg to about 4500 mg, about 100 mg to about 4000 mg, about 100 mg to about 3500 mg, about 100 mg to about 3000 mg, about 100 mg to about 2500 mg, about 300 mg to about 4500 mg, about 500 mg to about 4500 mg, about 600 mg to about 4500 mg, about 1200 mg to about 4500 mg, about 100 mg to about 2000 mg, about 200 mg to about 1500 mg, about 300 mg to about 600 mg, about 500 mg to about 1200 mg, or about 300 mg to about 1200 mg. In some embodiments, the antibody, or antigen-binding fragment thereof, is administered at a dose of about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2500 mg, about 3000 mg, about 3500 mg, about 4000 mg, about 4500 mg, or about 5000 mg.

[0518] In some embodiments, the antibody, or antigen-binding fragment thereof, is administered intravenously. In other embodiments, the antibody, or antigen-binding fragment thereof, is administered intramuscularly.

[0519] In some embodiments, the antibody, or antigen-binding fragment thereof, is administered at a dose of about 150 mg intramuscularly, about 300 mg intramuscularly, about 450 mg intramuscularly, about 500 mg intravenously, about 600 mg intramuscularly, about 1200 mg intramuscularly, or about 1200 mg intravenously.

[0520] In some embodiments, at least one of the antibody, or antigen-binding fragment thereof, is administered. In some embodiments, at least two of the antibody, or antigen-binding fragment thereof, are administered. In some embodiments, the anti-CoV-S antibody and antigen-binding fragment thereof, e.g., ADI-58125, may be used in combination with a second antibody, or antigen-binding fragment thereof, wherein the second antibody, or antigen-binding fragment thereof, is selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130, ADI-58131, or a combination thereof. In some embodiment, the second antibody, or antigen-binding fragment thereof, is ADI-58122. In one embodiment, the second antibody, or antigen-binding fragment thereof, is ADI-58127. In one embodiment, the second antibody, or antigen-binding fragment thereof, is ADI-58129. In one embodiment, the second antibody, or antigen-binding fragment thereof, is ADI-58131.

[0521] In one embodiment, the antibody, or antigen-binding fragment thereof, is administered once. In one embodiment, the antibody, or antigen-binding fragment thereof, is administered weekly. In another embodiment, the antibody, or antigen-binding fragment thereof, is administered daily, weekly, every two weeks, monthly, or every two months. In one embodiment, the antibody, or antigen-binding fragment thereof, is administered weekly for about four weeks, once weekly for about a month, weekly for about 5 weeks, weekly for about 6 weeks, weekly for about 7 weeks, or weekly for about two months.

[0522] In some embodiments, the methods further comprise obtaining a serum sample from the subject.

[0523] In some embodiments, the antibody, or antigen-binding fragment thereof, reaches a maximum concentration (Cmax) of about 10 μg/mL to about 1000 μg/mL, about 20 μg/mL to about 500 μg/mL, about 30 μg/mL to about 400 μg/mL, about 40 μg/mL to about 300 μg/mL, about 50 μg/mL to about 200 mg/mL, about 50 mg/mL to about 100 mg/mL, about 30 mg/mL to about 70 mg/mL, about 100 mg.mL to about 400 mg/mL, or about 150 mg/mL to about 350 mg/mL in the serum sample of the subject. In some embodiments, the antibody, or antigen-binding fragment thereof, reaches a maximum concentration (Cmax) of about 30 mg/mL, about 40 mg/mL, about 50 mg/mL, about 60 mg/mL, about 70 mg/mL, about 80 mg/mL, about 90 mg/mL, about 100 mg/mL, about 110 mg/mL, about 120 mg/mL, about 130 mg/mL, about 140 mg/mL, about 150 mg/mL, about 160 mg/mL, about 170 mg/mL, about 180 mg/mL, about 190 mg/mL,or about 200 mg/mL, about 210 mg/mL, about 220 mg/mL, about 230 mg/mL, about 240 mg/mL, about 250 mg/mL, about 260 mg/mL, about 270 mg/mL, about 280 mg/mL, about 290 mg/mL, about 300 mg/mL, about 350 mg/mL, or about 400 mg/mL in the serum sample of the subject.

[0524] In some embodiments, the median time for the antibody, or antigen-binding fragment thereof, to reach a maximum concentration in the serum sample of the subject is about 5-30 days, about 6-20 days, about 7-18 days, or about 8-15 days, or about 13-15 days after administration. In some embodiments, the median time for the antibody, or antigen-binding fragment thereof, to reach a maximum concentration in the serum sample of the subject is about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 days after administration.

[0525] In some embodiments, the antibody, or antigen-binding fragment thereof, reaches a maximum concentration (Cmax) of about 30 μg/mL to about 100 μg/mL, about 40 μg/mL to about 80 μg/mL, about 50 μg/mL to about 70 μg/mL, or about 30 μg/mL to about 65 μg/mL in the serum sample of the subject in about 6-20 days, about 7-18 days, about 8-15 or about 13-15 days after administration. [0526] In some embodiments, the area under the serum concentration-time curve from day 0 to day 21 (AUC0-21d) is about 100-2000 day* μg/mL, about 1000-2000 day* μg/mL, about 1400-2000 day* μg/mL, about 200-1500 day* μg/mL, about 400-1400 day* μg/mL, about 500-1300 day* μg/mL, about 600-1000 day* μg/mL, or about 800-900 day* μg/mL.

[0527] In some embodiments, the area under the serum concentration-time curve from day 0 to day 21 (AUC0-21d) is about 500 day* μg/mL, about 600 day* μg/mL, about 700 day* μg/mL, about 800 day* μg/mL, about 900 day* μg/mL, about 1000 day* μg/mL, about 1100 day* μg/mL, about 1200 day* μg/mL, about 1300 day* μg/mL, about 1400 day* μg/mL, about 1500 day* μg/mL, about 1600 day* μg/mL, about 1700 day* μg/mL, about 1800 day* μg/mL, about 1900 day* μg/mL, or about 2000 day* μg/mL.

[0528] In some embodiments, the area under the serum concentration-time curve from day 0 to day 90 (AUC0-90d) is about 1000-10000 day* μg/mL, about 2000-5000 day* μg/mL, about 3000-4000 day* μg/mL, about 5000-10000 day* μg/mL, about 5000-8000 day* μg/mL, or about 6000-8000 day* μg/mL.

[0529] In some embodiments, the area under the serum concentration-time curve from day 0 to day 90 (AUC0-90d) is about 1000 day* μg/mL, about 2000 day* μg/mL, about 3000 day* μg/mL, about 4000 day* mg/mL, about 5000 day* mg/mL, about 6000 day* mg/mL, about 7000 day* mg/mL, about 8000 day* mg/mL, about 9000 day* mg/mL, or about 10000 day* mg/mL.

[0530] In some embodiments, the area under the serum concentration-time curve from day 0 to day 180 (AUC0-180d) is about 1000-10000 day* mg/mL, about 2000-5000 day* mg/mL, about 3000-6000 day* mg/mL, about 5000-10000 day* mg/mL, about 5000-8000 day* mg/mL, or about 4000-6000 day* mg/mL.

[0531] In some embodiments, the area under the serum concentration-time curve from day 0 to day 180 (AUC0-180d) is about 1000 day* mg/mL, about 2000 day* mg/mL, about 3000 day* mg/mL, about 4000 day* mg/mL, about 5000 day* mg/mL, about 6000 day* mg/mL, about 7000 day* mg/mL, about 8000 day* mg/mL, about 9000 day* mg/mL, or about 10000 day* mg/mL.

[0532] In some embodiments, the area under the serum concentration-time curve from day 0 to day 365 (AUCo 365_d) is about 1000-30000 day* mg/mL, about 5000-30000 day* mg/mL, about 10000- 30000 day* mg/mL, about 10000-15000 day* mg/mL, about 20000-30000 day* mg/mL, or about 25000-30000 day* mg/mL.

[0533] In some embodiments, the area under the serum concentration-time curve from day 0 to day 365 (AUCo 365_d) is about 1000 day* mg/mL, about 2000 day* mg/mL, about 3000 day* mg/mL, about 4000 day* mg/mL, about 5000 day* mg/mL, about 6000 day* mg/mL, about 7000 day* mg/mL, about 8000 day* mg/mL, about 9000 day* mg/mL, about 10000 day* mg/mL, about 11000 day* mg/mL, about 12000 day* mg/mL, about 13000 day* mg/mL, about 14000 day* mg/mL, about 15000 day* mg/mL, about 20000 day* mg/mL, about 21000 day* mg/mL, about 22000 day* mg/mL, about 23000 day* mg/mL, about 24000 day* mg/mL, about 25000 day* mg/mL, about 26000 day* mg/mL, about 27000 day* mg/mL, about 28000 day* mg/mL, about 29000 day* mg/mL, or about 30000 day* mg/mL. [0534] In some embodiments, the antibody, or antigen-binding fragment thereof, has a serum half- life of about 50-200 days, about 50-160 days, about 50-140 days, about 40-130 days, about 50-100 days, about 60-100 days, about 60-90 days, about 70-90 days, about 90-100 days, about 70-80 days, about 80-130 days, about 100-150 days, about 110-140 days, about 120-140 days. In some embodiments, the antibody, or antigen-binding fragment thereof, has a serum half-life of about 50, 55, 60, 65, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118,

119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 165, 170, 75, 180, 185, 190, 195, or 200 days.

[0535] In some embodiments, the method further comprises obtaining an epithelial lining fluid (ELF) sample from the subject. The ELF sample may comprise an ELF sample from the upper airway, e.g., nasopharyngeal or oropharyngeal; the lower airway, e.g., lung, and/or an alveolar tissue. [0536] In some embodiments, the antibody, or antigen-binding fragment thereof, reaches a concentration of about 1 mg/mL to about 100 mg/mL, about 1 mg/mL to about 80 mg/mL, about 80 mg/mL to about 100 mg/mL, about 50 mg/mL to about 100 mg/mL, about 1 mg/mL to about 50 mg/mL, about 2 mg/mL to about 25 mg/mL, or about 2 mg/mL to about 10 mg/mL in the ELF sample of the subject.

[0537] In some embodiments, the antibody, or antigen-binding ragment thereof, has a receptor occupancy of at least 50%, 60%, 70%, 80%, or 90% in the ELF sample. Receptor occupany (RO) can be linked to a viral dynamic model to enable the prediction of the natural time course of viral load and the effect of the antibody, or antigen-binding fragment thereof, on viral clearance and infectivity rate. In some embodiments, RO can be calculated using: 1) in vitro SARS-CoV-2 binding kinetics of the antibody, or antigen-binding fragment thereof, e.g., the association rate constant (k_on) and the dissociation rate constant (k_0ff) , e.g., obtained from a Biacore assay; 2) time course of the concentrations of the antibody, or antigen-binding fragment thereof, in a sample, e.g., an ELF sample; and 3) time course of viral load following administration of the antibody, or antigen-binding fragment thereof.

[0538] In some embodiments, administration of the antibody, or antigen-binding fragment thereof, results in at least 50%, 60%, 70%, 80%, or 90% SARS-CoV-2 receptor occupancy in the ELF sample. In some embodiments, administration of the antibody, or antigen-binding fragment thereof, results in a durable, e.g., about 20-day, about 25-day, about 28-day, about 30-day, about 40-day, about 50-day, about 60-day, SARS-CoV-2 receptor occupancy in the ELF sample. In other embodiments, administration of the antibody, or antigen-binding fragment thereof, maintains the concentration of the antibody, or antigen binding fragment thereof, above a concentration (e.g., about 0.27 mg/L or about 0.5 mg/L) associated with about 95% or 100% viral growth suppression in an in vitro post infection assay.

[0539] In some embodiments, intramuscular (IM) administration of ADI-58125 at a dose of about 300 mg results in about 90% SARS-CoV-2 receptor occupacy in the ELF sample for at least 28 days, and maintains the concentration of ADI-58125 in the ELF sample above the concentration associated with 100% viral growth suppression in vitro, i.e., 0.5 mg/mL.

[0540] In some embodiments, intramuscular (IM) administration of ADI-58125 at a dose of about 300 mg results in about 90% SARS-CoV-2 receptor occupacy in the ELF sample for at least 28 days, and maintains the concentration of ADI-58125 in the ELF sample above the concentration associated with 95% viral growth suppression in vitro, i.e., 0.274 mg/mL.

[0541] In some embodiments, administration of the antibody, or antigen-binding fragment thereof, results in a 50% virus neutralization titer (MN50) of about 100-2000, e.g., within the range of peak serum virus-neutralizing antibody (sVNA) titers for COVID-19 vaccine recipients. In some embodiments, administration of the antibody, or antigen-binding fragment thereof, maintains a serum concentration of the antibody, or antigen-binding fragment thereof, about 100-fold higher than the in vitro 90% inhibitory concentration (IC₉₀) of 0.011 μg/mL against authentic SARS-CoV-2 (USA- WA1) for a minimum of 6 months.

[0542] In some embodiments, the virus neutralization titer of the antibody, or antigen-binding fragment thereof, is determined using a plaque reduction neutralization test (PRNT), as described in Example 1. The PRNT is a serological test which utilizes the ability of a specific antibody to neutralize a virus, in turn, preventing the virus from causing the formation of plaques in a cell monolayer (Stephen J. et al., The American Journal of Tropical Medicine and Hygiene. 81 (5): 825- 833). Typically, the assay involves mixing a constant amount of virus with dilutions of the serum specimen being tested, followed by plating of the mixture onto cells of an appropriate cell line for the individual virus. The concentration of plaque forming units can be determined by the number of plaques formed after a few days. A vital dye (e.g., neutral red) is then added for visualization of the plaques and the number of plaques in an individual plate is divided by the original number of virons to calculate the percentage neutralization. Depending on the virus, the plaque forming units are measured by microscopic observations, fluorescent antibodies, or specific dyes that react with the infected cell. Currently, the PRNT test is considered the "gold standard" for detecting and measuring antibodies that can neutralize the viruses that cause many diseases. It has a higher sensitivity and is more specific than many other serological tests for the diagnosis of some viruses. In some embodiments, the 80% neutralization titer is reported using a validated method, e.g., SOP-VC-M204. In some embodiments, the 50% neutralization titer is reported.

[0543] In some embodiments, the antibody, or antigen-binding fragment thereof, has a virus neutralizing titer of about 100-2000, about 200-1500, about 300-1500, or about 500-1500 in the serum sample of the subject about 3, 6, or 12 months after administration. In some embodiments, the antibody, or antigen-binding fragment thereof, has a virus neutralizing titer of about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900 or 2000 in the serum sample of the subject about 3, 6 or 12 months after administration.

[0544] In some embodiments, the 80% virus neutralization titer (MN80) of the antibody, or antigen binding fragment thereof, at about days 0-14, about days 7-21, about 3 months, or about 6 months after administration, is about 10-6000, about 50-600, about 500-1500, about 1000-2500, about 100- 2500, about 500-2000, about 500-1500, about 400-1200, about 200-1500, about 300-1000, about 400- 800, about 400-1000, or about 500-600 in the subject.

[0545] In some embodiments, the 80% virus neutralization titer (MN80) of the antibody, or antigen binding fragment thereof, at about day 7, day 14, or day 21 after administration, is about 300-2000, about 400-600, about 600-1500, about 1100-1700, about 500-1700, about 500-1500, about 400-1200, about 400-800, about 400-1000, or about 500-600 in the serum sample of the subject. [0546] In some embodiments, the 80% virus neutralization titer (MN80) of the antibody, or antigen binding fragment thereof, at about 3 months after administration, is about 200-1000, about 200-800, about 200-500, about 400-900, or about 400-600 in the serum sample of the subject.

[0547] In some embodiments, the 80% virus neutralization titer (MN80) of the antibody, or antigen binding fragment thereof, at about 6 months after administration, is about 10-500, about 300-500, or about 50-200 in the serum sample of the subject.

[0548] In some embodiments, the 50% virus neutralization titer (MN50) of the antibody, or antigen binding fragment thereof, at about days 0-14, about days 7-21, about 3 months, about 6 months, or about 12 months after administration, is about 100-6000, about 300-1500, about 1700-3800, about 3800-5200, about 300-5500, about 1200-4500, about 1300-4300, about 1200-4000, about 100-2500, about 500-2500, about 800-2000, about 1000-1800, about 800-1300, about 900-1100, or about 1300- 1500 in the serum sample of the subject.

[0549] In some embodiments, the 50% virus neutralization titer (MN50) of the antibody, or antigen binding fragment thereof, at about day 7, day 14 or day 21 after administration, is about 1000-4500, about 1200-4500, about 1300-4300, about 1200-3900, about 1500-4000, about 1800-3800, about 3800-4500, about 1000-1800 or about 1200-1500 in the serum sample of the subject.

[0550] In some embodiments, the 50% virus neutralization titer (MN50) of the antibody, or antigen binding fragment thereof, at about 3 months after administration, is about 800-1300 or about 900- 1100 in the serum sample of the subject. In some embodiments, the 50% virus neutralization titer (MN50) of the antibody, or antigen-binding fragment thereof, at about 6 months after administration, is about 200-500 or about 300-600 in the serum sample of the subject.

[0551] In some embodiments, the 50% virus neutralization titer (MN50) of the antibody, or antigen binding fragment thereof, at about 12 months after administration, is about 150-500 or about 200-400 in the serum sample of the subject.

[0552] In some embodiments, the serum concentration of the antibody, or antigen-binding fragment thereof, is about 1-300 mg/L, about 1-250 mg/L, about 1-200 mg/L, about 1-100 mg/L, about 100-250 mg/L, about 150-200 mg/L, about 120-170 mg/L, about 1-90 mg/L, about 1-80 mg/L, about 1-70 mg/L, about 1-60 mg/L, about 1-50 mg/L, about 1-40 mg/L, about 1-30 mg/L, about 1-20 mg/L, about 1-10 mg/L, about 2-9 mg/L, about 3-8 mg/L, about 4-6 mg/L, about 5-80 mg/L, about 10-70 mg/L, or about 10-60 mg/L in the subject about 3 months after administration.

[0553] In some embodiments, the serum concentration of the antibody, or antigen-binding fragment thereof, is about 1 mg/L, about 2 mg/L, about 3 mg/L, about 4 mg/L, about 5 mg/L, about 6 mg/L, about 7 mg/L, about 8 mg/L, about 9 mg/L, about 10 mg/L, about 11 mg/L, about 12 mg/L, about 13 mg/L, about 14 mg/L, about 15 mg/L, about 16 mg/L, about 17 mg/L, about 18 mg/L, about 19 mg/L, about 20 mg/L, about 25 mg/L, about 30 mg/L, about 35 mg/L, about 40 mg/L, about 45 mg/L, about 50 mg/L, about 55 mg/L, about 60 mg/L, about 65 mg/L, about 70 mg/L, about 75 mg/L, about 80 mg/L, about 85 mg/L, about 90 mg/L, about 95 mg/L, about 100 mg/L, about 110 mg/L, about 120 mg/L, about 130 mg/L, about 140 mg/L, about 150 mg/L, about 160 mg/L, about 170 mg/L, about 180 mg/L, about 190 mg/L, about 200 mg/L, about 210 mg/L, about 220 mg/L, about 230 mg/L, about 240 mg/L, about 250 mg/L, about 300 mg/L in the subject about 3 months after administration. [0554] In some embodiments, the serum concentration of the antibody, or antigen-binding fragment thereof, is about 1-100 mg/L, about 1-90 mg/L, about 1-80 mg/L, about 1-70 mg/L, about 1-60 mg/L, about 1-50 mg/L, about 1-40 mg/L, about 1-30 mg/L, about 1-20 mg/L, about 1-10 mg/L, about 2-9 mg/L, about 3-8 mg/L, about 4-6 mg/L, about 5-80 mg/L, about 10-70 mg/L, about 10-60 mg/L, about 5-25 mg/L, about 10-30 mg/L, about 15-25 mg/L, about 20-100 mg/L, about 30-100 mg/L, about 50- 80 mg/L, or about 60-70 mg/L in the subject about 6 months after administration.

[0555] In some embodiments, the serum concentration of the antibody, or antigen-binding fragment thereof, is about 1 mg/L, about 2 mg/L, about 3 mg/L, about 4 mg/L, about 5 mg/L, about 6 mg/L, about 7 mg/L, about 8 mg/L, about 9 mg/L, about 10 mg/L, about 11 mg/L, about 12 mg/L, about 13 mg/L, about 14 mg/L, about 15 mg/L, about 16 mg/L, about 17 mg/L, about 18 mg/L, about 19 mg/L, about 20 mg/L, about 25 mg/L, about 30 mg/L, about 35 mg/L, about 40 mg/L, about 45 mg/L, about 50 mg/L, about 55 mg/L, about 60 mg/L, about 65 mg/L, about 70 mg/L, about 75 mg/L, about 80 mg/L, about 85 mg/L, about 90 mg/L, about 95 mg/L, or about 100 mg/L in the subject about 6 months after administration.

[0556] In some embodiments, the serum concentration of the antibody, or antigen-binding fragment thereof, is about 0.1-30 mg/L, about 1-30 mg/L, about 1-20 mg/L, about 1-10 mg/L, about 10-20 mg/L, about 0.1-3 mg/L, about 0.5-8 mg/L, about 0.5-10 mg/L, about 2-9 mg/L, about 5-15 mg/L, about 3-8 mg/L, or about 4-6 mg/L in the subject about 12 months after administration.

[0557] In some embodiments, the serum concentration of the antibody, or antigen-binding fragment thereof, is about 0.1 mg/L, about 0.2 mg/L, about 0.3 mg/L, about 0.4 mg/L, about 0.5 mg/L, about 0.6 mg/L, about 0.7 mg/L, about 0.8 mg/L, about 0.9 mg/L, about 1 mg/L, about 2 mg/L, about 3 mg/L, about 4 mg/L, about 5 mg/L, about 6 mg/L, about 7 mg/L, about 8 mg/L, about 9 mg/L, about 10 mg/L, about 15 mg/L, about 20 mg/L, about 25 mg/L, or about 30 mg/L in the subject about 12 months after administration.

[0558] In some embodiments, the clearance rate for the antibody, or antigen-binding fragment thereof, is about 0.1-10 mL/d, about 0.1-5.0 mL/d, about 0.1-3.0 mL/d, about 0.5-2.5 mL/d, or about 1.0-2.0 mL/d.

[0559] In some embodiments, the steady state volume of distribution for the antibody, or antigen binding fragment thereof, is about 1-10 L, about 2-8 L, about 4-9 L, about 4-8 L, or about 5-7L.

[0560] In some embodiments, administration of the antibody, or antigen-binding fragment thereof, reduces the risk of COVID-19 hospitalization or death of the subject. In some embodiments, the risk of COVID-19 hospitalization or death is reduced by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%.

[0561] In some embodiments, administration of the antibody, or antigen-binding fragment thereof, reduces viral load in the subject. In some embodiments, the viral load is reduced by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%. In some embodiments, the viral load is reduced by at least about 0.5 loglO copies/mL, at least about 0.6 loglO copies/mL, at least about 0.7 loglO copies/mL, at least about 0.8 loglO copies/mL, at least about 0.9 loglO copies/mL, at least about 1.0 loglO copies/mL, at least about 1.1 loglO copies/mL, at least about 1.2 loglO copies/mL, at least about 1.3 loglO copies/mL, at least about 1.4 loglO copies/mL, at least about 1.5 loglO copies/mL, at least about 1.6 loglO copies/mL, at least about 1.7 loglO copies/mL, at least about 1.8 loglO copies/mL, at least about 1.9 loglO copies/mL, at least about 2.0 loglO copies/mL, at least about 2.1 loglO copies/mL, at least about 2.2 loglO copies/mL, at least about 2.3 loglO copies/mL, at least about 2.4 loglO copies/mL, at least about 2.5 loglO copies/mL, at least about 2.6 loglO copies/mL, at least about 2.7 loglO copies/mL, at least about 2.8 loglO copies/mL, at least about 2.9 loglO copies/mL, or at least about 3.0 loglO copies/mL.

[0562] In a preferred embodiment, the anti-CoV-S antibodies described herein, or anti-CoV-S antigen-binding fragments thereof, as well as combinations of said antibodies or antigen-binding fragments thereof, are administered to a recipient subject with a frequency of once every twenty-six weeks or less, such as once every sixteen weeks or less, once every eight weeks or less, once every four weeks or less, once every two weeks or less, once every week or less, or once daily or less. [0563] According to preferred embodiments, the antibody containing medicament or pharmaceutical composition is peripherally administered to a subject via a route selected from one or more of: orally, sublingually, buccally, topically, rectally, via inhalation, transdermally, subcutaneously, intravenously, intra-arterially, or intramuscularly, via intracardiac administration, intraosseously, intradermally, intraperitoneally, transmucosally, vaginally, intravitreally, epicutaneously, intra- articularly, peri-articularly, or locally.

[0564] Fab fragments may be administered every two weeks or less, every week or less, once daily or less, multiple times per day, and/or every few hours. In one embodiment, a patient receives Fab fragments of 0.1 mg/kg to 40 mg/kg per day given in divided doses of 1 to 6 times a day, or in a continuous perfusion form, effective to obtain desired results.

[0565] It is to be understood that the concentration of the antibody or Fab administered to a given patient may be greater or lower than the exemplary administration concentrations set forth above. [0566] A person of skill in the art would be able to determine an effective dosage and frequency of administration through routine experimentation, for example guided by the disclosure herein and the teachings in, Goodman & Gilman's The Pharmacological Basis of Therapeutics, Brunton, L.L. et al. editors, 11^th edition, New York, New York: McGraw-Hill (2006); Howland, R. D. et al, Pharmacology, Volume 864, Lippincott's illustrated reviews., Philadelphia, PA: Lippincott Williams & Wilkins (2006); and Golan, D. E., Principles of pharmacology: the pathophysiologic basis of drug therapy, Philadelphia, PA: Lippincott Williams & Wilkins (2007).

[0567] In another embodiment, the anti-CoV-S antibodies described herein, or CoV-S binding fragments thereof, as well as combinations of said antibodies or antigen-binding fragments thereof, are administered to a subject in a pharmaceutical formulation. In a preferred embodiment, the subject is a human.

[0568] In some embodiments, the subject is an adult. In some embodiment, the subject is an adolescent. In some embodiments, the subject is a child or a pediatric subject. In one embodiment, the subject is a pediatric subject, e.g., from birth to age of 11 years old, e.g., birth to < 1 month, 1 month to <2 years, or 2-11 years old. In other embodiments, the adolescent is 12-17 years old or 12- 15 years old. In one embodiment, the adult is over the age of 18. In some embodiments, the subject has no known recent exposure to COVID-19. In some embodiments, the subject has a known recent exposure to COVID-19. In one embodiment, recent exposure is within the last 14 days, within the last 10 days, within the last 7 days, within the last 6 days, 5 days, 4 days, 3 days, 2 days, or 24 hours. In some embodiments, the subject has COVID-19 symptoms or an active COVID-19 infection. In some embodiments, the subject has had COVID-19 symptoms for less than 5 days, less than 4 days, less than 3 days, less than 2 days, or less than 1 day. In some embodiments, the subject is treated within 5 days, 4 days, 3 days, 2 days or 1 day of symptom onset. In some embodiments, early treatment, e.g., receiving treatment within 5 days, 4, days, 3 days, 2 days or 1 day of symptom onset, provides a reduction in the risk of COVID-19 related hospitalization and all-cause death. In some embodiments, the subject, e.g., the adult, the adolescent, or the child, is vaccinated or has received a COVID-19 vacination. In some embodiments, the subject, e.g., the adult, the adolescent, or the child, is not vaccinated or has not received a COVID-19 vacination. In some embodiments, the subject, e.g., the adult, the adolescent, or the child, is at risk of COVID-19 exposure. For example, the subject may be a first responder, doctor, nurse, clinican, etc.

[0569] In some embodiments, the subject is immunocompromised. In some embodiments, the subject is a significantly immune compromised subject, e.g., adult subject or pediatric subject, but whose underlying medical condition(s) or treatments to treat those conditions cause to the subjects to be immunocompromised, and/or put them at increased risk of developing severe symptomatic COVID- 19. In some embodiments, the subject has no known recent exposure to COVID-19. In some embodiments, the subject has a known recent exposure to COVID-19. In one embodiment, recent exposure is within the last 14 days, within the last 10 days, within the last 7 days, within the last 6 days, 5 days, 4 days, 3 days, 2 days, or 24 hours. In some embodiments, the immunocomprised subject includes, but is not limited to, an individual who is actively treated for solid tumor or hematologic malignancies; solid organ transplant (SOT) recipient taking immunosuppressive therapy; CAR-T-cell therapy or HCT recipient; subjects having moderate or severe primary immunodeficiency; subjects having advanced or untreated HIV infection, or who are taking high-dose corticosteroids, alkylating agents, antimetabolites, or TNF blockers. In some embodiments, the immunocompromised subject is vaccinated or has received a COVID-19 vacination. In some embodiments, the immunocompromised subject is not vaccinated or has not received a COVID-19 vacination.

[0570] In some embodiments, the subject is at a high risk of COVID progression. In some embodiments, the subjects at a high risk of disease progression are age 50 years old or above with no comorbid conditions or additional risk factors for progression of COVID-19.

[0571] In some embodiments, the subjects at a high risk of disease progression are those about 18 to about 50 years old and with one or more preexisting medical conditons selected from the group consisting of (i) obesity (body mass index (BMI) > 30 kg/m²), (ii) diabetes (type 1 or type 2); (iii) chronic kidney disease (eGFR calculated by modification of diet in renal disease (MDRD) of 59 mL/min/1.73 m² or less, including end-stage renal disease on hemodialysis); (iv) chronic lung disease (emphysema/chronic obstructive pulmonary disease, chronic bronchitis, interstitial lung disease [including idiopathic pulmonary fibrosis], cystic fibrosis, or moderate to severe asthma [defined as requiring daily therapy]); (v) cardiac disease (heart failure, coronary artery disease, cardiomyopathies, or hypertension [with at least one medication prescribed or recommended]); (vi) sickle cell disease or thalassemia; (vii) solid organ or blood stem cell transplant recipients; (viii) other immunodeficiency due to underlying illness or immunosuppressant medication (e.g., corticosteroids >20 mg/day prednisone or equivalent); (ix) Down Syndrome, (x) stroke or cerebrovascular disease, which affects blood flow to the brain; (xi) substance use disorder; or (xii) pregnant.

[0572] In some embodiments, the subjects at a high risk of disease progression are those about 12 to about 17 years old (inclusive) and with one or more preexisting medical conditions selected from the group consisting of (i) BMI >85th percentile for age and sex based on United States Center for Disease Control (CDC) growth charts; (ii) diabetes (Type 1 or Type 2); (iii) chronic kidney disease; (iv) sickle cell disease or thalassemia; (v) congenital or acquired heart disease; (vi) neurodevelopmental disorders (e.g., cerebral palsy, Down syndrome); (vii) a medically-related technological dependence (e.g., tracheostomy, gastrostomy, or positive pressure ventilation not related to COVID-19); (viii) asthma, reactive airway or other chronic respiratory disease that requires daily medication for control; (ix) solid organ or blood stem cell transplant recipients; (x) other immunodeficiency due to underlying illness or immunosuppressant medication; (xi) substance use disorder; or (xii) pregnant.

[0573] In some embodiments, the subject is age 50 or above with no comorbid conditions or additional risk factors for progression of COVID-19. [0574] In some embodiments, the subject has hypertension with at least one medication prescribed or recommended.

[0575] In some embodiments, the subject has moderate to severe asthma requiring daily therapy. [0576] A “pharmaceutical composition” or “medicament” refers to a chemical or biological composition suitable for administration to a subject, preferably a mammal, more preferably a human. Such compositions may be specifically formulated for administration via one or more of a number of routes, including but not limited to buccal, epicutaneous, epidural, inhalation, intraarterial, intracardial, intracerebroventricular, intradermal, intramuscular, intranasal, intraocular, intraperitoneal, intraspinal, intrathecal, intravenous, oral, parenteral, rectally via an enema or suppository, subcutaneous, subdermal, sublingual, transdermal, and transmucosal. In addition, administration can occur by means of injection, powder, liquid, gel, drops, or other means of administration.

[0577] In one embodiment, the anti-CoV-S antibodies or antigen-binding fragments thereof, as well as combinations of said antibodies or antigen-binding fragments thereof, may be optionally administered in combination with one or more active agents. Such active agents include (i) an antiviral drug, optionally, remdesivir, favipiravir, darunavir, nelfinavir, saquinavir, lopinavir, or ritonavir; (ii) an antihelminth drug, optionally ivermectin; (iii) an antiparasitic drug, optionally hydroxychloroquine, chloroquine, or atovaquone; (iv) antibacterial vaccine, optionally the tuberculosis vaccine BCG; or (v) an anti-inflammatory drug, optionally a steroid such as ciclesonide, a TNF inhibitor (e.g., adalimumab), a TNF receptor inhibitor (e.g., etanercept), an IL-6 inhibitor (e.g., clazakizumab), an IL-6 receptor inhibitor (e.g., toclizumab), or metamizole; (vi) an antihistamine drug, optionally bepotastine; (vii) an ACE inhibitor, optionally moexipril; or (viii) a drug that inhibits priming of CoV-S, optionally a serine protease inhibitor, further optionally nafamostat.

[0578] An anti -histamine can be any compound that opposes the action of histamine or its release from cells (e.g., mast cells). Anti-histamines include but are not limited to acrivastine, astemizole, azatadine, azelastine, betatastine, brompheniramine, buclizine, cetirizine, cetirizine analogues, chlorpheniramine, clemastine, CS 560, cyproheptadine, desloratadine, dexchlorpheniramine, ebastine, epinastine, fexofenadine, HSR 609, hydroxyzine, levocabastine, loratadine, methscopolamine, mizolastine, norastemizole, phenindamine, promethazine, pyrilamine, terfenadine, and tranilast.

[0579] In CoV infection, respiratory symptoms are often exacerbated by additional bacterial infection. Therefore, such active agents may also be antibiotics, which include but are not limited to amikacin, aminoglycosides, amoxicillin, ampicillin, ansamycins, arsphenamine, azithromycin, azlocillin, aztreonam, bacitracin, carbacephem, carbapenems, carbenicillin, cefaclor, cefadroxil, cefalexin, cefalothin, cefalotin, cefamandole, cefazolin, cefdinir, cefditoren, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftobiprole, ceftriaxone, cefuroxime, cephalosporins, chloramphenicol, cilastatin, ciprofloxacin, clarithromycin, clindamycin, cloxacillin, colistin, co-trimoxazole, dalfopristin, demeclocycline, dicloxacillin, dirithromycin, doripenem, doxycycline, enoxacin, ertapenem, erythromycin, ethambutol, flucloxacillin, fosfomycin, furazolidone, fusidic acid, gatifloxacin, geldanamycin, gentamicin, gly copeptides, herbimycin, imipenem, isoniazid, kanamycin, levofloxacin, lincomycin, linezolid, lomefloxacin, loracarbef, macrolides, mafenide, meropenem, methicillin, metronidazole, mezlocillin, minocycline, monobactams, moxifloxacin, mupirocin, nafcillin, neomycin, netilmicin, nitrofurantoin, norfloxacin, ofloxacin, oxacillin, oxytetracycline, paromomycin, penicillin, penicillins, piperacillin, platensimycin, polymyxin B, polypeptides, prontosil, pyrazinamide, quinolones, quinupristin, rifampicin, rifampin, roxithromycin, spectinomycin, streptomycin, sulfacetamide, sulfamethizole, sulfanilamide, sulfasalazine, sulfisoxazole, sulfonamides, teicoplanin, telithromycin, tetracycline, tetracyclines, ticarcillin, tinidazole, tobramycin, trimethoprim, trimethoprim- sulfamethoxazole, troleandomycin, trovafloxacin, and vancomycin.

[0580] Active agents also include aldosterone, beclomethasone, betamethasone, corticosteroids, cortisol, cortisone acetate, deoxycorticosterone acetate, dexamethasone, fludrocortisone acetate, glucocorticoids, hydrocortisone, methylprednisolone, prednisolone, prednisone, steroids, and triamcinolone. Any suitable combination of these active agents is also contemplated.

[0581] A “pharmaceutical excipient” or a “pharmaceutically acceptable excipient” is a carrier, usually a liquid, in which an active therapeutic agent is formulated. In one embodiment, the active therapeutic agent is a humanized antibody described herein, or one or more fragments thereof. The excipient generally does not provide any pharmacological activity to the formulation, though it may provide chemical and/or biological stability, and release characteristics. Exemplary formulations can be found, for example, in Remington’s Pharmaceutical Sciences, Gennaro, A. editor, 19^th edition, Philadelphia, PA: Williams and Wilkins (1995), which is incorporated by reference.

[0582] As used herein “pharmaceutically acceptable carrier” or “excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic, and absorption delaying agents that are physiologically compatible. In one embodiment, the carrier is suitable for parenteral administration. Alternatively, the carrier can be suitable for intravenous, intraperitoneal, intramuscular, or sublingual administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the disclosure is contemplated. Supplementary active compounds can also be incorporated into the compositions. [0583] Pharmaceutical compositions typically must be sterile and stable under the conditions of manufacture and storage. The disclosure contemplates that the pharmaceutical composition is present in lyophilized form. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. The disclosure further contemplates the inclusion of a stabilizer in the pharmaceutical composition. The proper fluidity can be maintained, for example, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.

[0584] In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, or sodium chloride in the composition. Absorption of the injectable compositions can be prolonged by including an agent that delays absorption, for example, monostearate salts and gelatin. Moreover, the alkaline polypeptide can be formulated in a time-release formulation, for example in a composition that includes a slow release polymer. The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, poly anhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid, polylactic and polyglycolic copolymers (“PLG”). Many methods for the preparation of such formulations are known to those skilled in the art. [0585] For each of the recited embodiments, the compounds can be administered by a variety of dosage forms. Any biologically acceptable dosage form known to persons of ordinary skill in the art, and combinations thereof, are contemplated. Examples of such dosage forms include, without limitation, reconstitutable powders, elixirs, liquids, solutions, suspensions, emulsions, powders, granules, particles, microparticles, dispersible granules, cachets, inhalants, aerosol inhalants, patches, particle inhalants, implants, depot implants, injectables (including subcutaneous, intramuscular, intravenous, and intradermal), infusions, and combinations thereof.

[0586] The above description of various illustrated embodiments of the disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. While specific embodiments of, and examples for, the disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the disclosure, as those skilled in the relevant art will recognize. The teachings provided herein of the disclosure can be applied to other purposes, other than the examples described herein.

[0587] Certain anti-CoV-S antibody polynucleotides and polypeptides are disclosed in the sequence listing accompanying this patent application filing, and the disclosure of said sequence listing is herein incorporated by reference in its entirety.

[0588] The entire disclosure of each document cited (including patents, patent applications, journal articles, abstracts, manuals, books, or other disclosures) in the Background, Detailed Description, and Examples is herein incorporated by reference in their entireties. [0589] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the subject disclosure and are not intended to limit the scope of what is regarded as the invention. Efforts have been made to ensure accuracy with respect to the numbers used (e.g. amounts, temperature, concentrations, etc.), but some experimental errors and deviations should be allowed for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees centigrade; and pressure is at or near atmospheric.

EXAMPLES

Example 1: Phase 1, Randomized, Double-blind, Single Ascending Dose Study [0590] This Example provides safety, pharmacokinetics, and virus neutralizing antibody titer data of ADI-58125 in a Phase 1, randomized, double-blinded, single ascending dose study. In this Phase 1 study, three dose levels of ADI-58125: 300 mg IM, 500 mg IV, and 600 mg IM, were assessed in healthy participants. All dose levels utilized a 100 mg/ml concentration of ADI-58125.

[0591] Biefly, subjects were randomized 8 active:2 placebo, and each dose level had a sentinel cohort of 1 active: 1 placebo. To accommodate differences in anticipated Tmax, IM and IV subjects were confined to the Phase 1 unit for 72 and 24 hours after dosing, respectively. Subjects in the IM cohorts were assessed for injection site reactions daily through discharge. Safety monitoring was ongoing, with weekly phone calls and clinic visits at 3, 6, 9, and 12 months after randomization. Demographics

[0592] Thirty healthy volunteers received ADI-58125 or placebo in this study. Baseline characteristics were well balanced among cohorts (Table 10). The average age of participants was 37.3 (range: 18 - 55) years and 53% (16) are female; 40% (12) participants identified as Hispanic or Latino. One subject identified as American Indian or Alaska Native, three participants identified as Black or African American, one participant identified as Asian, two participants identified as Native Hawaiian or Other Pacific Islander, and 24 participants identified as White. Participants were permitted to select more than one race. The average BMI of participants was 24.0 (range: 19.9 - 29.4) kg/m². All subjects received the full dose of study medication and all remain in the study.

Table 10. Baseline characteristics

Safety and Tolerability

[0593] No serious adverse events, adverse events of special interest, study drug-related adverse events, discontinuations, deaths, or injection site reactions, or hypersensitivity reactions were observed.

[0594] Cohort 1 includes 300 mg IM ADI-58125 (N=8) and placebo (N=2) participants. One participant from Cohort 1 (300 mg IM) reported a single episode of dizziness, which occurred shortly after IM injection and resolved after the participant was permitted to eat. This AE was graded mild, deemed unrelated to study medication, and resolved without concomitant medication administration (see, Tables 11 and 12).

[0595] Cohort 2 includes 500 mg IV ADI-58125 (N=8) and placebo (N=2) participants. One participant in Cohort 2 (500 mg IV) reported musculoskeletal chest pain beginning approximately 10 hours after infusion and resolving prior to discharge the following morning. No abnormalities were found on physical exam or on an ECG performed during the event. This event was graded mild, deemed unrelated to study medication, and resolved without intervention or concomitant medication administration.

[0596] A second participant in Cohort 2 (500 mg IV) reported a single episode of vomiting. This event occurred approximately 24 hours after infusion and resolved immediately after the event and prior to discharge. No abnormalities were found on physical exam shortly after the event. This event was graded mild, deemed unrelated to study medication, and resolved without intervention or concomitant medication administration.

[0597] Cohort 3 includes 600 mg IM ADI-58125 (N=8) and placebo (N=2) participants. One participant in Cohort 3 (600 mg IM) reported bruising on their left thigh, which they noticed incidentally 11 days after their injection and reported at her Day 14 visit. This finding was not noted during injection site monitoring, which included physical exams, nor was it noted or reported at their Day 7 visit. This event was graded mild, deemed unrelated to study medication.

[0598] All available adverse event, laboratory, physical exam and vital sign data for Cohort 1 were evaluated and it was concluded that the single adverse event in Cohort 1 was unrelated to study drug. No clinically relevant laboratory, physical exam or vital sign values were found during the review. No other concerns were identified.

Table 11. Summary of Adverse Events (Solicited and Unsolicited), Safety Population - Cohort 1 through Day 2.

0599] AE= Adverse event, TEAE = Treatment emergent adverse event, SAE = Serious adverse event. N is number of participants in the Safety Population. Percentages are based on the total number of participants in Safety [0600] Population.

[0601] [1] Only study procedure AEs were collected from the time that informed consent was obtained until study drug dosing.

[0602] [2] TEAE is defined as any event not present prior to the initiation of study drug or any event already present that worsens in either intensity or frequency following exposure to study drug.

[0603] [3] Solicited AEs are recorded through Day 4 following study drug administration. Local reactions after Day 4 are considered non-solicited AEs. Missing relationship to study drug is imputed as “Related” and all solicited AEs are assumed to be “Related”. Missing severity is imputed as “Severe”. A Grade 4 (potentially life threatening) solicited AE is considered a SAE.

[0604] For participant counts, if participants experienced one or more events, they are counted only once. For AE counts, each occurrence of an AE is counted. AEs are summarized at maximum Severity and strongest Relationship to study drug.

[0605] Adverse event terms are coded using MedDRA version 23.1.

Table 12. Summary of Treatment-Emergent Adverse Events (Solicited and Unsolicited) by System Organ Class, Preferred Term and Severity, Safety Population - Cohort 1 through Day 21.

[0606] TEAE = Treatment emergent adverse event. N is number of participants in the Safety Population. Percentages are based on the total number of participants in Safety Population.

[0607] At each level of summarization (SOC or PT), participants who experienced more than one TEAE were only counted once at maximum Severity.

[0608] Missing severity of study adverse event is imputed as “Severe”.

[0609] Solicited AEs are local reactions to the IM injection and are collected through Study Day 4 and are imputed as related to study drug.

[0610] TEAEs is defined as any event not present prior to the initiation of study drug or any event already present that worsens in either intensity or frequency following exposure to study drug.

[0611] Adverse event terms are coded using MedDRA version 23.1.

[0612] Through a minimum of 12 weeks post dose, 11 AEs were reported in 7 participants (2/10 [20%] Cohort 1; 3/10 [30%] Cohort 2; 2/10 [20%] Cohort 3); all were mild in severity and considered unrelated to study drug.

Pharmacoki neti cs

[0613] Pharmacokinetics (PK) of 300 mg IM dose were evaluated using blood samples collected prior to dosing (predose) and at 8 h, 24 h (Day 2), Day 3, Day 4, Day 7, Day 14, and Day 21 postdose. ADI-58125 serum concentrations were measured using a validated LB A (ligand binding assay)-hybrid LC -MS/MS assay at Q2 Solutions (Ithaca, NY) with a quantitative range of 0.5 μg/mL to 200 μg/mL. Blinding to treatment was maintained for study team personnel. Only external testing labs (Q2 Solutions and Viroclinics) and pharmacology vendors (Certara and ePD/ICPD) were unblinded to individual participant treatment.

[0614] Preliminary interim pharmacokinetic analysis demonstrated observable serum concentrations in 8 subjects following a single IM administration of 300 mg ADI-58125 (Figure 1). Maximum concentration (Cmax), median time to maximum concentration (Tmax), and area under the serum concentration-time curve from 0 to 20 days (AUCo 20_d) are summarized in Table 13. Based upon these data, the quantitative systems pharmacology/physiologically based pharmacokinetic (QSP/PBPK) model predicted the observed ADI-58125 concentrations well and with relatively little bias across the 21 -day sampling interval (Figure 2). An approximate 80-day ADI-58125 terminal elimination half- life was predicted by the QSP/PBPK model.

[0615] Consistent with the model predicted half-life, further pharmacokinetic analysis also demonstrated that ADI-58125 had a potential for prolonged protection. As shown in Figure 17, a half-life of about 60-100 days was observed for a single IM adminsitration of 300 mg ADI-58125 (n=8).

[0616] Safety, tolerability and pharmacokinetics (PK) were also assessed 3 months and 6 months post dose. Through 3 months post dose, 8 adverse events (AEs), mild in severity, were reported; no study drug-related AEs, serious AEs, injection-site reactions, or hypersensitivity reactions were reported. The PK profile through Day 180 for a single 300 mg IM injection of ADI-58125 and through Day 90 for 500 mg IV and 600 mg IM doses of ADI-58125 was dose proportional and consistent with an extended-half-life mAh (Figure 19).

[0617] The median time to maximum concentration (T_max) was 13 days (range: 6-20) after a single 300 mg IM injection.

[0618] Based on the 6-month data cohecte from participants who received 300 mg IM, the estimated half-life of ADI-58125 was 96.8 days.

Table 13. Preliminary Pharmacokinetic Paramater Estimates of ADI-58125

Includes only participants who received ADI-58125.

Abbreviations: AUC = area under the serum concentration-time curve, Cmax = maximum concentration, SD = standard deviation, Tmax = time to maximum concentration, T_1/2, half life.

Neutralizing Antibodies

[0619] Virus neutralizing antibody (VNA) titers generated in the context of prior infection or vaccination have been shown to be a key correlate of protection from COVID-19 (Khoury DS, et al, , medRxiv. 2021 Jan 1; Earle KA, et al, medRxiv. 2021 Jan 1). These data provide a useful supportive marker for evaluating the proposed dose of ADI-58125 for use in the setting of prevention.

[0620] The peak 50% SARS-CoV-2 neutralizing geometric mean titer (GMT) of 437 generated two weeks post second dose of the mRNA vaccine BNT162b2 (Mulligan MJ, et al, Nature. 2020 Oct;586(7830):589-593) was originally used to evaluate the proposed ADI-58125 dose of 300 mg IM, with the goal of maintaining VNA near this threshold. However, recent analysis of 6-month follow-up data from the pivotal trial for BNT162b2 demonstrated vaccine efficacy of 91.3% through 6 months, when VNA titers are likely to be much lower than the peak observed two weeks after the second dose. Although neutralizing antibody titer data are not available for the corresponding population for which vaccine efficacy was reported, other studies have shown an approximately 10-fold decrease in neutralizing antibody titers through Day 150 for subjects vaccinated with BNT162b2 (Wang Z, et al, Nature, 2021 Feb 10: 1-7). Similar decay in neutralizing antibody titer profiles have been demonstrated for convalescent sera (Wheatley AK, et al, Nat Commun. 2021 Feb 19; 12(1): 1162) and neutralizing antibody responses induced by the Moderna mRNA vaccine (Widge et al, N Engl J Med. 2021 Jan 7;384(l):80-82; Wang et al, Nature. 2021 Feb 10:1-7). For example, peak live virus ID50 geometric mean VNA titers for the Moderna vaccine mRNA- 1273 were -1000 for all age groups tested at Day 43 post vaccination 1 and decayed to 406, 171 and 131 by Day 209 in participants aged 18 to 55, 56 to 70 and 71 years of age or older, respectively (Doria-Rose N, et al, N Engl J Med. 2021 Apr 6). Taken together, these data support the idea that lower VNA titers are protective against symptomatic disease.

[0621] Serum virus neutralizing titers were evaluated using blood samples collected prior to dosing (predose) and at 8 h, 24 h (Day 2), Day 7, and Day 14 postdose. A plaque reduction neutralization test (PRNT) run at Viroclinics Biosciences (Rotterdam, NL) was used to measure serum titers against SARS-CoV-2 variant BavPat-1/2020 (with D614G). Virus was incubated with serial dilutions of serum, and virus/serum mixtures were then added to a confluent monolayer of Vero-E6 cells. Infected areas were immunostained 16-24 hours after infection and quantified using automated detection. The 80% neutralization titer (MN80) is reported using a validated method (SOP-VC-M204); the 50% neutralization titer (MN50) is a nonvalidated readout and reported for informational purposes.

[0622] Analysis of serum neutralizing titers from participants receiving a single 300 mg IM dose of ADI-58125 was presented in Figure 3. By day 13 post-injection, 80% neutralization titers [MN80, geometric mean (CV%)] were 569 (43.8%) and 50% neutralization titers [MN50, geometric mean (CV%)] were 1382 (32.7%). Samples from participants receiving placebo demonstrated no consistent response above the lower limit of detection (LLOD).

[0623] A linear regression model was fit to the time-matched individual MN50 titers and ADI-58125 concentrations demonstrated a strong correlation between the two measures (R²=0.955). Linear interpolation of the QSP/PBPK model-predicted median ADI-58125 concentration at 6 months post injection (8.03 μg/mL) predicts a median MN50 titer of approximately 247.

[0624] This value is likely within the range of 50% SARS-CoV-2 neutralizing GMT titers remaining -6 months post vaccination for mRNA vaccines such as BNT162b2 and mRNA-1273 (Wang et al, Nature. 2021 Feb 10:1-7; Doria-Rose N, et al., N Engl J Med. 2021 Apr 6).

[0625] Serum viral neutralizing antibody (sVNA) titers were also assessed Day 2, Day 7, Day 14, Day 21, 3 months, and 6 months post dose in subjects following a single IM administration of 300 mg ADI-58125, a single IM administration of 600 mg ADI-58125, and a single IV administration of 500 mg ADI-58125. The sVNA data are presented in Table 14. ADI-58125 sVNA titers against authentic SARS-CoV-2 were compared with AZD1222- and mRNA-1273-induced titers measured by plaque reduction neutralization assay. ADI-58125 serum concentration was highly predictive of the MN50 sVNA titer (Figure 20). Table 14. Neutralizing Antibody Titers by Study Day and Treatment Groups

Abbreviations: IM = intramuscular, IV = intravenous, MN50 = 50% neutralization titer, MN80 = 80% neutralization titer.

Values shown as geometric mean (coefficient of variation %).

[0626] After a single 300 mg IM dose of ADI-58125, 50% sVNA titers (geometric mean) were 346 on Day 2, 1380 on Day 14, and were maintained through Day 21. By Day 2, MN50 sVNA titers significantly exceeded peak titers associated with AZD1222 and were similar to peak titers associated with mRNA-1273 (Figure 18). By Day 7, MN50 sVNA titers associated with ADI-58125 were significantly higher than pean titers associated with AZD1222 (P<0.0001) and mRNA-1273 (P<0.01), and were maintained at comparable levels to titers associated with mRNA-1273 through Study Month 6 (Figure 18), suggesting that the ADI-58125 neutralizing antibody titers also support potential for prolonged protection.

[0627] sVNA titers following ADI-58125 administration were also determined by plaque reduction assay for SARS-CoV-2 BavPat (D614G), B.1.351/Beta and the B.1.617.2/Delta variants. These were compared with titers 7-30 days after the second dose of authorized vaccines in a separate cohort of volunteers. As shown in Figure 27, 80% neutralization (MN80) sVNA titres following a single 300 mg IM injection of ADI-58125 exceeded titers against each of the BavPat, B.1.351/Beta and B.1.617.2/Delta variants 7-30 days following 2-dose mRNA-1273 vaccination, and this trend was maintained for at least 3 months. By 6 months, ADI-58125 sVNA titres were 0.6-, 1.4-, and 1.8-fold of peak titers induced by mRNA-1273 vaccination for variants tested. Statistical summary of MN80 comparisons following ADI-58125 administration and 2-dose mRNA 1273 vaccination was shown in Table below. P-values were determined by two-sided Mann Whitney U test. Thus, these results further support the potential for a single 300 mg IM injection of ADI-58125 to provide prolonged protection against symptomatic COVID-19 for a minimum of 6 months.

Conclusions

[0628] In summary, no safety or tolerability issues were observed in any of the dose cohorts, including the 300 mg IM dose and two higher doses to establish a safety margin (500 mg IV and 600 mg IM). Thus, a single dose of ADI-58125, up to 600 mg IM, was well tolerated. Preliminary interim data indicate that ADI-58125 PK following IM administration of a single 300 mg dose was consistent with the QSP/PBPK model predictions. These PK data and the sVNA titer data support the potential for a single 300 mg IM injection of ADI-58225 to treat COVID-19 and provide prolonged protection from COVID-19 for a minimum of 6 months.

[0629] Taken altogether, the absence of safety and tolerability signals, PK results that confirm previous model predictions, and adequate early VNA titers provided in this Example support further evaluation of a single 300 mg IM injection of ADI-58125 in the ongoing Phase 2/3 trials for the prevention and treatment of COVID-19.

Example 2: Serum Titers of ADI-58125 Against SARS-CoV-2 Variants by Plaque Reduction Neutralization Test

[0630] Plaque reduction neutralization test (PRNT) was used to measure serum titers against SARS- CoV-2 D614G and B.1.351 variants. Briefly, 400 PFU SARS-CoV-2 virus was incubated with serial dilutions of ADI-58125 for 1 hour. Virus/antibody mixtures were then added to a confluent monolayer of Vero-E6 cells and incubated for 48 hours before adding neutral red agar overlay. Plaques were counted 24 hours after infection and the concentration of antibody that reduced the plaques by 50% (PRNT50) or 90% (PRNT90) relative to control (i.e., virus alone with no antibody) was calculated (Figure 4). The neutralizing antibody titers to reduce the ability of both virus variants from infecting host cells by 50% or 90% were shown in the table below.

Example 3: Post-Infection Assay with ADI-58125 Against SARS-CoV-2 Variants [0631] A post-infection assay was performed to measure the concentration of antibody required to prevent viral replication of the SARS-CoV-2 D614G and B.1.351 variants in infected cells. Briefly, cells were infected with the SARS-CoV-2 D614G or B.1.351 variants. After 1 hour incubation, unbound virus was washed away, and medium containing various concentration of ADI-58125 antibody was added to infected-cell monolayers. Viral supernatant was sampled daily and infectious viral burden was quantified by plaque assay on Vero E6 cells (Figure 5).

[0632] The concentration curves showing the amount of antibody required to prevent viral replication in infected cells were shown in Figure 6. As shown in Figure 6, 0.125 μg/ml ADI-58125 was able to reduce the viral burden for both variants when compared to the control, and the viral burden decreased significantly as the concentration of the antibody increased.

Example 4: Potent Neutralizing Activity of ADI-58125 and ADI-58122 Against a Broad Panel of Variants

[0633] Neutralizing activity of ADI-58125 and ADI-58122 against naturally circulating SARS-CoV- 2 variants with single and/or double point mutations and emerging lineages including the Alpha/B.1.1.7 varaint, the Beta/B.1.351 variant, the Gamma/P.l variant, the B.1.617 variants (e.g.,

B.1.617.1/Kappa and B.1.617.2/Delta), the Omicron lineages BA.l., BA.1.1, and BA.2, the

C.37/Lambda variant, and the Mu/B.1621 variant were assessed. Several other SARS-CoV-2 antibodies were included as comparators. Briefly, neutralizing activity against authentic SARS-CoV-2 virus varaints was assessed in a focus reduction neutralization test using Vero cells. Half-maximal inhibitory concentration (IC₅₀) values were determined using nonlinear regression curve fitting.

Several SARS-CoV-2 variants containing single or double amino acid mutations in the spike protein and full sets of mutations observed in variants of interest and variants of concern (VOCs) were assessed in a lentivial pseudovirus assay. D614G, an early variant of SARS-CoV-2, was used as a reference to calculate the IC₅₀ fold change in neutralizing activity of the antibodies. In vitro neutralizing activity of ADI-58125 against SARS-CoV-2 variants, including those reported to exhibit reduced susceptibility to emergency-use authorized (EUA) mAbs, was assessed in a non-replicative vesicular stomatitis virus pseudovirus assay. Fold reduction was calculated by dividing the IC50 of a variant by the mean IC50 (14.6 ng/mL) of the D614G reference strain.

[0634] As shown in Figure 7, Figure 8A and Figure 8B, ADI-58125 and ADI-58122 were able to neutralize all common circulating SARS-CoV-2 variants and emerging lineages. In particular, ADI- 58125 retained in vitro neutralizing activity within 0.4- to 5.1-fold relative to the reference D614G variant for all pseudovirus variants tested, including the newly emerging lineages including the Alpha/B.1.1.7 variant, the Beta/B.1.351 variant, the Gamma/P.l variant, the B.1.617 (e.g.,

B.1.617.1/Kappa and B.1.617.2/Delta), the Delta plus/AY.l, the C.37/Lambda, and the Mu/B.1621 variants (Figure 8A) and variants with single -/double-spike mutations (Figure 8B). Furthremore, ADI-58125 maintained neutralizing activity against all tested SARS-CoV-2 variants incorporating mutations reported to confer increased resistance to EUA m Abs (Figure 8C). IC50 values for ADI- 58125 (within 0.6- to 2.4-fold of the D614G strain) were lower than those observed for bamlanivimab, etesevimab, casirivimab, imdevimab, and sotrovimab. These data support further clinical investigation of ADI-58125 not only for COVID-19 but also for potential utility in future outbreaks caused by other SARS-like viruses.

Example 5: A Whole-Body Quantitative System Pharmacology Physiologically-Based Pharmacokinetic (QSP/PBPK) Model that a priori Predicts Intramuscular (IM) Pharmacokinetics of ADI-58125: an Extended Half-life Monoclonal Antibody for the Treatment and Prevention of Coronavirus Disease ( COVID-19 )

[0635] This Example provides a QSP/PBPK model, which was constructed using ADI-58125- specific physiochemical properties and published non-human primate (NHP) and human PK data for other antibodies, to a priori predict and confirm NHP and human PK.

[0636] An existing QSP/PBPK model was modified to include 3 distinct lung sub-compartments: upper airway, lower airway, and alveolar tissue (Figure 9A). Each sub-compartment (Figure 9B) contained an epithelial lining fluid (ELF) space (Figure 9B). The model was fit separately to digitized NHP and human serum PK data for 7 extended half-life antibodies to estimate the apparent neonatal Fc receptor (FcRn) binding affinity

and bioavailability by drug. Nasopharyngeal swab (upper airway) and lung (lower airway) ELF PK data from 4 additional antibodies were used to optimize a single rate constant for transcytosis in lung. Patches of positive charge was a covariate on the rate of pinocytosis of antibody entry and exit from the endosomal space (Figure 9B). Observed NHP (ADI- 58125 10 mg/kg IM) and human (ADI-58125 300 mg IM) PK data collected over the initial 21 days post dose were compared with model forecasts from a 1000-iteration simulation.

[0637] The distribution of fitted NHP K_D,FcRn provided accurate predictions of NHP serum PK data (Figure 9C). NHP ADI-58125 K_D,FcRn was optimized to be 35.7 nM and human ADI-58125 K_D,FcRn (9.55 nM) was derived using a mean NHP:human K_D,FcRn ratio of 3.74 across antibodies. Model-based simulated human serum PK data using inter-subject variability from NHP and actual weight distribution from an ongoing Phase 1 study aligned with initial 21 -day data (Figure 9D). Using an adult CDC weight distribution (45-150 kg), the simulated median half-life was 74.4 days.

[0638] For initial QSP/PBPK model projections, the modified QSP whole-body PBPK model, estimated BHP and human apparent K_D,FcRn distributions, an a reference US Centers for Disease Control body weight distribution were used to provide initial stimulation (1000 iterations) forecast of NHP and human ADI-58125 serum concentration-time profiles. When measured NHP ADI-58125 serum concentration became available, the raw data were overlaid on the initial median and 90% prediction interval (PI) forecast for NHPs.

[0639] For optimized QSP/PBPK model projections, the modified QSP/PBPK model was optimized by estimating NHP intramuscular (IM) bioavailability and ADI-58125 K_D,FcRn and applying an NHP:human K_D,FcRn ratio to the NHP K_D,FcRn values estimated for ADI-58125 to better forecast human ADI-58125 concentration-time profiles. When measured human ADI-58125 serum concentration became available, the raw data were overlaid on the forecasted median and 90% prediction interval (PI) forecast for human. The QSP/PBPK model was then optimized by estimating K_D,FcRn and IM availability using the interim human PK data, along with estimating inter-individual variability for some key parameters to better reflect observed variability.

[0640] Histograms of simulated human body weight and K_D,FcRn distributions in humans and NHPs are shown in Figures 21A-21C.

[0641] Figures 22A-22B show the initial QSP/PBPK model-forecasted NHP median (90% prediction interval (PI)) serum ADI-58125 concentration-time profile following a single intravenous (IV) and intramuscular (IM) administration of 10 mg/kg ADI-58125 with measured concentration data overlaid. Figures 23A-23B show the optimized QSP/PBPK model-forecasted NHP median (90% PI) serum ADI-58125 concentration-time profile following a single intravenous (IV) and intramuscular (IM) administration of 10 mg/kg ADI-58125 with measured concentration data overlaid. The QSP whole -body PBPK model was optimized by estimating K_D,FcRn (4.27 nM) and IM bioavailability (92%) using the interim human PK data, along with estimating inter-individual variability for some key parameters to better reflect observed variability. Figures 24A-24D show the observed and optimized QSP/PBPK model-forecasted human median (90% PI) serum ADI-58125 concentration-time profiles in healthy adult participants following a 300 mg IM, 500 mg IM or 500 mg IV administration of ADI-58125 with measured concentration data overlaid.

[0642] The modeling strategy involved the modification of a platform whole-body PBPK model designed for wild-type IgGl mAbs to forecast the PK of an extended half-life mAh. The modified QSP/PBPK model account for the altered binding affinity to FcRn and included patches of positive charge (PPC) as a covariate on the rate of pinocytosis into the endosomal space (CLup). The model adequately a priori predicted the observed ADI-58125 PK in NHPs and human, thus supporting the selected dose. This innovative QSP-based modeling and simulation approach enabled the evaluation of candidate dose regimens prior to the availability of PK data, supporting the rapid advancement of the ADI-58125 clinical program during the COVID-19 pandemic. Example 6: A Whole-Body Quantitative System Pharmacology Physiologically-Based Pharmacokinetic (QSP/PBPK) Model to Support Dose Selection of ADI-58125 for the Treatment of Coronavirus Disease (COVID-19)

[0643] This Example provides a QSP/PBPK model to support dose selection for a Phase 2/3 COVID- 19 treatment study of ambulatory patients with mild to moderate COVID-19 (STAMP: NCT04805671).

[0644] The QSP/PBPK model comprised 15 specific tissues and one representing the rest of the body; each tissue was connected through blood and lymph flow to the systemic circulation. In tissue endothelial spaces, mAbs enter by pinocytosis (CL_up) and via the interaction with neonatal Fc receptor (FcRn), FcRn-bound mAh is recycled, and unbound drug is eliminated (K_deg). The QSP/PBPK model was modified such that the lung compartment was subdivided into alveoli and upper (naso- /oropharyngeal) and lower lung airway compartments (bronchi; Figure 9A). It was assumed that the upper, lower, and alveoli sub-compartments contribute 8.5%, 8.5%, and 83.0% toward lung volume and 2.5%, 5.0%, and 92.5% toward lung blood flow, respectively. It was assumed that FcRn concentrations in each lung sub-compartment were the same, mAbs recycle back to EFF and interstitial compartments, CF_upin lung epithelium was 10-times slower than vascular endothelial cells, and the endosomal space was 0.5% of cellular space for pulmonary epithelial cells. mAbs were also allowed to cross epithelial cells by transcytosis (k_trans) and, upon entering the interstitial space, to either exit the lung via lymph flow or re-ente the vascular space via FcRn-mediated recycling k_trans was calibrated using serum PK data along with EFF and nasopharyngeal swab PK data from reference mAbs MHAA4549A, VIS-410, ASN-1, and ASN-2. It was assumed that binding to SARS-CoV-2 virus does not impact the ADI-58125 PK at clinically relevant doses.

[0645] A QSP/PBPK model was used to simulate receptor occupancy (RO) and drug exposure in the upper airway (nasopharyngeal/oropharyngeal epithelial lining fluid [EFF] compartment). RO was linked to an existing viral dynamic model to enable the prediction of the natural time course of viral load and the effect of ADI-58125 on viral clearance and infectivity rate.

[0646] RO was calculated using: 1) in vitro ADI-58125-SARS-CoV-2 binding kinetics (association rate constant (k_on) of 1.52E+06 M ^-1•s^-1 and dissociation rate constant (k_0ff) of 2.81E-04 s^-1 from a Biacore assay; 2) time course of QSP/PBPK model-forecasted ADI-58125 concentrations in upper aiway EFF of lung; and 3) time course of viral load following ADI-58125 administration at peak viral load ( e.g ., log 10⁷ to log 10⁹ copies/mF for all patients) using in vitro 50% half maximal concentration (IC₅₀) of 0.007 μg/mF against authentic SARS-CoV-2 (e.g., Delta variant). Molar SARS-CoV-2 viral binding site capacity was calculated assuming 40 spike proteins per virion, 3 binding sites per spike, for all patients.

[0647] The QSP/PBPK model and a 2018 CDC reference body weight distribution (45-150 kg) were used to simulate 1000 concentration-time profiles for a range of candidate ADI-58125 regimens. ADI- 58125 regimens were evaluated against 2 criteria: 1) ability to attain near complete (>90%), and durable (28-day) SARS-CoV-2 RO in the ELF; and 2) ability to maintain ELF ADI-58125 concentrations >0.27 mg/L, which was associated with 95% viral growth suppression in an in vitro post-infection assay against the Beta variant.

[0648] A single 300 mg IM ADI-58125 dose met the dose selection criteria in terms of RO (Figure 10A) and viral growth suppression (Figure 10B). Figure 10A shows the QSP model-predicted median (90% prediction interval, PI) ADI-58125 PK profiles associated with viral growth suppression. Times to attaining relevant target concentrations are provided below.

[0649] Table 15 shows ADI-58125 potency against SARS-CoV-2 variants of concern.

Table 15. ADI-58125 potency against SARS-CoV-2 variants of concern

[0650] As shown in Figure 10A and Table 15, ADGI-58125 attained ELF concentration above 10 times the IC90 of other variants of concern.

[0651] Figure 10B shows the ADI-58125 receptor occupancy at various Delta variant virion densities after a single 300 mg IM injection of ADI-58125.

[0652] These data support the evaluation of an ADI-58125 300 mg IM dose for the treatment of COVID-19. ADI-58125 is forecasted to attain near complete (>90%) SARS-CoV-2 RO in the ELF and maintain ELF ADI-58125 concentrations above that associated with 95% viral growth suppression in vitro.

[0653] In conclusion, the 300 mg IM regimen has a projected ability to rapidly achieve and maintain target tissue concentrations at key tissue sites of viral replication, including the ability to attain near complete (>90%) and durable (28-day) SARS-Cov-2 across a range of baseline viral loads. Example 7: A Whole-Body Quantitative System Pharmacology Physiologically-Based Pharmacokinetic (QSP/PBPK) Model to Support Dose Selection of ADI-58125 for the Prevention of Coronavirus Disease (COVID-19)

[0654] This Example provides a QSP/PBPK model to support dose selection for a Phase 2/3 COVID- 19 prevention study (EVADE: NCT04859517).

[0655] Using the QSP/PBPK model and a CDC reference body weight distribution (45-150 kg),

1000 concentration-time profiles were simulated for a range of candidate ADI-58125 single injection regimens.

[0656] Prior to availabity of human PK data, the QSP PBPK model forecasts in humans were based upon the estimated IM bioavilability from NHP, while the K_D,FcRn value of 9.55 nM was derived based upon multiplying the mean NHP:human K_D,FcRn ratio for other extended half-life antibodies to the NHP K_D,FcRn value for ADI-581258. The QSP/PBPK model was later optimized by estimating K_D,FcRn (4.27 nM) and IM bioavailability (92.2%) using the interim human PK data, along with estimating inter-individual variability for some key parameters to better reflect observed variability.

[0657] ADI-58125 IM dosing regimens were evaluated against two criteria: (1) the ability to attain measured 50% neutralization (MN50) serum virus-neutralizing antibody (sVNA) titers within the range of peak sVNA titers for COVID-19 vaccine recipients; and (2) the ability to maintain serum ADI-58125 concentrations 100-fold higher than the in vitro 90% inhibitory concentration (IC90) of 0.011 μg/mL against authentic SARS-CoV-2 (USA-WA1) for a minimum of 6 months in >90% of simulated patients. This threshold was based on a precedent with respiratory syncytial virus and HIV, in which serum concentrations approximately 100-fold higher than the in vitro IC50 were associated with protection in animal models and/or in humans.

[0658] After measured human ADI-58125 serum concentrations became available, the QSP/PBPK model was optimized by refitting to the human data, allowing for formal estimation of interindividual variability, and ADI-58125 dose regimen simulations were updated.

[0659] Histograms of the simulated human body weight and K_D,FcRn distributions in humans are shown in Figures 21A-B.

[0660] Using the original model, single ADI-58125 IM injections of 300 mg or greater were projected to maintain serum coencentration in most simulated patients for up to 12 months (Figures 25A-C). Table 16A shows the ADI-58125 potency against SARS-CoV-2 variants of concern.

[0661] The optimized model confirmed these predictions and suggests that the single 300 mg IM injection provides a margin of coverage of SARS-CoV-2 variants with high IC90 values than those of the original variant used to support this target (Figures 26A-C).

[0662] Based on the data from the first-in-human Phase 1 study (see Example 1), ADI-58125 maintains MN50 titers within the range of those achieved by COVID-19 vaccine recipients following 2 doses (AZD1222, mean titer 80: mRNA-1273, mean titer 327). Given a QSP/PBPK projected ADI- 58125 52-week post-dose medium serum concentration of 5.3 mg/L and a regression relating ADI- 58125 concentration and MN50 titer, the predicted MN50 is 231 one year post-dose.

Table 16A. ADI-58125 potency against SARS-CoV-2 variants of concern

[0663] These data support the evaluation of a single 300 mg IM injection of ADI-58125 for the prevention of COVID-19 in both preOand post-exposure settings. The single 300 mg IM regimen has a projected ability to rapid exceed the IC90 target in the majority of simulated patients, to maintain effective concentrations for up to 12 months, and to provide greater efficacy margins than lower disease for coverage against SARS-CoV-2 variants.

Example 8: In vivo Prophylactic Efficacy of ADI-58125 in Syrian Hamster [0664] The prophylactic efficacy of ADI-58125 was assessed in vivo in hamster. Briefly, Syrian hamsters were dosed intraperitoneally with a range of ADI-58125 doses (n=40; 9.25 - 2000 μg) or control mAh (sham-treated isotype matched IgG) (n=20; either 9.25 or 2000 μg) 24 hours prior to intranasal challenge with le5 plaque-forming units (pfu) of SARS-2/WA-1 to evaluate the prophylactic efficacy of ADI-58125 (Figure 11).

[0665] Hamseters were weighed daily over 6 days, while antibody titers, viral load and lung histopathology were assessed fowlloing sacrifice of five animals from each group on Day 3 and 6 post-challenge.

[0666] As shown in Figure 12A, an ADI-58125 dose of > 55 μg was associated with protection from weight loss compared with controls at Day 6. Hamsters receiving about 333 and 2000 μg doses displayed limited histopathological evidence of pneumonia (Figure 12B). Hamsters receiving the highest dose (2000 μg) had no detectable virus in lung samples (Figure 13). Specifically, treatment with 333 μg and 2000 μg of ADI-58125 significantly reduced infectious viral loads at Day 3 post exposure compared with controls (P<0.005). Similar trends were observed for viral sub-genomic RNA (sgRNA), which was produced during active viral infection. In addition, no evidence of antibody-dependent enhancement was observed across all ADI-58125 doses, including subtherapeutic doses. [0667] In sum, these data demonstrated that prophylactic administration of ADI-58125 provides dose-dependent protection from SARS-CoV-2 infection in the Hamster model, and ADI-58125 conferred significant protection from weight loss and lung pathology and inhibited viral replication at the 333 and 2000 μg doses versus control antibody.

Example 9: In vivo Prophylactic Efficacy of ADI-58125 in Non Human Primates [0668] The prophylactic efficacy of ADI-58125 was further assessed in vivo in non human primates (NHP). Briefly, rhesus macaques were dosed intravenously with ADI-58125 (n=8; 5 or 25 mg/kg), or control mAh (sham-treated isotype matched IgG) (n=4; 25 mg/kg) 3 days prior to intranasal / intratracheal challenge with le6 pfu of SARS-2/WA-1 to evaluate prophylactic efficacy of ADI- 58125 (Figure 14).

[0669] Viral load was assessed in nasopharyngeal (NP) and oropharyngeal (OP) samples (daily), and in bronchoalveolar lavage (BAL) samples (Days 1, 3, and 5) by reverse transcription-polymerase chain reaction (RT-PCR, all samples) and plaque assays (NP and OP swabs only).

[0670] As shown in Figure 15, an ADI-58125 dose of 25 mg/kg was associated with reduced viral replication in the upper and lower airways with sgRNA below the limit of detection in all respiratory compartments tested. Specifically, a similar trend was observed for genomic RNA data (data not shown). Substantial protection was also observed at the 5 mg/kg dose level, as demonstrated by accelerated clearance of infectious virus. In addition, no viral particles were detected in NP and OP compartments at the 25 mg/kg ADI-58125 dose (Figure 16).

[0671] These data demonstrated that ADI-58125 confers potent protection from SARS-CoV-2 infection at dose ranges from 5-25 mg/kg in a NHP model. These results support further investigation of ADI-58125 for the prevention of COVID-19 in humans.

Example 10: A Phase 1/2, Open-Label, Comparator-Controlled Study Evaluating the Safety, Tolerability, and SARS-CoV-2 Antibody Titers of ADI-58125 Supplementation vs. BNT162b2 COVID-19 Vaccine Boost in Previously Vaccinated Adults

[0672] A Phase 1/2, randomized, open label, comparator-controlled, study is conducted in adults with no known history of Coronavirus Disease 19 (COVID-19) or Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and who are a minimum of 6 months out from completion of a primary BNT162b2 COVID-19 vaccine series at the time of study drug dosing. Participants receive a single open-label IM injection of ADI-58125 or BNT162b2 vaccine boost and will be followed for 12 months.

[0673] Participants per cohort receive study drug (ADI-58125 or BNT162b2). Adult male and female participants must be age >18 years at the time of consent. Participants who are healthy or have stable chronic medical conditions, and who are a minimum of 6 months out from completion of a primary COVID-19 vaccine series at the time of study drug dosing are enrolled and screened for participation within 28 days before the scheduled administration of study drug.

[0674] Screening procedures commence after written informed consent is obtained and include confirmation of inclusion and exclusion criteria, medical history, documentation of prior COVID-19 vaccination and medications (i.e., medications taken within 30 days before the scheduled dose of study drug), viral RT-PCR and serology tests, baseline laboratory testing including serum virus neutralizing antibody titers, vital sign measurements, and physical examination.

[0675] Key inclusion criteria include male or female subjects age >18 years at the time of consent; healthy or with stable chronic medical conditions, including immunocompromise, defined as disease not requiring significant change in therapy or hospitalization for worsening disease during the 6 weeks before enrollment; received and completed BNT162b2 COVID-19 vaccine series under EUA or approved dosing guidelines at least 6 months prior to study drug dosing.

[0676] Key inclusion criteria include known history of SARS-CoV-2 infection, prior administration of SARS-CoV vaccine other than the BNT162b2 COVID-19 vaccine series, orior administration of SARS-CoV-2 monoclonal antibody, history of severe adverse reaction associated with a vaccine or monoclonal antibody and/or severe allergic reaction (eg, anaphylaxis) to any component of the study intervention(s), bleeding diathesis of condition associated with prolonged bleeding that would m in the opinion of the investigator, contraindicate intramuscular injection.

[0677] Participants eligible for randomization are admitted to the clinical unit the morning of Day 1 and are confined in the clinical unit for a minimum of 1 hour following study drug administration. Each participant receives a single IM dose of the study drug.

[0678] Participants are required to complete an e-diary to monitor and record local reactions, systemic events and antipyretic medication usage for 7 days following administration of study drug. [0679] Additional safety assessments include monitoring of AEs, vital sign measurements, and physical examinations. Participants are monitored for all adverse events up to Day 90 and for SAEs and AESIs through 12 months via routine clinic visit, telehealth or telephone contact.

[0680] Serum virus binding and neutralizing antibody titers are assessed at specific timepoints through 12 months.

[0681] Participants are monitored for potential cases of COVID-19. If, at any time, a participant develops acute respiratory illness, the participant can contact the site and an in-person or telehealth visit should occur during which a SARS-CoV-2 RT-PCR test is conducted and serum virus neutralizing antibody titers are measured.

[0682] Blood samples are collected for PK and ADA throughout the follow-up period in ADI-58125 recipients only. Sampling timepoints for PK are determined based on modeling and simulation of human PK, using data generated with ADI-58125 in Phase 1 and Phase 2 studies. [0683] Primary endpoints include:

• Geometric mean titer (GMT) of SARS-CoV-2 neutralizing activity on Days 7, 14, 28 and Months 2, 6 and 12

• Levels of SARS-CoV-2 spike protein binding antibodies, including antibodies to the NTD, RBD and S2 subunits on Days 7, 14, 28 and Months 2, 6 and 12

• Assessment of safety and tolerability of ADI-58125 based on the occurrence of treatment- emergent adverse events (TEAEs), local reactogenicity, systemic reactogenicity and use of antipyretics

• Changes from baseline in physical examination, vital signs (body temperature, pulse rate, respiration rate, and systolic and diastolic blood pressure)

[0684] Secondary endpoints include:

• Geometric mean-fold rise (GMFR) in neutralizing titer from baseline to 7, 14 and 28 days post dose

• Percentage of patients with > 4-fold rise in SARS-CoV-2 specific serum neutralizing titers on Days 7, 14 and 28

• Change from baseline in SARS-CoV-2 spike protein binding antibodies, including antibodies to the NTD, RBD and S2 subunits on Days 7, 14, 28 and Months 2, 6 and 12

• Incidence of RT-PCR confirmed, symptomatic COVID-19

• PK parameters of ADI-58125

• Immunogenicity of ADI-58125 (ADA response)

[0685] Exploratory endpoints include incidence of asymptomatic SARS-CoV-2 infection as determined by positive serology to N protein.

Immunology Analysis

[0686] For SARS-CoV-2 specific serum neutralizing titers, geometric mean titers and 2-sided 95% CIs are provided for each treatment group at baseline (prior to dosing) and on Days 7, 14, 28 and Months 3, 6 and 12.

[0687] Geometric mean titers (GMT) and the associated 2-sided CIs are derived by calculating means and CIs on the natural log scale based on the t-distribution, and then exponenting the results. [0688] GMFR and 2-sided 95% CIs are provided for each treatment group at the following timepoints: Days 7, 14 and 28; GMFRs are limited to participants with nomissing values at baseline and the specified post-dose time point. The GMFR is calculated as the mean of the difference of logarithmically transformed assay results (later time point - baseline) and transformed back to the original scale. Two-sided CIs are obtained by calculating CIs using Student’s t-distribution for the mean difference of the logarithmically transformed assay results and transforming the limits back to the original scale.

[0689] Percentages (and 2-sided 95% CIs) of participants with > 4-fold rise are provided for each treatment group at the following timepoints: Days 7, 14 and 28. The Clopper-Pearson method is used to calculate CIs.

Safety Analysis

[0690] No formal statistical testing is performed on safety variables. Descriptive statistics for demographics and other baseline characteristics are provided. The Medical Dictionary for Regulatory Activities (MedDRA®) is used to classify all AEs with respect to system organ class and preferred term. Local and systemic reactogenicity, use of antipyretic medications and TEAEs are summarized for each cohort. The incidence of TEAEs, relationship to study drug, and severity are presented by system organ class and preferred term according to MedDRA coding dictionary. For vital signs, descriptive statistics are used to summarize for each cohort the observed results at each time point and the changes from baseline.

PK Analysis

[0691] Serum PK parameters are calculated for ADI-58125 using non-compartmental analysis methods. Descriptive statistics (min, max, median, mean, standard deviation, and coefficient of variation) of all PK parameters are provided.

[0692] Accordingly, this study provides evaluation of the magnitude of the SARS-CoV-2 neutralizing/binding antibody response in previously vaccinated adults receiving ADI-58125 supplementation compared to COVID-19 vaccine boost; the safety and tolerability of ADI-58125 supplementation; the pharmacokinetics and the immunogenecity of ADI-58125; and the incidence of RT-PCR confirmed, symptomatic COVID-19 in previously vaccinated adults receiving ADI-58125 supplementation compared to COVID-19 vaccine boost.

Example 11: Evaluation of ADI-58125 as a Preventive Option in Immunocompromised Individuals

[0693] This Example provides evaluation of ADI-58125 in an immunocompromised population in the prevention of symptomatic COVID-19.

[0694] This cohort includes significantly immune compromised adult participants with no known recent exposure but whose underlying medical condition(s) put them at increased risk of developing severe symptomatic COVID-19. Enrolled participants include, for example, subjects actively treated for solid tumor or hematologic malignancies, SOT recipient taking immunosuppressive therapy, CAR-T-cell therapy or HCT recipient, subjects having moderate or severe primary immunodeficiency, subjects having advanced or untreated HIV infection, or subjects currently taking high-dose corticosteroids, alkylating agents, antimetabolites, or TNF blockers. [0695] Participants are assigned to receive a single IM dose of ADI-58125 (up to N=200).

The study evaluates the safety, tolerability, PK, and sVNA titers of ADI-58125 in significantly immune compromised adults in a single arm, open-label fashion.

Example 12: Evaluation of ADI-58125 as a Treatment or Preventive Option in Pediatric Population

[0696] This Examples provides evaluation of ADI-58125 in pediatric population. A separate open- label cohort including children from bith to 11 years of age is added to (1) the phase 2/3 randomized, double-blinded, placebo-controlled trial to evaluate the efficacy and safety of ADI-58125 in the treatment of ambulatory participants with mild or moderate COVID-19 (STAMP), and (2) the phase 2/3 randomized, double blind, placebo controlled trial to evaluate the efficacy and safety of ADI- 58125 in the prevention of COVID-19 (EVADE).

Treatment study

[0697] For the treatment study (STAMP), an open label treatment with ADI-58125 is given to children from birth to 11 years with mild or moderate COVID-19. The objective of this cohort is to evaluate the safety, tolerability and pharmacokinetics of ADI-58125 in children with mild to moderate COVID-19.

[0698] Three age groups, birth to <1 month, 1 month to <2 years and 2 years to 11 years are enrolled within this cohort .The proposed dose for study is expected to vary by age and will not exceed the anticipated adult treatment dose of 300 mg IM. For example, in one embodiment, the dosing regimen can be the below: a) 15 mg/kg for children from birth to < 1 month b) 10 mg/kg for 1 month to < 2 years c) 5 mg/kg for 2 to 11 years

[0699] Final dose selection is based on modeling and simulation, and is informed by the established pharmacokinetics of similar monoclonal antibodies and the pharmacokinetics of ADI-58125 observed in adults and adolescents. In addition, PK in children birth to 11 years of age is reviewed on an ongoing basis to ensure exposures are within the desired targets.

[0700] Children from birth to 11 years of age with symptoms of mild or moderate COVID-19 and a positive SARS-CoV-2 test are enrolled to receive a single IM dose of ADI-58125. Participants are enrolled simultaneously across age groups. ADI-58125 is administered at the study site and participants are monitored after dosing for acute worsening of disease, hypersensitivity, and injection site reactions. After Day 1, participants are monitored through Day 29 for safety, PK, viral titers and clinical outcome. In addition, participants continue long-term follow-up for safety, PK, ADA and development of post-acute sequelae of COVID-19 through approximately 5 half-lives. Prevention study

[0701] For the prevention study (EVADE), an open label treatment with ADI-58125 is given to children from birth to 11 years at risk for developing SARS CoV-2 infections. The objective of this cohort is to evaluate the safety, tolerability and pharmacokinetics of ADI-58125 in children at risk for developing SARS CoV-2 infection.

[0702] Three age groups, birth to < 1 month, 1 month to <2 years and 2 years to 11 years will be enrolled. The proposed dose designed to achieve a minimum of 6-months protection in this study is expected to vary by age and will not exceed the anticipated adult treatment dose of 300 mg IM. For example, in one embodiment, the dose regimen can be the below: a) 10 mg/kg for birth to < 1 month (with a second 10 mg/kg dose 4 months post first dose) b) 10 mg/kg for 1 month to < 2yrs c) 5 mg/kg for 2 to 11 years

[0703] Final dose selection is based on modeling and simulation and is informed by the established pharmacokinetics of similar monoclonal antibodies and the pharmacokinetics of ADI-58125 observed in adults and adolescents. In addition, PK in children birth to 11 years of age is reviewed on an ongoing basis to ensure exposures are within the desired targets.

[0704] The preliminary sample size estimations for the planned pediatric studies are based on a predicted CV% of 30% in relevant PK parameters [e.g., area under the concentration-time curve (AUC) and maximum observed concentration (C_max)]. It is expected that between 4 and 8 children for each age group will be enrolled to provide > 80% power to obtain reasonably precise estimates (i.e., 95% Cl with 60 and 140% of the geometric mean) of AUC and C_max for each age group. To ensure adequate sample size in each age category, PK data for each age group are pooled across the two studies for analysis. It is anticipated that the total sample size includes 16 participants in the 2 to 11 and 1 month to < 2 year age groups and 8 participants in the birth to < 1 month age group.

[0705] Children from birth to 11 years of age are enrolled to receive a single IM dose of ADI-58125. Participants are enrolled simultaneously across age groups. ADI-58125 will be administered at the study site and participants will be monitored after dosing for acute hypersensitivity and injection site reactions. After Day 1, participants are monitored through approximately 5 half-lives for safety, PK, ADA and the development of SARS-CoV-2 infection (symptomatic or asymptomatic). Participants who develop signs or symptoms consistent with a COVID-like illness (CLI) are evaluated for laboratory confirmed COVID-19. Participants with laboratory confirmed COVID-19 are monitored for clinical and virological outcomes. Example 13: Population Pharmacokinetics (PPK) of ADI-58125, an Extended-Half-life Monoclonal Antibody Being Developed for the Treatment and Prevention of COVID-19 [0706] This Examples provides a population pharmacokinetics (PPK) model that describes the serum ADI-58125 concentration-time profile following intravenous (IV) and intramuscular (IM) administration in Phase 1 and Phase 2/3 COVID-19 prevention and treatment studies.

[0707] The ADI-58125 PPK model was developed on PK data from a phase 1 first-in-human, single- ascending dose study (24 adults, IV and IM) and from phase 2/3 COVID-10 prevention (EVADE, 659 adults, IM) and treatment (STAMP, 189 adults, IM) studies. 1,486 PK samples were included in the analysis. Data from a phase 1 study were used to develop the base structural model describing the serum disposition of ADI-58125. The base structural model was adapted from a preliminary model developed using data from non-human primate studies. As feasible, the impact of body weight was included in the model, consistent with models for other mAbs. The model was qualified using visual predictive check (VPC) plots, and the precision of PPK parameters was evaluated using bootstrap/resampling methods. The impact of covariates (e.g. body weight, age, and baseline viral load) on ADI-58125 serum disposition were evaluated. Prediction-corrected visual predictive check (PC- VPC) plots were used to qualify the PPK model. Subject-specific estimates of ADI-58125 exposures were generated using individual, post hoc PK parameters.

[0708] The PPK model comprised 2 systemic compartments, zero-order infusion for IV administration and first-order absorption for IM administration, and provided a robust fit to the data based on the VPC plots (Figure 28) and goodness-of-fit plots (Figure 49). The impact of body weight on the variability in total body clearance, distributional clearance, and distributional volume parameters was evaluated and included in the model. A fitted exponent of 0.658 was found to be most appropriate for the relationship between body weight and the two clear ane terms, body clearance and distributional clearance, while a direct linear relationship with an exponent of 1.0 was most appropriate for the volume of the central and peripheral compartments.

[0709] Body weight influenced clearance, intercompartmental clearance, and central and peripheral volume compartments. The relationship between body weight and clearance was not suggestive of the need for dose adjustment over the population weight range studied (38.6 to 178.7 kg). There was no apparent impact of baseline viral load or age on ADI-58125 clearance. The median [range] half-lives in days by study; Phase 1 (a 1.71 [1.18-2.46]; b 125 [117-149]), Phase 2/3 prevention (a 1.86 [0.640- 3.13]; b 136 [105-209]), and Phase 2/3 treatment (a 1.89 [0.631-3.01]; b 136 [108-206]). The population mean IM bioavailability estimate was 90.5%. Figure 54 shows the PPK model median (90% confidence interval) concentration-time profile following a single 300 mg IM ADI-58125 dose by study.

[0710] The population pharmacokinetic model provides a precise and unbiased fit to observed ADI- 58125 concentration-time in healthy adults. The VPC plots shows that model-based simulations recapture the observed data reliable (Figure 28). In addition, the traditional goodness-of-fit plots showed that the fit to the data is precise and unbiased both on a population mean and individual basis (Figure 49). The conditional weighted residual plots indicate that there is minimal bias relative to the population fitted concentrations and time since dose.

[0711] The post hoc empirical Bayesian PK parameter estimates were used to calculate derived PK parameters of AUC, Cmax and half-life, which are summarized in Table 16B below. The distribution of the dose-independent PK parameters in the 24 subjects included in the analysis are provided in

Figure 50.

Table 16B. Pharmacokinetic Parameters for ADI-58125 across all doses.

AUC: area under the curve. Cmax: maximum serum concentration. CL: clearance. Tm· half-life. Vss: steady state volume of distribution.

[0712] The median population prediction of elimination half-life was 123 days, ranging from 79-277 days. The results are consistent with the intended PK characteristics of ADI-58125 (i.e., prolonged half-life and high IM bioavailability). The median AUC from time zero to 6 months and Cams increased in a dose-proportional manner when comparing the 300 mg and 600 mg IM groups. This is consistent with the linear elimination found to be most appropriate during population PK model development.

[0713] Figure 51 shows the population mean predicted concentrations overtime with IV or iM administration. At a dose of 300 mg, ADI-58125 had a robust IM bioavailability. Absorpotion from the IM depot resulted in lower peak concentrations than those seen with the IV depot, but profiles are similar after about 2 months. The population mean estimate of IM bioavailability was 92.2%, which is also confirmed by the population PK model.

[0714]

[0715] In conclusion, a 2-compartment PPK model with linear elimination and first-order IM absorption provided a precise and unbiased fit to the observed ADI-58125 concentration-time data. Moreover, ADI-58125 demonstrated high IM bioavailability and a median terminal elimination half- life of 125 to 136 days. The results are consistent with the intended PK characteristics of ADI-58125 in terms of prolonged half-life and high IM bioavailability. This PPK model is useful for future PK- pharmacodynamic analyses and simulations conducted to support phase 2/3 dose selection.

Example 14. Addressable Patient Populations for ADI-58125

Pre-exposure prophylasis

[0716] ADI-58125 can be used in adults and pediatric individuals:

• Who are not currently infected with SARS-CoV-2 and who have not had a known recent exposure to an individual infected with SARS-CoV-2 and o Who have moderate to severe immune compromise due to a medical condition or receipt of immunosuppressive medications or treatments and may not mount an adequate immune response to COVID-19 vaccination; or o For whom vaccination with any available COVID-19 vaccine, according to the approved or authorized schedule, is not recommended due to a history of severe adverse reaction (e.g., severe allergic reaction) to a COVID-19 vaccine(s) and/or COVID-19 vaccine component(s).

[0717] The following patient populations are also eligible to receiving ADI-58125:

• Patients who are within 1 year of receiving B-cell depleting therapies (e.g., rituximab, ocrelizumab, ofatumumab, alemtuzumab)

• Patients receiving Bruton tyrosine kinase inhibitors

• Chimeric antigen receptor T cell recipients

• Post-hematopoietic cell transplant recipients who have chronic graft versus host disease or who are taking immunosuppressive medications for another indication

• Patients with hematologic malignancies who are on active therapy

• Lung transplant recipients

• Patients who are within 1 year of receiving a solid-organ transplant (other than lung transplant)

• Solid-organ transplant recipients with recent treatment for acute rejection with T or B cell depleting agents

• Patients with severe combined immunodeficiencies

• Patients with untreated HIV who have a CD4 T lymphocyte cell count <50 cells/mm³

Treatment

[0718] The CDC COVID-19 Treatment Guidelines prioritize the following risk groups for anti- SARS-CoV-2 therapy based on 4 key elements: age, vaccination status, immune status, and clinical risk factors. The groups are listed by tier in descending order of priority, and these patient populations are eligible to receiving ADI-58125 as a treatment for COVID: [0719] Tier 1:

• Immunocompromised individuals not expected to mount an adequate immune response to COVID-19 vaccination or SARS-CoV-2 infection due to their underlying conditions, regardless of vaccine status (see Immunocompromising Conditions below); or

• Unvaccinated individuals at the highest risk of severe disease (anyone aged >75 years or anyone aged >65 years with additional risk factors)

[0720] Tier 2:

• Unvaccinated individuals at risk of severe disease not included in Tier 1 (anyone aged >65 years or anyone aged <65 years with clinical risk factors)

[0721] Tier 3

• Vaccinated individuals at high risk of severe disease (anyone aged >75 years or anyone aged >65 years with clinical risk factors)

[0722] Tier 4

• Vaccinated individuals at risk of severe disease (anyone aged >65 years or anyone aged <65 with clinical risk factors).

Post-Exposure Prophylaxis

[0723] ADI-58125 may be used in adults and pediatric individuals for post-exposure prophylaxis of

COVID-19 in individuals who are at high risk for progression to severe COVID-19, including hospitalization or death, and are o not fully vaccinated or o who are not expected to mount an adequate immune response to complete SARS- CoV-2 vaccination (for example, individuals with immunocompromising conditions including those taking immunosuppressive medications) and

^■ have been exposed to an individual infected with SARS-CoV-2 consistent with close contact criteria per Centers for Disease Control and Prevention (CDC) or

^■ who are at high risk of exposure to an individual infected with SARS-CoV-2 because of occurrence of SARS-CoV-2 infection in other individuals in the same institutional setting (for example, nursing homes, prisons)

[0724] The following patient populations are also eligible to receiving ADI-58125 as a prophylactic alternative:

• Exposed patients concerned about “Long COVID” seeking to rapidly drive down their viral load in case they have COVID; and

• Exposed patients for whom quarantining is not an option due to impending travel, work obligations, or other reasons. Pediatrics

[0725] Although children are at lower risk of developing severe COVID-19 compared to adults, a subset of children experience poor outcomes, including severe acute disease, such as the multisystem inflammatory syndrome, or MIS-C, and long-term sequelae of disease, also known as long COVID. Safe and effective therapies are needed to prevent severe disease and hospitalization in high-risk children as well as complications of COVID-19 such as MIS-C and long COVID. Similarly, although there is a paucity of data regarding the immune response to COVID-19 vaccines in children with moderate to severe immunocompromise, a subset of these children may have suboptimal immune responses to vaccines similar to adults with certain forms of immunocompromise and thus have the potential to benefit from a passive immune approach. Currently, the CDC recommends that children ages 5 to 11 with moderate to severe immunocompromise receive a 3 dose primary series of the Pfizer-BioNTech vaccine and that pre-teens and adolescents with moderate to severe immunocompromise receive a total of 4 doses of a mRNA COVID-19 vaccine. ADI-58125 can be used in pediatric individuals:

Example 15. Development of Broad and Potent Neutralizing Antibodies to Combat SARS-CoV- 2 and Future Emerging SARS-like Viruses

[0726] The neutralizing antibodiy response to SARS-CoV-2 is dominated by three classes of public RBD antibodies which share common escape mutations (Figures 29A and 29B). A newly emerged Omicron (B.1.1.529/BA.1) variant contains mutations in the epitopes of all three public classes of antibodies (Figure 30). Conserved spike mutations in the Omicron (B.1.1.529/BA.1) variant include A67V, D69-70, T95I, G142D/A143-145, A211/L212I, ins214EPE, G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493K, G496S, Q498R, N501Y, Y505H, T547K, D614G, H655Y, N679K, P681H, N764K, D796Y, N856K, Q954H, N969K, and L981F (Figure 30). [0727] Many clinical stage/EUA authorized antibodies target common epitopes, such as LY-C0VOI6 (etesevimab), REGN10933 (casirvimab) (both in class 1); LY-CoV555 (bamlanivimab), ADZ8895 (COV2-2196 or tixagevimab), CT-P59 (regdanvimab) (ah in class 2); and REGN10987 (imdevimab) and AZD1061 (COV2-2130 or cilgavimab) (both in class 3). Escape mutations from these antibodies are determined by deep mutational scanning as described previously; in particular, E484 and Q493 for Ly-Cov555; K417 for Ly-CoV16; K417, E484, and Q493 for REGN10933; G446 and N440 for REGN10987; G446 for AZD1061; and G339 for sotrovimab, among others (Starr T., et al, Science, 2021; Greany, A. et al., Nat. Comm., 2021; Dong J. et al, Nat. Micro., 2021). As shown in Figures 30, 31, 32A and 32B, ADI-58125 binds to an epitope distinct from those recognized by commonly elicited nAbs. The inherent features of the claimed broadly neutralizing antibodies, such as ADI- 58125, offer a high barrier to resistance by targeting of immunoquiescent epitopes (protected from immune pressure) and recognition of highly conserved residues (likely important for viral fitness). [0728] Figure 41 depicts the average fold change in IC50 relative to the D614G reference strain of ADI-58125 in a lenti viral pseudo virus assay. All spike variants contain the D614G substitution. To minimize the impact of potential assay variability, D614G was tested in parallel with each variant, and the variant-matched D614G IC50 value was used to calculate the fold change in IC50. Variants of concern and their descendent lineages are highlighted in red. Data represents the mean of at least two indepdendent experiments, and error bars represent standard deviation. As shown in Figure 41, ADI- 58125 exhibited a 328-fold loss in neutralization activity against the newly emergent B.1.1.529/BA.l/Omicron variant of concern. Similarly, B.1.1 -529/Omicron pseudovirus containing the R346K mutation, which is currently present in approximately 10% of sequenced Omicron variants, led to a 286-fold reduction in IC50 relative to D614G. However, despite the reduction in neutralization activity, ADI-58125 still maintained neutralization potency against Omicron. Figure 42A_shows the neutralization curves for ADI-58125 and ADI-58122 against Omicron (BA.l) and D614G (also referred to as wild type, WT), and Figure 42B_shows the neutralization curves for ADI- 58125 against D614G and Omicron sublineages (BA.l, BA.1.1, and BA.2) using a pseudovirus neutralization assay. As shown in Figure 42A, ADI-58125 retained partial potency against theOmicron (BA.l) variant, with an IC50 against Omicron of about 211.8 ng/mL and an IC50 against D614G of about 0.6 ng/ml. The IC50 for ADI-58122 was shown to have an IC50 of about 8.5 ng/mL for D614 and about >4000 ng/ml for the Omicron variant. Figure 42B also shows the in vitro neutralizing activity of ADI-58125 against the Omicron BA.l and BA.1.1 sub-lineages.

[0729] Further in vitro studies examined the neutralization potencies of large panels of mAbs against the Omicron variant (B.1.1.529/BA.1) in both authentic and pseudovirus assays. Findings across the studies show that among mAbs in late-stage clinical development or with Emergency Use Authorization (EUA), ADI-58125 is one of only a few mAbs that demonstrated neutralizing activity against Omicron. Across two distinct authentic neutralization assays against Omicron, the data show that ADI-58125 had an IC₅₀, a measurement of neutralization potency, of approximately 0.2 to 1.1 μg/mL and an IC90 of about 9.943 μg/mL. See also, e.g., Dejnirattisai et al. (2022) SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses; Planas et al. (2021) Considerable escape of SARS-CoV-2 variant Omicron to antibody neutralization; Liu et al. (2021) Strikig antibody evasion manifested by the Omicron variant of SARS-CoV-2; Cameroni et al. (2021) Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift; and Lusvarghi et al. (2022) Comparison of SARS-CoV-2 Omicron neutralization by therapeutic antibodies, convalescent sera, and post-mRNA vaccine booster sera, the entire contents of each of which are expressly incorporated herein by reference. [0730] Additional binding and neutralization assays were performed on Victoria and all variants of concern, Alpha, Beta, Gamma, Delta and Omicron (BA.l., BA.1.1, and BA.2). Omicron (where not specified Omicron refers to sub-lineage BA.l) contains an unprecedented number of mutations concentrated in the Spike (S) gene which carries 30 substitutions plus the deletion of 6 and insertion of 3 residues. BA.1.1 has an additional R346K mutation than BA.l. BA.2 differs from BA.l at 6 positions in the RBD. A slightly increased affinity of BA.2 RBD for ACE2 was observed, which may underlie its increased transmissibility. Neutralization of BA.l to BA 1.1 and BA.2 was also compared, where both BA.1.1 and BA.2 were shown to be modestly more difficult to neutralize than BA.l using vaccine serum.

[0731] The neutralization potential of antibodies was measured using a Focus Reduction Neutralization Test (FRNT). Briefly, the reduction in the number of the infected foci is compared to a negative control well without antibody. Briefly, serially diluted Ab or plasma was mixed with SARS- CoV-2 strains and incubated for 1 hr at 37°C. The mixtures were then transferred to 96-well, cell culture -treated, flat-bottom microplates containing confluent Vero cell monolayers in duplicate and incubated for a further 2 hrs followed by the addition of 1.5% semi-solid carboxymethyl cellulose (CMC) overlay medium to each well to limit virus diffusion. A focus forming assay was then performed by staining Vero cells with human anti-NP mAh (mAb206) followed by peroxidase- conjugated goat anti-human IgG (A0170; Sigma). Finally, the foci (infected cells) approximately 100 per well in the absence of antibodies, were visualized by adding TrueBlue Peroxidase Substrate. Virus-infected cell foci were counted on the classic AID EliSpot reader using AID EFISpot software. The percentage of focus reduction was calculated and IC₅₀ was determined using the probit program from the SPSS package.

[0732] Authentic neutralization assays were performed for antibodies being developed for commercial use (Figures 43 and 44). As shown in Figures 43 and 44, although neutralization of BA.2 was knocked out for ADI-58125, it was still able to neutrali e BA.l and BA.1.1. See also, e.g., Nutalai et al, (2022) Potent cross-reactive antibodies following Omicron breakthrough in vaccinees, the entire contents of which are expressly incorporated herein by reference.

[0733] These data uniformly support that ADI-58125 is among the few mAbs to demonstrate neutralizing activity against the Omicron variant, and also consistently support the findings from a variety of preclinical studies showing that ADI-58125 retains activity against other variants of concern including Alpha, Beta, Delta and Gamma, and that ADI-58125 retains neutralizing activity against a diverse panel of circulating SARS-CoV-2 variants, including the Fambda, Mu and Delta plus variants, thus, warranting its continued development.

Sarbecovirus cross-reactivity binding assay

[0734] ADI-58125 and human ACE2 (hACE2; expressed in a bivalent format as a C-terminal IgGl Fc conjugate with an approximate molecular weight of 290 kDa; Sino Biological, Cat # 10108-H02H) binding to surface-displayed RBD was first assessed at a single 100 nM concentration against the panel of 17 yeast-surface displayed sarbecovirus RBD-SD1 proteins. 0.1 OD induced cells per well were aliquoted into 96-well plates and washed out of induction media with PBSF (PBS with 0.1% w/v BSA). Next, cells were resuspended in 100 pL of ADI-58125 at 15 μg/mL or hACE2 at 29 ug/ml and incubated at 24 °C for 30 minutes, followed by two washes with PBSF. Cells were subsequently labeled with 50 pL of 1:100 diluted allophycocyanin (APC)-conjugated monoclonal mouse anti hemagglutinin tag (HA).11 antibody (BioLegend, Cat # 901524), 1:100 diluted phycoerythrin (PE)- conjugated goat anti-human IgG polyclonal antibodies (Southern Biotech, Cat # 2040-09), and 5 μg/mL propidium iodide (Invitrogen, Cat # P1304MP); and incubated on ice for 20 minutes. For each sarbecovirus, an additional sample was labeled with only secondary reagents to establish background signal levels. Cells were washed out of secondary staining reagents with PBSF twice before analyzing via flow cytometry on a BD FACS Canto II. Normal and live yeast cells (as determined by forward scatter-side scatter (FSCxSSC) and propidium iodide incorporation, respectively) were collected for each sample to measure mean fluorescence intensity (MFI) of surface RBD-SD1 expression and ADI- 58125/ACE2 binding.

SARS-CoV-2 variants binding assay

[0735] SARS-CoV-2 variants commonly present in GISAID were evaluated for ADI-58125/ADI- 58122 binding. To more comprehensively assess the impact of different substitutions at D405, G502, G504, and Y505 residues, RBDs incorporating ah 19 substitutions at each residue were generated. Antibody binding experiments were performed essentially as described with sarbecovirus binding, with the difference that yeast cells were stained with ADI-58125 at its KDApp concentration, 0.43 nM, to maximize the dynamic range of differences in binding affinity to variants compared to the Wuhan-Hu-1 RBD-SD1. Binding signal was normalized N-terminal HA expression signal and background staining by dividing mean PE MFI by the mean APC MFI and subtracting the PE/APC ratio of non-primary labeled cells and expressed as a percentage of SARS-CoV-2 wildtype binding by ADI-58125.

[0736] Affinity maturation of ADI-58125 against the SARS-CoV-2 BA.l Omicron variant was performed by introducing diversities into the heavy chain and light chain variable regions. Briefly,

VH and VF CDR diversification was obtained by odering forward priming oligos with variation in each cdr. FR1-FR4 oligos containing homology to the CDRs above were ordered in the reverse priming direction for the assembly and amplification of the entire heavy or light chain variable regions via PCR. The heavy chain variable regions (FR1-FR4) were transformed into yeast containing the light chain plasmid of the parent. The light chain variable regions (FR1-FR4) were transformed into yeast containing the heavy chain plasmid of the parent. Selections were performed with rounds of FACS, sorting for the highest affinity biotinylated SARS-CoV-2 spike protein binders using antigen titration. [0737] Figure 52A provides a graph comparing binding affinity of ADI-58125 and affinity maturation progenies for the SI from the Omicron BA.l varaint. Figure 52B provides a graph comparing the ability of ADI-58125 and affinity maturation progenies to neutralize the Omicron BA.l varaint. As shown in Figure 52A, affinity maturation progenies were able to increase the binding affinity against the Omicron BA.l SI protein by over 100-fold (K_D of 291 nM for ADI-58125 vs. K_D of 2.11 nM for affinity maturation progenies). Similarly, affinity maturation progenies were able to improve the neutralization against the Omicron BA.l varaint by about 40 folds (ICso of 0.215 μg/mL for ADI-58125 vs. IC₅₀ of 0.0.005 μg/mL for affinity maturation progenies), while maintaining activity against other VOCs and SARS-CoV (Figure 52B).

[0738] Figure 53A provides a graph comparing binding affinity of re-engineered ADI-58125 progenies for various SARS-CoV-2 variants, including the BA.l Omicron variant, the Beta variant, the Delta variant and D614G, and SARS-CoV. Figure 53B shows the corresponding neutralization IC₅₀ of re-engineered ADI-58125 progenies. As shown in Figures 53A and 53B, affinity matured ADI-58125 progenies maintained binding and neutralizing activities against the variants of concern.

Example 16. Efficacy of ADI-58125 Against SARS-CoV-2 in Rhesus Macaque Intratrachel- intranasal Exposure Model

[0739] This study demonstrated ADI-58125 treatment offers protection against SARS-CoV-2 infection, resulting in only minimal to mild pulmonary inflammation. Rhesus macaque were exposed to SARS-CoV-2 after receiving ADI-58125 (25 mg/kg or 5 mg/kg), or irrelevant control monoclonal antibody (mAh) (5 mg/kg), 3-days prior. Evaluation of microscopic pulmonary lesions among the groups with comparing and contrasting the findings aims to support the development of an mAh that provides prophylactic and therapeutic benefit.

[0740] Methods and Materials

[0741] A total of 12 rhesus macaques were included in the study. The study was comprised of 3 groups: group 1 received 25 mg/kg Control mAh; group 2 received 25 mg/kg ADI-58125; and group 3 received 5 mg/kg ADI-58125 Each group had 4 NHPs of the same species that were randomly assigned, balanced by sex and body weight. See Table 17.

[0742] Challenge agent: Groups 1-3 SARS-CoV-2

[0743] Target Challenge Dose/Route: IT/IN exposure 1 x 10⁶ pfu.

[0744] All necropsies were performed by a veterinary pathologist within 5 hours of euthanasia, study days 5 and 6 respectively. All necropsies were performed IAW Pathology Division SOPs. All gross findings were recorded as appropriate in the currently validated version of Pristima. Tissues were collected IAW Pathology Division SOPs and fixed by immersion into labeled containers of 10% neutral buffered formalin for the specified time according to the currently validated pathogen-specific inactivation time. Tissues were collected for each animal. Additional tissues were also collected when gross observations warrant histopathologic evaluation.

[0745] Tissues were removed from biocontainment IAW Pathology Division SOPs and transported to the USAMRIID histology lab for processing. The tissues were trimmed, processed, embedded in paraffin, cut by microtomy, stained, coverslipped and screened IAW Pathology Division SOPs. Tissue blocks and slides were produced.

[0746] Replicate lung, nasal turbinates, trachea, larynx, tracheobronchial lymph node and olfactory bulb tissue sections were placed on positively-charged slides and stained by immunohistochemistry (IHC) procedures IAW Pathology Division SOPs.

[0747] All slides were examined by the veterinary pathologist and all findings were recorded into the currently validated version of Pristima. Following the conclusion of slide evaluation, the specimens were stored or archived by USAMRIID personnel IAW Pathology Division SOPs.

[0748] Results

[0749] All animals survived to study day 5 or 6 and were euthanized at the end of the study. Animals surviving to and euthanized at the end of the study were referred to as survivors. Survivor data was detailed in Table 17. Table 17. Animal Table

[0750] Necropsy Findings

[0751] Group 1: The most consistent gross finding in this group was enlarged (1.5 times to 3 times normal) tracheobronchial lymph nodes (present in 3/4 NHPs in the group). Additional gross findings in this group that at the time of necropsy were suspected to be disease or challenge related included moderate red discoloration and consolidation of the hilar region of the right caudal lung lobe (present 1/4 NHP (1221) in this group) (see Figures 33 and 34). Mild multifocal red discoloration was noted in all lung lobes (present 1/4 NHP (1294) in this group) (see Figure 39). Mild multifocal red discoloration was noted in the lower left nasal turbinate (present 1/4 NHP (624R) in this group). [0752] Group 2: The most consistent gross finding in this group was enlarged (1.5 times to 3 times normal) tracheobronchial lymph nodes (present in 3/4 NHPs in the group). Additional gross findings in this group that at the time of necropsy were suspected to be disease or challenge related included mild multifocal red discoloration noted in all lung lobes (present 1/4 NHP (0246) in this group) and in the left cranial and caudal lung lobes (present 1/4 NHP (8011) in this group).

[0753] Group 3: The most consistent gross finding in this group was enlarged (1.5 times to 3 times normal) tracheobronchial lymph nodes (present in all NHPs in the group). Additional gross finding in this group that at the time of necropsy were suspected to be disease or challenge related included mild multifocal red discoloration noted in all lung lobes along with a locally extensive fibrinous adhesion from the left caudal lung lobe to the thoracic wall (present 1/4 NHP (5240) in this group) (see Figure 40).

[0754] Other recorded gross necropsy findings in these groups are considered not to be disease or challenge related.

[0755] Microscopic Findings

[0756] A summary of the major histopathologic findings in the lungs graded by severity for each NHP was present in Table 18. A summary of the histological findings in the nasal turbinates graded by severity for each NHP was present in Table 19.

[0757] Group 1: The disease-related microscopic lesions present in this group were noted predominately in the lung. Additionally, nasal turbinates and the trachea had lesions that were suspected to be either challenge or disease related. All NHPs in this group had mild to moderate multifocal interstitial (expansion of the alveolar septae), perivascular and/or peribronchiolar pulmonary inflammation composed predominately of lymphocytes and histiocytes with fewer neutrophils. Additional pulmonary findings present in 3/4 NHPs in this group were minimal to mild type 2 pneumocyte hyperplasia and 2/4 NHPs (1221 and 642R) had mild fibrin deposition either within alveolar lumina or expanding the alveolar septa. IHC was multifocally minimally to mildly positive in areas of inflammation in all NHPs in this group (see Figure 35). [0758] All NHPs in this group had mild to moderate inflammation in one or more sections of the nasal turbinates composed predominately of lymphocytes and plasma cells with fewer neutrophils with areas of erosion or ulceration, degeneration and necrosis and edema (see Figure 36). All NHPs in this group had minimal to mild inflammation in the submucosa of the trachea composed of lymphocytes, plasma cells and neutrophils. Rare epithelial cells lining the trachea were IHC positive in 2 NHPs (7137 and 1221) in this group along with rare epithelial cells lining the nasal turbinates were IHC positive in 1 NHP (7137). IHC as negative in all of the sections of nasal turbinates for 3/4 NHPs in this group.

[0759] All NHPs in this group had mild multifocal sinus histiocytosis in the tracheobronchial lymph node. Two NHPs in this group (642R and 1221) were also draining neutrophilic inflammation. IHC was negative in all sections of the tracheobronchial lymph node and in one olfactory bulb (1221) examined in all NHPs in this group. Three olfactory bulbs (642R, 1294 and 7137) and all larynx tissue were missing at time of trimming.

[0760] Group 2: The suspected disease -related microscopic lesions in this group were noted predominately in the lung. Additionally, nasal turbinates and the trachea had lesions that were suspected to be challenge related. The principle histological lesion present in the lungs of all animals in this group was multifocal and/or focal minimal to mild inflammation composed predominately of histiocytes and lymphocytes with fewer neutrophils. Of the eight sections of lung lobes examined in each NHP the multifocal mild inflammation was present in two sections (0246) and in one section (7175 and 6334). Multifocal minimal inflammation was present in two sections (6334) and in one section (8011). Focal minimal inflammation was also noted in one section of the eight examined (6334). The inflammation was present around vessels and it expanded alveolar septa and occasionally extended into the alveolar lumina in all animals. IHC was negative in all areas of inflammation in the lung tissue examined in all NHPs in this group (see Figure 37).

[0761] All NHPs in this group had mild to marked inflammation in one or more sections of the nasal turbinates composed predominately of lymphocytes and plasma cells with fewer neutrophils with areas of erosion or ulceration, degeneration and necrosis and edema. Three out of four NHPs (7175, 6334 and 8011) in this group had minimal submucosal inflammation in the trachea composed of lymphocytes, plasma cells and neutrophils. One NHP in this group (6334) had multifocal mild inflammation in the submucosa of the larynx composed of lymphocytes, plasma cells and neutrophils. IHC was negative in all of the sections of nasal turbinates, trachea and larynx.

[0762] All NHPs in this group had mild multifocal sinus histiocytosis in the tracheobronchial lymph node. IHC was negative in all sections of tracheobronchial lymph node, olfactory bulbs (8011, 7175, 6334) and larynx (8011, 7175, 6334). Olfactory bulb and larynx was missing at time of trim for NHP 0246. [0763] Group 3: The suspected disease-related microscopic lesions in this group were noted predominately in the lung. Additionally, nasal turbinates and the trachea had lesions that were suspected to be challenge related. The principle histological lesion present in the lungs of 3/4 animals in this group was multifocal and/or focal minimal to mild inflammation composed predominately of histiocytes and lymphocytes with fewer neutrophils. Of the eight sections of lung lobes examined in each NHP the multifocal mild inflammation was present in one of the eight sections examined (5240, 1430 and 3471). Multifocal minimal inflammation was present in one sections (3471). The inflammation was present around bronchi or bronchioles (3471 and 5420), and it expanded alveolar septa and occasionally extended into the alveolar lumina (3471 and 1430). IHC was negative in all areas of inflammation in all NHPs in this group (see Figure 38).

[0764] All NHPs in this group had mild to moderate inflammation in one or more sections of the nasal turbinates composed predominately of lymphocytes and plasma cells with fewer neutrophils with areas of erosion or ulceration, degeneration and necrosis and edema. All NHPs in this group had minimal to mild inflammation in the submucosa of the trachea composed of lymphocytes, plasma cells and neutrophils. One NHP (3471) had a focal erosion of the tracheal mucosa. Three out of the four NHPs in this group (8075, 5240 and 1430) had multifocal mild inflammation within the submucosa of the larynx. IHC was negative in all of the sections of nasal turbinates, trachea and larynx examined for all NHPs in this group.

[0765] Two NHPs in this group had minimal to mild lymphoid hyperplasia and all NHPs had mild multifocal sinus histiocytosis in the tracheobronchial lymph node. IHC was negative tracheobronchial lymph node and olfactory bulb for all NHPs in this group. Olfactory bulb and larynx was missing at time of trim for NHP 3471.

[0766] Other recorded microscopic findings occurred in these groups and are considered incidental findings and are not disease related.

Table 18. Pulmonary Lesions Based on Severity

[0767] Summary

[0768] Gross to Microscopic Correlations

[0769] Group 1: The moderate red discoloration and consolidation of the hilar region of the right caudal lung lobe in NHP 1221 did correlate to disease related microscopic findings (see Figure 33). Extensive area of inflammation, edema, type II pneumocyte hyperplasia and fibrin deposition were noted within peripheral and central sections taken from the right caudal lung lobe. These lesions were IHC positive. The multifocal red discoloration noted throughout the lung lobes in NHP 1294 may correlate to disease related microscopic findings. In the affected lobes there was hemorrhage, edema and minimal to mild inflammation (all central sections examined and one peripheral sections examined). Lung tissue from this NHP was IHC positive. The grossly enlarged tracheobronchial lymph nodes in 3/4 NHPs (1294, 642R and 1221) in this group correlated to mild sinus histiocytosis this finding was most consistent with a reactive lymph node. Reactive lymph nodes had increased lymphatic flow which was evident by increased drainage from tissue by the presence of increased numbers of phagocytic cells (macrophages/histiocytes) within the medullary sinuses (sinus histiocytosis). This microscopic finding was likely evidence of antigenic stimulation from SARS- CoV-2 viral challenge. The red discoloration present on the lower left turbinate of NHP 642R did not correlate to any disease related microscopic findings.

[0770] Group 2: The multifocal mild red discoloration noted in all lung lobes (0246) and limited to the left cranial and caudal lung lobes (8011) did not correlate to disease related microscopic findings. Microscopically these sections of lung had either edema or congestion which were considered non specific histological findings. Grossly enlarged tracheobronchial lymph nodes in 3/4 NHPs (0246, 7175 and 8011) in this group correlated to mild sinus histiocytosis this finding was most consistent with a reactive lymph node. Reactive lymph nodes had increased lymphatic flow which was evident by increased drainage from tissue by the presence of increased numbers of phagocytic cells (macrophages/histiocytes) within the medullary sinuses (sinus histiocytosis). This microscopic finding was likely evidence of antigenic stimulation from SARS-CoV-2 viral challenge.

[0771] Group 3: The pulmonary adhesions present in NHP 5240 from the left caudal lung lobe to the left thoracic wall and multiple areas of red discoloration did not correlate to disease related microscopic findings. Fibrous adhesions were noted between lung lobes microscopically; however, there were no microscopic changes to the underlying pulmonary parenchyma in the areas of pleural fibrosis and IHC was negative. Pleural or subpleural fibrosis with or without lung adhesions to adjacent lung lobes or the thoracic cavity were commonly encountered in the lungs of macaques. Grossly enlarged tracheobronchial lymph nodes in all NHPs in this group correlated to minimal to mild lymphoid hyperplasia in two NHPs (8075 and 5240) and mild sinus histiocytosis in all NHPs. These histological findings were most consistent with a reactive lymph node. Reactive lymph nodes had increased lymphatic flow which was evident by increased drainage from tissue by the presence of increased numbers of phagocytic cells (macrophages/histiocytes) within the medullary sinuses (sinus histiocytosis). This microscopic finding was likely evidence of antigenic stimulation from SARS- CoV-2 viral challenge.

[0772] Histopathology

[0773] Group 1: All NHPs in this group had mild to moderate lymphoplasmacytic and neutrophilic inflammation in one or more sections of the nasal turbinates. 2/4 NHPs (7137 and 642R) had mild submucosal edema, 2 NHPs had ulceration and/or erosion of the nasal epithelium (7137 and 1294) and two NHPs had degeneration and necrosis within the mucosa or submucosa (7137 and 1294). The cause of the inflammation and other microscopic findings were not evident histologically. It was suspected that these findings were the result of SARS-CoV-2 infection within the nasal turbinates as noted by the presence of few epithelial cells being IHC positive in NHP 7137. However, the inflammation could also be the related to the manipulations associated with experimental challenge route.

[0774] The other microscopic finding in this group that was suspected to be related to either the result of SARS-CoV-2 infection or experimental challenge route/manual manipulations (broncho- alveolar lavage performed on days 1 and 3 of the study) was the multifocal to mild inflammation noted in the trachea. IHC as positive in occasional tracheal epithelium in 2/4 NHPs (1221 and 7137) in this group.

[0775] Group 2: All NHPs in this group had mild to marked lymphoplasmacytic and neutrophilic inflammation in one or more sections of the nasal turbinates. The cause of the inflammation was not evident histologically. It was suspected that these findings were the result of SARS-CoV-2 infection within the nasal turbinates. However, the inflammation could also be the related to the manipulations associated with experimental challenge route. [0776] Other microscopic finding in this group that were suspected to be related to experimental challenge route/manual manipulations (broncho-alveolar lavage performed on days 1 and 3 of the study) were present in the trachea and larynx. Three out of four NHPs (7175, 6334 and 8011) in this group had minimal submucosal inflammation in the trachea. One NHP in this group (6334) had multifocal mild inflammation in the submucosa of the larynx. IHC was negative in all sections of trachea and larynx examined.

[0777] Group 3: All NHPs in this group had mild to moderate lymphoplasmacytic and neutrophilic inflammation in one or more sections of the nasal turbinates. The cause of the inflammation or focal ulceration was not evident histologically. It was suspected that these findings were the result of SARS-CoV-2 infection within the nasal turbinates. However, the inflammation could also be the related to the manipulations associated with experimental challenge route.

[0778] Other microscopic finding in this group that were suspected to be related to experimental challenge route/manual manipulations (broncho-alveolar lavage performed on days 1 and 3 of the study) were present in the trachea and larynx. All NHPs in this group had minimal to mild inflammation in the submucosa of the trachea with a focal area of mucosal erosion noted in one NHP (3471). Three out of the four NHPs in this group (8075, 5240 and 1430) had multifocal mild inflammation within the submucosa of the larynx.

[0779] Conclusion

[0780] The gross findings in the lungs in one NHP in group 1 (1221), histological findings present in the lungs in 3/4 NHPs in group 1 and IHC results in all animals in group 1 parallel reported histopathological findings in rhesus macaques with SARS-CoV-2 infection (Munster VJ, et al.

Nature. 2020 Sep;585(7824):268-72). All animals were affected with varying degrees of pulmonary inflammation on 2 to 5 of the 8 sections of lungs examined. Positive immunohistochemistry present in all animals in this group in the areas of inflammation and within the respiratory epithelium supported SARS-CoV-2 as the underlying cause for the microscopic findings in the lungs in this group.

[0781] The predominate microscopic finding in the lungs of all group 2 NHPs was multifocal minimal to mild inflammation on 1 to 3 of the 8 sections of lungs examined. No other significant microscopic lesions were present in the lungs. Additionally IHC was negative on all sections of lungs examined for all NHPs in this group. It was suspected that the antibody treatment offered some protection resulting in only minimal to mild pulmonary inflammation on the histological section examined for this group.

[0782] The predominate microscopic finding in the lungs of 3/4 group 3 NHPs was multifocal minimal to mild inflammation on 1 to 2 of the 8 sections of lungs examined. No other significant microscopic lesions were present in the lungs. It is important to note that one NHP (8075) did not have the pulmonary inflammation typically associated with SARS-CoV-2 infection. Additionally IHC was negative on all sections of lungs examined for all NHPs in this group. It was suspected that the antibody treatment offered some protection resulting in only minimal to mild pulmonary inflammation on the histological section examined for this group.

Example 17. Omicron-Based Dose Selection of ADI-58125 for the Prevention and Treatment of SARS-CoV-2

[0783] In the primary analysis population, the pre-Omicron group, patients infected with or exposed to a non-Omicron variant, ADI-58125 met the primary objectives with statistical significant across all three indications (pre- and post-exposure prophylaxis and treatment of COVID-19), demonstrating statistically significant and clinically meaningful efficacy. In pre -exposure and post-exposure prophylaxis, ADI-58125 was associated with 71% and 75% relative risk reductions compared to placebo, respectively, in the prevention of RT-PCR confirmed symptomatic COVID-19. In an exploratory analysis of the post-Omicron group, patients exposed to the Omicron variant, in pre exposure prophylaxis, ADI-58125 was associated with a clinically meaningful reduction in the risk of developing RT-PCR confirmed symptomatic COVID-19 compared with placebo. In treatment, ADI- 58125 was associated with a 66% relative risk reduction compared to placebo in the incidence COVID-19 related hospitalization or all cause death through Day 29. In patients treated within three days of symptom onset, ADI-58125 was associated with a reduced risk of COVID-19 hospitalization or death from any cause through Day 29 by 77% compared to placebo. A preliminary analysis of available safety data in each trial revealed no safety concerns for ADI-58125.

Prevention of SARS-CoV-2: ADI-58125-PREV-001 (EVADE)

[0784] In order to determine an appropriate pharmacodynamic target for prevention, available clinical data from vaccine and other monoclonal antibody (mAh) programs were evaluated to determine a neutralizing antibody titer threshold associated with protection against symptomatic COVID-19. To perform this analysis, published vaccine efficacy data (Polack 2020; Abu-Raddad 2021; Andrews 2021; AstraZeneca 2021; Clemens 2021; Emary 2021; Falsey 2021; Hitchings 2021; Liu 2021a; Lopez Bernal 2021; Madhi 2021; Nasreen 2021; O'Brien 2021; Tartof 2021; UKHSA

2021) were utilized, as well as geometric mean serum neutralization IC50 values for samples obtained fromChAdOxl nCoV-19/AZD1222 (AstraZeneca) and BNT162b2 (BioNTech/Pfizer) vaccinees at different time points following administration and against different variants of concern (AstraZeneca 2021; Liu 2021a). All of the vaccinee serum samples were evaluated using the same authentic virus neutralization assay. This assay was also used to determine the neutralization IC50 values for ADI- 58125, other clinical-stage mAbs, and mAbs authorized for emergency use (including REGEN -COV [Regeneron] and AZD7442 [AstraZeneca]) against an ancestral strain of SARS-CoV-2 (Victoria) as well as all variants of concern (Alpha, Beta, Gamma, Delta, and Omicron) (Liu 2021a; Dejnirattisai

2022). This allowed for a direct comparison of measured vaccine-induced neutralizing antibody titers and projected serum neutralizing titers following passive antibody administration, which was then correlated to the respective reported efficacies (AstraZeneca 2021; O'Brien 2021; Regeneron 2021). [0785] The projected serum neutralizing titers for the mAbs were calculated by dividing the neutralization IC50 values by the estimated serum antibody concentration at a given timepoint following antibody administration based on internal (ADI-58125) or published (REGEN -COV and AZD7442) pharmacokinetic data (FDA 2020; Loo 2021). Based on the correlation between serum neutralizing antibody titers and reported vaccine and mAh efficacy against symptomatic COVID-19 (Figure 45), a threshold serum neutralizing titer of -1:100 was associated with -70% protection against symptomatic disease relative to placebo. Given the in vitro IC50 value of 1.029 μg/mL for ADI-58125 against the Omicron variant in this assay, a serum ADI-58125 concentration of - 100 μg/mL would be required to reach this threshold neutralizing titer.

[0786] To evaluate the dosing regimens of ADI-58125, a preliminary population PK (PopPK) model was developed based on data from a phase 1, first-in-human (FIH), single-ascending dose study of ADI-58125 in 24 healthy adult participants. The PopPK model utilized a two-compartment model with linear clearance (CL) from the central compartment. For IM administration, a first-order rate constant was used to describe the extravascular absorption. CL and volume of distributions were ahometricahy scaled from parameters. The median and 80% (10-90%) prediction interval (PI) were estimated from 500 randomly simulated subjects based on weight distribution of the subjects enrolled in the pivotal trial (EVADE or STAMP).

[0787] The 1200 mg IM dose for evaluation of the prevention of symptomatic COVID-19 in EVADE was chosen based on the projected ability to achieve the following targets after the initial absorption phase: 1) a median concentration of ADI-58125 (100 mg/L) in serum for three months (or 12 weeks) that is projected to be associated with a serum virus neutralizing titer of -1:100 as estimated above based on IC50 value; and 2) a median concentration (99.4 mg/L) of ADI-58125 in serum for three months (or 12 weeks) after dosing that is projected to achieve 90% neutralizing concentration (IC90, 9.94 μg/mL) against the Omicron variant in the epithelial lining fluid (ELF), assuming an ELF:serum ratio of -10% (Wohacott 2016; Deng 2018) (Figure 46). The IC50 and IC90 values generated against authentic virus were used for dose selection to maintain consistency across prior dose selection efforts.

[0788] As shown in Figure 45, predicted month 3 serum neutralizing antibody titers against the Omicron variant following IM administration of 1200 mg ADI-58125 exceed the neutralization titers predicted for AZD7442 following the single 300 mg IM dose currently authorized under EUA. In order to provide protection beyond the initial 3 months, a re-dosing strategy for ADI-58125 will be devised.

[0789] To establish safety margins, exposures anticipated for the proposed 1200 mg IM dose determined from the PopPK model described above were compared against exposures achieved in the GLP rat toxicology study. These data suggest safety margins of ~ 3-fold and 51 -fold for AUC and Cmax, respectively, relative to the 1200 mg IM dose in humans, as shown in Table 20.

Table 20: Estimated Safety Margins for Proposed ADI-58125 Clinical Dose Based on Serum Exposures and Body Weight Extrapolation

Abbreviations: AUC=area under the serum concentration-time curve, AUCo 52weeks=AUC from time zero to 52 weeks post dose, AUC_0-inf=AUC from time zero to infinity, Cmax=maximum serum concentration, IM=intramuscular; IV=intravenous, NOAEL=no observed adverse-effect level.* Doses evaluated in the FIH study. Note: Simulations presented in Table 20 are based on the PopPK model with a typical subject (weight = 80.9 kg). Safety margins were calculated by dividing the sex- combined rat mean Day 22 parameters at the NOAEL of 300 mg/kg (IV) (Cmax: 7890 μg/mL, AUC_o _inf: 1590000 hr*μg/mL) by the simulated human Cmax and AUCo 52 weeks. AUC-related safety margin calculations are based on AUC_0-inf data.

[0790] Data generated to date across the clinical program also suggest that ADI-58125 had been well-tolerated across diverse study populations. No injection site reactions, hypersensitivity reactions, or other study-drug related AEs had been observed at any dose level in review of blinded safety data with a minimum of 9 months of follow-up. Similarly, ongoing internal review of blinded safety data from STAMP and EVADE has revealed no safety concerns. A single hypersensitivity event (urticaria/hives) has been reported, which was graded by the investigator as mild and was self-limited (did not require any treatment). The independent data monitoring committee (iDMC) has also reviewed unblinded data on three occasions, with a blinded safety update provided for EVADE, and recommended that the studies continue.

[0791] Based on enrollment to date, approximately 1460 participants had received ADI-58125 at dose levels ranging from 300 mg IM to 500 mg IV/600 mg IM across the clinical trials. Given the lack of identified safety signals to date, the adequate safety margins (based on AUC, Cmax, and body weight extrapolation), the lack of ADI-58125 -specific binding in human TCR studies, the lack of ADI-58125-specific findings in the rat GLP toxicology study, and the prospect for benefit in the setting of prevention in the face of the surging Omicron variant, the potential benefit of the 1200 mg IM dose outweighs the potential risk to participants and the proposed dose can be incorporated into the EVADE trial with safety oversight. Treatment of SARS-CoV-2: ADI-58125 -TRMT-001 (STAMP)

[0792] The dose selection fof ADI-58125 for the treatment indication against the Omicron variant was evaluated and compared to prior variants, and it was concluded that both a higher dose and alternative administration route (intravenous) were needed to achieve desired exposures for treatment of disease resulting from this variant.

[0793] In order to identify the appropriate dosing regimen in the setting of treatment, the above mentioned PopPK model based on phase 1 data was used. Dose selection was designed to achieve a tissue-adjusted concentration exceeding the in vitro IC90 for the Omicron variant in 90% of simulated patients, evaluating ELF: serum ratios of 10% and 15%. A dose of 1200 mg administered IV is projected to achieve concentrations of ADI-58125 in serum associated with ELF concentrations at or above IC90 for Omicron as well as other SARS-CoV-2 VOI/VOCs through 28 days in 90% of simulated patients using an ELF: serum ratio of 10%. The IC90 value generated against authentic virus was used for dose selection to maintain consistency with prior dose selection efforts.

[0794] Exposures anticipated for the proposed 1200 mg IV dose level determined from the PopPK model and safety margins based on the GLP rat toxicology study are presented in Table 20. These data suggest safety margins of 2.3-fold and 26-fold for AUC and Cmax, respectively, relative to the 1200 mg IV dose in humans.

[0795] Based on enrollment to date, approximately 1460 participants had received ADG20 at dose levels ranging from 300 mg IM to 500 mg IV/600 mg IM across the clinical trials. Given the lack of identified safety signals to date, the adequate safety margins (based on AUC, Cmax, and body weight extrapolation), the lack of ADG20-specific binding in human TCR studies, the lack of ADG20- specific findings in the rat GLP toxicology study, and the prospect for benefit in the setting of treatment in the face of the surging Omicron variant, the potential benefit of the 1200 mg IV dose outweighs the potential risk to participants and that the proposed dose can be incorporated into the STAMP study with safety oversight.

Additional Omicron Neutralization Results

[0796] ADI-58125 activity against the Omicron variant were evaluated in multiple authentic and pseudotyped VLP neutralization assays across different laboratories (Table 21). As presented in Table 21, IC50 values against Omicron range from 0.129 to 1.703 μg/mL. For the purpose of dose selection, the IC50 and IC90 values were used to maintain consistency across prior dose selection efforts. ADI- 58125 neutralized authentic Omicron virus with an IC50 of 1.029 μg/mL and IC90 of 9.943 μg/mL, representing 257- and 663-fold reductions in activity relative to the Victoria reference strain, respectively. Furthermore, authorized mAbs were tested in parallel in the same assay. In addition to ADI-58125, only S309, AZD1061, and AZD8895, as well as the AZD7442 cocktail, achieved >50% neutralization within the antibody concentrations tested, and these mAbs displayed IC50 values ranging from 0.319 to 2.03 mg/mL (Figure 48). However, AZD1061 and AZD8895 did not reach 90% neutralization, while S309 and AZD7442 exhibited IC90 values of 5.92 and 2.03 mg/mL, respectively. REGN10933, REGN10987, LY-C0VI6, and LY-CoV555 displayed complete or near-complete loss of activity. Across two pseudotyped lentiviral neutralization assays, ADI-58125 displayed 65- to 328- fold reduced potency against B.1.1.529/BA.1.

Table 21: Summary of Omicron Neutralization Results

VSV=vesicular stomatitis virus a IC50 and IC90 values shown were separately calculated using raw percentage neutralization data from Dejnirattisai 2022. Neutralization curves were fitted using nonlinear regression with four- parameter variable slope to calculate the IC50. IC90 was determined by constraining parameter F (fraction of maximal response) to 90. All analyses were performed using GraphPad Prism (version 9.3.1).

[0797] Additional studies conducted using ADI-58125 and ADI-58124 were also summarized in Table 21. These included authentic and pseudotyped vesicular stomatitis virus (VSV) neutralization assays that demonstrated 21- to 183-fold changes in IC50 compared to each study's respective reference strain. ADI-58125 and ADI-58124 activity had also been evaluated in pseudotyped viral- like particles (VLPs) expressing the full set of Omicron spike mutations plus an R346K mutation, which has been detected in a subset of circulating Omicron variants. Based on lentiviral and VSV pseudo virus neutralization data, ADI-58125 activity against Omicron+R346K appeared to be similar to its reported activity against Omicron (Table 21) (Liu 2021b). Detailed assay methodologies for each study are provided in Table 22.

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Example 18. Preliminary Results from the Phase 2/3 Randomized, Double-Blind, Placebo- Controlled Trial to Evaluate the Efficacy and Safety of ADI-58125 in the Treatment of Ambulatory Participants with Mild or Moderate COVID-19 (STAMP)

[0798] The STAMP trial is evaluating the safety and efficacy of ADI-58125 as a potential treatment for mild or moderate COVID-19 in ambulatory patients with a high risk of disease progression based on age or comorbidities.

[0799] Patients were enrolled if they had a positive SARS-CoV-2 test and symptom duration of 5 days or less. Patients were randomized 1:1 to receive ADI-58125 or placebo administered by a single intramuscular (IM) injection and were followed through Day 29 for primary efficacy. The primary efficacy endpoint was COVID-19 related hospitalization or all-cause death through Day 29 in patients with disease due to confirmed or suspected SARS-CoV-2 variants other than Omicron.

[0800] In the primary efficacy analysis, which included 336 patients (n=169 ADI-58125, n=167 placebo), ADI-58125 was associated with a statistically significant reduction in the risk of COVID- 19-related hospitalization or all-cause death through Day 29 compared with placebo (8 [4.7%] vs. 23 [13.8%]), demonstrating a 66% relative risk reduction (RRR) in favor of ADI-58125. The standardized risk difference was -8.6% (95% Cl: -14.65, -2.57; p=0.0052). The favorable treatment effect for ADI-58125 was observed across key subgroups. Among patients treated within 3 days of symptom onset, ADI-58125 reduced the risk of COVID-19 hospitalization or all-cause death compared to placebo, with a standardized RRR of 75%. ADI-58125 provided a greater reduction in viral load from baseline to Day 5 compared with placebo as assessed by saliva samples, with an adjusted least-squares mean difference of -0.81 logio copies/mL (95% Cl: -1.3, -0.3; p=0.0020). The median follow-up for safety analyses was 99 days (n=192 ADI-58125, n=200 placebo). No study drug related SAEs, including deaths, and no hypersensitivity reactions were reported. The most frequently reported AEs were solicited injection site reactions, all of which were mild to moderate in severity and similar in incidence between arms. [0801] A single dose of ADI-58125 300 mg IM provided a statistically significant and clinically meaningful reduction in the risk of COVID-19 related hospitalization and all-cause death compared to placebo in high-risk ambulatory patients with mild to moderate COVID-19. ADI-58125 was well tolerated with a safety profile similar to that of placebo.

Example 19. Clinical and Virologic Outcomes with Early ADI-58125 Monoclonal Antibody Therapy in Mild and Moderate COVID-19

[0802] Peak SARS-CoV-2 viral replication occurs in the upper respiratory tract in presymptomatic and early symptomatic phases. Administration of a monoclonal antibody may be most beneficial in the early time period immediately after symptom onset. Here the effect of early therapy on efficacy in patients receiving ADI-58125 was evaluated.

[0803] High risk patients with mild or moderate COVID-19 were enrolled in the ADI-58125 treatment study (STAMP), with primary endpoint of COVID-19 related hospitalization or all-cause death through Day 29 in patients with disease due to confirmed or suspected SARS-CoV-2 variants other than Omicron. Patients were randomized 1 : 1 to receive ADI or placebo administered by a single intramuscular (IM) injection. For this subgroup analysis, patients that had received therapy within 3 days of symptom onset were evaluated.

[0804] In the overall population, the study met the primary endpoint demonstrating 66% relative risk reduction of COVID-19 hospitalization or all cause death in 336 patients. Among 261 patients receiving therapy within 3 days of symptom onset (n=133 ADI-58125, n=128 placebo), ADI- 58125 was associated with a statistically significant reduction in the risk of COVID-19-related hospitalization or all-cause death through Day 29 compared with placebo (4 [3%] vs. 15 [11.7%], standardized risk difference -8%, 95% Cl: -14.11, -1.86, p=0.0106), demonstrating a 72% standardized relative risk reduction in favor of ADI-58125. When given as early therapy, ADI-58125 provided a greater reduction in viral load from baseline to Day 5 compared with placebo as assessed by saliva samples, with an adjusted least-squares mean difference of - 0.97 loglO copies/mL (95% Cl: -1.540, -0.391; p=0.0011). No study drug related SAEs, including deaths, and no hypersensitivity reactions were reported.

[0805] Early therapy with a single dose of ADI-58125 300 mg IM provided a 72% reduction in the risk of COVID-19 related hospitalization and all-cause death compared to placebo in high-risk ambulatory patients with mild to moderate COVID-19. Therapy within the first 3 days also led to a greater reduction in viral load compared to placebo and favorable outcomes in patients who are at high risk for progression of disease. Example 20. Validation of a Predictive Model to Correlate Neutralization Titers and Efficacy for the Prevention of COVID-19

[0806] Most anti-viral vaccines, including COVID-19 vaccines, induce neutralizing antibodies as a correlate of protection (CoP). Here a novel model was decribed to predict the absolute serum neutralizing antibody titer required for prevention of symptomatic COVID-19, and its validation from Phase 2/3 clinical trial of ADI-58125 for prevention.

[0807] To determine neutralizing antibody (nAb) titers that were associated with protection against symptomatic COVID-19, a literature search was conducted to evaluate efficacy data from vaccines and monoclonal antibodies (mAh). Median authentic virus serum neutralizing titers induced by vaccination or passive mAB therapy were measured experimentally or projected based on mAh pharmacokinetic (PK) and neutralization IC50 data. From previous FIH study of ADI-58125, PK and neutralizing titers correlate in a predictable manner. Therefore, to validate the CoP, serum concentrations from population PK model based on Phase 2/3 data of ADI-58125 on days 55 and 76 (Omicron BA.1/BA1.1), and 90 (Delta) were used to calculate predictive nAb titers and corresponding efficacy for the Delta and Omicron variants and then compared to clinical efficacy results from the EVADE clinical trial in prevention of COVID-19.

[0808] A CoP was identified as an authentic virus serum neutralizing titer of 1 : 100 which would provide approximately 70% protection against development of symptomatic COVID-19. Population PK median serum concentrations of ADI-58125 at 55, 76, and 90 days were 29.8 mg/L, 26.7 mg/L, and 24.6 mg/L, respectively. The neutralizing titer against Delta was extrapolated to be 1:4100 at day 90, predicting ADI-58125 would have at least 70% protection. This was consistent with the observed clinical outcome from the EVADE trial where patients taking ADI-58125 experienced a 71% reduction in development of symptomatic COVID-19 through 3 months. Neutralizing titers against Omicron were extrapolated to be 1:29 and 1:26, at days 55 and 76, respectively. The model predicted an efficacy of approximately 50% and 46.6% for ADI-58125 against Omicron given a higher IC50. This was in range of the observed efficacy of 62.3% and 50.9% at a median follow-up of 55 and 76 days in EVADE (Figure 55).

[0809] In conclusion, an authentic virus serum neutralizing titer of 1 : 100 was established as a CoP for the prevention of symptomatic COVID-19 and validated using Phase 2/3 clinical data in a model that could be used to predict expected outcomes and redosing strategy based on IC50 of the circulating variant.

[0810] Having fully described and enabled the invention, the invention is further described by the claims that follow. In general, in the following claims, the terms used should not be construed to limit the disclosure to the specific embodiments disclosed in the specification and the claims. Accordingly, the invention is not limited by the disclosure, but instead the scope of the invention is to be determined entirely by the following claims.

[0811] The disclosure may be practiced in ways other than those particularly described in the foregoing description and examples. Numerous modifications and variations of the disclosure are possible in light of the above teachings and, therefore, are within the scope of the appended claims.

Table 6. Antibody VL sequences

Claims

Claims What is claimed is:

1. A method of inducing an immune response against a coronavirus (CoV) in a subject in need thereof, the method comprising administering to the subject an isolated antibody, or antigen-binding fragment thereof, which binds to the spike protein of a coronavirus (“CoV-S”), wherein said antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising a VH CDR1 comprising SEQ ID NO:52, a VH CDR2 comprising SEQ ID NO:54, and a VH CDR3 comprising SEQ ID NO:56, and a light chain variable region (VL) comprising a VL CDR1 comprising SEQ ID NO:252, a VL CDR2 comprising SEQ ID NO:254, and a VL CDR3 comprising SEQ ID NO:256;

(a) wherein the antibody, or antigen-binding fragment thereof, reaches a maximum concentration (Cmax) of about 10 μg/mL to about 1000 μg/mL, about 20 μg/mL to about 500 μg/mL, about 30 μg/mL to about 400 μg/mL, about 40 μg/mL to about 300 μg/mL, about 50 μg/mL to about 200 μg/mL, about 50 μg/mL to about 100 μg/mL, or about 30 μg/mL to about 70 μg/mL, about 100 μg/mL to about 400 μg/mL, about 150 μg/mL to about 350 μg/mL in serum of the subject;

(b) wherein the median time (Tmax) for the antibody, or antigen-binding fragment thereof, to reach a maximum concentration in serum of the subject is about 0.01-30 days, about 3-20 days, about 6-20 days, about 7-18 days, about 8-15 or about 13-15 days;

(c) wherein the antibody, or antigen-binding fragment thereof, reaches a maximum concentration of about 30 μg/mL to about 200 μg/mL, about 100 μg/mL to about 200 μg/mL, about 30 μg/mL to about 100 μg/mL, about 40 μg/mL to about 80 μg/mL, about 50 μg/mL to about 70 μg/mL, or about 30 μg/mL to about 65 μg/mL in serum of the subject in about 0.01-20 days, about 3-20 days, about 6-20 days, about 7-18 days, about 8-15 or about 13-15 days after administration;

(d) wherein the area under the serum concentration-time curve from day 0 to day 21 (AUC_{0 -21 d}) is about 100-2000 day* μg/mL, about 1000-2000 day* μg/mL, about 1400-2000 day* μg/mL, about 200-1500 day* μg/mL, about 400-1400 day* μg/mL, about 500-1300 day* μg/mL, about 600- 1000 day* μg/mL, or about 800-900 day* μg/mL;

(e) wherein the area under the serum concentration-time curve from day 0 to day 90 (AUC_{0 -90 d}) is about 1000-10000 day* μg/mL, about 2000-8000 day* μg/mL, about 2000-5000 day* μg/mL, about 3000-4000 day* μg/mL, about 5000-10000 day* μg/mL, about 2000-4000 day* μg/mL, about 5000-8000 day* μg/mL, or about 6000-8000 day* μg/mL;

(f) wherein the area under the serum concentration-time curve from day 0 to day 180 (AUC_{0 -180d}) is about 1000-10000 day* μg/mL, about 2000-5000 day* μg/mL, about 3000-6000 day* μg/mL, about 5000-10000 day* μg/mL, about 5000-8000 day* μg/mL, or about 4000-6000 day* μg/mL; (g) wherein the area under the serum concentration-time curve from day 0 to day 365 (AUC_0-365d) is about 1000-30000 day* mg/mL, about 5000-30000 day* mg/mL, about 10000-30000 day* mg/mL, about 10000-15000 day* mg/mL, about 20000-30000 day* mg/mL, or about 25000-30000 day* mg/mL; and/or

(h) wherein the antibody, or antigen-binding fragment thereof, has a serum half-life of about 50-200 days, about 50-160 days, about 50-140 days, about 40-130 days, about 50-100 days, about 60-100 days, about 60-90 days, about 70-90 days, about 90-100 days, about 70-80 days, about 80-130 days, about 100-150 days, about 110-140 days, or about 120-140 days.

2. A method of preventing a coronavirus infection in a subject in need thereof, the method comprising administering to the subject an isolated antibody, or antigen-binding fragment thereof, which binds to the spike protein of a coronavirus (“CoV-S”), wherein said antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising a VH CDR1 comprising SEQ ID NO:52, a VH CDR2 comprising SEQ ID NO:54, and a VH CDR3 comprising SEQ ID NO:56, and a light chain variable region (VL) comprising a VL CDR1 comprising SEQ ID NO:252, a VL CDR2 comprising SEQ ID NO:254, and a VL CDR3 comprising SEQ ID NO:256;

(e) wherein the area under the serum concentration-time curve from day 0 to day 90 (AUC_{0 -90 d}) is about 1000-10000 day* μg/mL, about 2000-8000 day* μg/mL, about 2000-5000 day* μg/mL, about 3000-4000 day* mg/mL, about 5000-10000 day* mg/mL, about 2000-4000 day* mg/mL, about 5000-8000 day* mg/mL, or about 6000-8000 day* mg/mL;

(f) wherein the area under the serum concentration-time curve from day 0 to day 180 (§UC_{0 -180d}) is about 1000-10000 day* mg/mL, about 2000-5000 day* mg/mL, about 3000-6000 day* mg/mL, about 5000-10000 day* mg/mL, about 5000-8000 day* mg/mL, or about 4000-6000 day* mg/mL;

(g) wherein the area under the serum concentration-time curve from day 0 to day 365 (AUC_0-365d) is about 1000-30000 day* mg/mL, about 5000-30000 day* mg/mL, about 10000-30000 day* mg/mL, about 10000-15000 day* mg/mL, about 20000-30000 day* mg/mL, or about 25000-30000 day* mg/mL; and/or

3. A method of treating a coronavirus infection in a subject in need thereof, the method comprising administering to the subject an isolated antibody, or antigen-binding fragment thereof, which binds to the spike protein of a coronavirus (“CoV-S”), wherein said antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising a VH CDR1 comprising SEQ ID NO:52, a VH CDR2 comprising SEQ ID NO:54, and a VH CDR3 comprising SEQ ID NO:56, and a light chain variable region (VL) comprising a VL CDR1 comprising SEQ ID NO:252, a VL CDR2 comprising SEQ ID NO:254, and a VL CDR3 comprising SEQ ID NO:256;

(c) wherein the antibody, or antigen-binding fragment thereof, reaches a maximum concentration of about 30 μg/mL to about 200 μg/mL, about 100 μg/mL to about 200 μg/mL, about 30 μg/mL to about 100 μg/mL, about 40 μg/mL to about 80 μg/mL, about 50 μg/mL to about 70 μg/mL, or about 30 μg/mL to about 65 μg/mL in serum of the subject in about 0.01-20 days, about 3-20 days, about 6-20 days, about 7-18 days, about 8-15 or about 13-15 days after administration; (d) wherein the area under the serum concentration-time curve from day 0 to day 21 (AUC_{0 -21 d}) is about 100-2000 day* mg/mL, about 1000-2000 day* mg/mL, about 1400-2000 day* mg/mL, about 200-1500 day* mg/mL, about 400-1400 day* mg/mL, about 500-1300 day* mg/mL, about 600- 1000 day* mg/mL, or about 800-900 day* mg/mL;

(e) wherein the area under the serum concentration-time curve from day 0 to day 90 (AUC_{0 -90 d}) is about 1000-10000 day* mg/mL, about 2000-8000 day* mg/mL, about 2000-5000 day* mg/mL, about 3000-4000 day* mg/mL, about 5000-10000 day* mg/mL, about 2000-4000 day* mg/mL, about 5000-8000 day* mg/mL, or about 6000-8000 day* mg/mL;

(f) wherein the area under the serum concentration-time curve from day 0 to day 180 (AUC_{0 -180d}) is about 1000-10000 day* mg/mL, about 2000-5000 day* mg/mL, about 3000-6000 day* mg/mL, about 5000-10000 day* mg/mL, about 5000-8000 day* mg/mL, or about 4000-6000 day* mg/mL;

4. A method of treating a symptom of a coronavirus infection in a subject in need thereof, the method comprising administering to the subject an isolated antibody, or antigen-binding fragment thereof, which binds to the spike protein of a coronavirus (“CoV-S”), wherein said antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising a VH CDR1 comprising SEQ ID NO:52, a VH CDR2 comprising SEQ ID NO:54, and a VH CDR3 comprising SEQ ID NO:56, and a light chain variable region (VL) comprising a VL CDR1 comprising SEQ ID NO:252, a VL CDR2 comprising SEQ ID NO:254, and a VL CDR3 comprising SEQ ID NO:256;

(b) wherein the median time (Tmax) for the antibody, or antigen-binding fragment thereof, to reach a maximum concentration in serum of the subject is about 0.01-30 days, about 3-20 days, about 6-20 days, about 7-18 days, about 8-15 or about 13-15 days; (c) wherein the antibody, or antigen-binding fragment thereof, reaches a maximum concentration of about 30 mg/mL to about 200 mg/mL, about 100 mg/mL to about 200 mg/mL, about 30 mg/mL to about 100 mg/mL, about 40 mg/mL to about 80 mg/mL, about 50 mg/mL to about 70 mg/mL, or about 30 mg/mL to about 65 mg/mL in serum of the subject in about 0.01-20 days, about 3-20 days, about 6-20 days, about 7-18 days, about 8-15 or about 13-15 days after administration;

(d) wherein the area under the serum concentration-time curve from day 0 to day 21 (AUC_{0 -21 d}) is about 100-2000 day* mg/mL, about 1000-2000 day* mg/mL, about 1400-2000 day* mg/mL, about 200-1500 day* mg/mL, about 400-1400 day* mg/mL, about 500-1300 day* mg/mL, about 600- 1000 day* mg/mL, or about 800-900 day* mg/mL;

5. The method of claim 4, wherein the symptom comprises at least one of bronchitis, pneumonia, respiratory failure, acute respiratory failure, organ failure, multi-organ system failure, pediatric inflammatory multisystem syndrome, acute respiratory distress syndrome, blood clot, a cardiac condition, myocardial injury, myocarditis, heart failure, cardiac arrest, acute myocardial infarction, dysrhythmia, venous thromboembolism, post-intensive care syndrome, shock, anaphylactic shock, cytokine release syndrome, septic shock, disseminated intravascular coagulation, ischemic stroke, intracerebral hemorrhage, microangiopathic thrombosis, psychosis, seizure, nonconvulsive status epilepticus, traumatic brain injury, stroke, anoxic brain injury, encephalitis, posterior reversible leukoencephalopathy, necrotizing encephalopathy, post-infectious encephalitis, autoimmune mediated encephalitis, acute disseminated encephalomyelitis, acute kidney injury, acute liver injury, pancreatic injury, immune thrombocytopenia, subacute thyroiditis, a gastrointestinal complication, aspergillosis, increased susceptibility to infection with another virus or bacteria, and/or a pregnancy-related complication.

6. A method of decreasing the risk of mortality, hospitalization, mechanical ventilation, or a combination thereof, in a subject infected by a coronavirus, the method comprising administering to the subject an isolated antibody, or antigen-binding fragment thereof, which binds to the spike protein of a coronavirus (“CoV-S”), wherein said antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising a VH CDR1 comprising SEQ ID NO:52, a VH CDR2 comprising SEQ ID NO:54, and a VH CDR3 comprising SEQ ID NO:56, and a light chain variable region (VL) comprising a VL CDR1 comprising SEQ ID NO:252, a VL CDR2 comprising SEQ ID NO:254, and a VL CDR3 comprising SEQ ID NO:256;

(f) wherein the area under the serum concentration-time curve from day 0 to day 180 (AUC_{0 -180d}) is about 1000-10000 day* μg/mL, about 2000-5000 day* μg/mL, about 3000-6000 day* μg/mL, about 5000-10000 day* μg/mL, about 5000-8000 day* μg/mL, or about 4000-6000 day* μg/mL; (g) wherein the area under the serum concentration-time curve from day 0 to day 365 (AUCo 365_d) is about 1000-30000 day* mg/mL, about 5000-30000 day* mg/mL, about 10000-30000 day* mg/mL, about 10000-15000 day* mg/mL, about 20000-30000 day* mg/mL, or about 25000-30000 day* mg/mL; and/or

7. The method of any one of claims 1-6, wherein the CoV-S is the spike protein of SARS-CoV (“SARS-CoV-S”) or the spike protein of SARS-CoV-2 (“SARS-CoV-2-S”).

8. The method of any one of claims 1-7, wherein the antibody, or antigen-binding fragment thereof, cross-reacts with SARS-CoV-S and SARS-CoV -2-S.

9. The method of any one of claims 1-8, wherein SARS-CoV-S comprises an amino acid sequence of SEQ ID NO: 401, and wherein SARS-CoV-2-S comprises an amino acid sequence of SEQ ID NO: 403.

10. The method of any one of claims 1-9, wherein the SARS-CoV -2-S is a B.1.1.7 variant, a B. 1.351 variant, a B.1.1.28 variant, a B. 1.429 variant, a P.l variant, a B.1.617 variant, a B.1.617.2 variant, a C.37 variant, a 1.621 variant, a AY.l variant, a 1.623 variant, a C.36 variant, a A.27 variant, a AV.l variant, a B.1.1.482 variant, a B.1.1.523 variant, a B.1.427 variant, a AY.4 variant, a AY.ll variant, a D614G variant of SEQ ID NO: 403, a B.1.1.529/BA.1 variant, a BA.1.1 variant, or a BA.2 variant.

11. A method for inducing an immune response against a coronavirus Omicron variant in a subject in need thereof, for treating a coronavirus infection caused by an Omicron variant in a subject in need thereof, for preventing a coronavirus infection caused by an Omicron variant in a subject in need thereof, for treating a symptom of an infection of a subject by an Omicron variant in a subject in need thereof, and/or for decreasing the risk of mortality, hospitalization, mechanical ventilation, or a combination thereof, in a subject infected by an Omicron variant, the method comprising administering to the subject an isolated antibody, or antigen-binding fragment thereof, wherein said antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising a VH CDR1 comprising SEQ ID NO:52, a VH CDR2 comprising SEQ ID NO:54, and a VH CDR3 comprising SEQ ID NO:56, and a light chain variable region (VL) comprising a VL CDR1 comprising SEQ ID NO:252, a VL CDR2 comprising SEQ ID NO:254, and a VL CDR3 comprising SEQ ID NO:256.

12. The method of claim 11, wherein the Omicron variant comprises a B.1.1.529/BA.1 variant, a BA.1.1 variant, or a BA.2 variant.

13. The method of any one of claims 1-12, wherein the VH comprises a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:58 and the VL comprises a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:258.

14. The method of any one of claims 1-13, wherein the VH comprises or consists of SEQ ID NO:58 and the VL comprises or consists of SEQ ID NO:258.

15. The method of any one of claims 1-14, wherein the subject is a human subject.

16. The method of any one of claims 1-15, wherein the subject is an adult, an adolescent, or a child.

17. The method of any one of claims 1-16, wherein the subject has at least one risk factor which renders them more prone to a poor clinical outcome.

18. The method of claim 17, wherein the at least one risk factor is selected from the group consisting of: an old age selected from the group consisting of over 55, over 60 or over 65 years old; diabetes, a chronic respiratory condition, obesity, hypertension, a cardiac or cardiovascular condition, a chronic inflammatory or autoimmune condition, and an immune compromised status.

19. The method of any one of claims 1-18, wherein the subject is immunocompromised.

20. The method of any one of claims 1-19, wherein the subject is at a high risk of disease progression.

21. The method of claim 20, wherein the subject is (a) age 50 years or above with no comorbid conditions or additional risk factors for progression of COVID-19; (b) between about 18 to about 50 years old and with one or more preexisting medical conditions selected from the group consisting of obesity, diabetes, chronic kidney disease, chronic lung disease, cardiac disease, sickle cell disease or thalassemia, solid organ or blood stem cell transplant recipient, other immunodeficiency due to underlying illness or immunosuppressant medication, Down Syndrome, stroke or cerebrovascular disease, substance use disorder, and pregnancy; or (c) between about 12 to about 17 years old and with one or more preexisting medical conditions selected from the group consisting of obesity, diabetes, chronic kidney disease, sickle cell disease or thalassemia, congenital or acquired heart disease, neurodevelopmental disorder, a medically-related technological dependence, asthma or chronic respiratory disease, solid organ or blood stem cell transplant recipient, other immunodeficiency due to underlying illness or immunosuppressant medication, Down Syndrome, stroke or cerebrovascular disease, substance use disorder, and pregnancy.

22. The method of claim 20 or 21, wherein the subject is age 50 or above with no comorbid conditions or additional risk factors for progression of COVID-19.

23. The method of claim 20 or 21 , wherein the subject has hypertension with at least one medication prescribed or recommended.

24. The method of claim 20 or 21, wherein the subject has moderate to severe asthma requiring daily therapy.

25. The method of any one of claims 1-24, wherein the antibody, or the antigen-binding fragment thereof, is administered intramuscularly or intravenously.

26. The method of any one of claims 1-25, wherein the antibody, or the antigen-binding fragment thereof, is administered at a dose of about 100 mg to about 5000 mg, about 300 mg to about 4500 mg, about 500 mg to about 4500 mg, about 1200 mg to about 4500 mg, about 100 mg to about 2000 mg, about 200 mg to about 1500 mg, about 300 mg to about 600 mg, about 500 mg to about 1200 mg, about 300 mg to about 1200 mg; or at a dose of about 4500 mg, a dose of about 1200 mg, a dose of about 600 mg, or a dose of about 500 mg; or as two doses of 600 mg each on the same day, or as two doses of 300 mg each on the same day.

27. The method of any one of claims 1-26, wherein the antibody, or antigen-binding fragment thereof, is administered once, or is administered weekly.

28. The method of any one of claims 1-27, wherein the method further comprises obtaining an epithelial lining fluid (ELF) sample from the subject.

29. The method of any one of claims 1-28, wherein the ELF sample comprises an ELF sample from an upper airway, an lower airway, and/or an alveolar tissue.

30. The method of any one of claims 1-29, wherein the antibody, or antigen-binding fragment thereof, reaches a concentration of about 1 μg/mL to about 100 μg/mL, about 1 μg/mL to about 80 μg/mL, about 80 μg/mL to about 100 μg/mL, about 50 μg/mL to about 100 μg/mL, about 1 μg/mL to about 50 μg/mL, about 2 μg/mL to about 25 μg/mL, or about 2 μg/mL to about 10 μg/mL, in the ELF sample of the subject.

31. The method of any one of claims 1-30, wherein the antibody, or antigen-binding fragment thereof, has a receptor occupancy of at least 50%, 60%, 70%, 80%, or 90% in the ELF sample.

32. The method of any one of claims 1-31, wherein the antibody, or antigen-binding fragment thereof, has a receptor occupancy of at least 50%, 60%, 70%, 80%, or 90% in the ELF sample for about 28 days after administration.

33. The method of any one of claims 1-32, wherein the antibody, or antigen-binding fragment thereof, has a virus neutralizing titer of about 100-2000, about 200-1500, about 300-1500, or about 500- 1500 in serum of the subject about 6 months after administration.

34. The method of any one of claims 1-33, wherein a 80% virus neutralization titer (MN80) of the antibody, or antigen-binding fragment thereof, at about days 0-14, about days 7-21, about 3 months, or about 6 months after administration, is about 10-6000, about 50-600, about 500-1500, about 1000-2500, about 100-2500, about 500-2000, about 500-1500, about 400-1200, about 200-1500, about 300-1000, about 400-800, about 400-1000, or about 500-600 in the subject.

35. The method of claim 34, wherein the 80% virus neutralization titer (MN80) of the antibody, or antigen-binding fragment thereof, at about day 7, day 14, or day 21 after administration, is about 300- 2000, about 400-600, about 600-1500, about 1100-1700, about 500-1700, about 500-1500, about 400- 1200, about 400-800, about 400-1000, or about 500-600 in the serum sample of the subject.

36. The method of claim 34, wherein the 80% virus neutralization titer (MN80) of the antibody, or antigen-binding fragment thereof, at about 3 months after administration, is about 200-1000, about 200- 800, about 200-500, about 400-900, or about 400-600 in the serum sample of the subject.

37. The method of claim 34, wherein the 80% virus neutralization titer (MN80) of the antibody, or antigen-binding fragment thereof, at about 6 months after administration, is about 10-500, about 300- 500, or about 50-200 in the serum sample of the subject.

38. The method of any one of claims 1-37, wherein a 50% virus neutralization titer (MN50) of the antibody, or antigen-binding fragment thereof, at about days 0-14, about days 7-21, about 3 months, about 6 months, or about 12 months after administration, is about 100-6000, about 300-1500, about 1700-3800, about 3800-5200, about 300-5500, about 1200-4500, about 1300-4300, about 1200-4000, about 100-2500, about 500-2500, about 800-2000, about 1000-1800, about 800-1300, about 900-1100, or about 1300-1500 in the serum sample of the subject.

39. The method of claim 38, wherein the 50% virus neutralization titer (MN50) of the antibody, or antigen-binding fragment thereof, at about day 7, day 14 or day 21 after administration, is about 1000- 4500, about 1200-4500, about 1300-4300, about 1200-3900, about 1500-4000, about 1800-3800, about 3800-4500, about 1000-1800 or about 1200-1500 in the serum sample of the subject.

40. The method of claim 38, wherein the 50% virus neutralization titer (MN50) of the antibody, or antigen-binding fragment thereof, at about 3 months after administration, is about 800-1300, or about 900-1100 in the serum sample of the subject.

41. The method of claim 38, wherein the 50% virus neutralization titer (MN50) of the antibody, or antigen-binding fragment thereof, at about 6 months after administration, is about 200-500, or about 300-600 in the serum sample of the subject.

42. The method of claim 38, wherein the 50% virus neutralization titer (MN50) of the antibody, or antigen-binding fragment thereof, at about 12 months after administration, is about 150-500, or about 200-400 in the serum sample of the subject.

43. The method of any one of claims 33-42, wherein the virus neutralization titer is determined using a plaque reduction neutralization test (PRNT).

44. The method of any one of claims 1-43, wherein the serum concentration of the antibody, or antigen-binding fragment thereof, is about 1-300 mg/L, about 1-250 mg/L, about 1-200 mg/L, about 1- 100 mg/L, about 100-250 mg/L, about 150-200 mg/L, about 120-170 mg/L, about 1-90 mg/L, about 1- 80 mg/L, about 1-70 mg/L, about 1-60 mg/L, about 1-50 mg/L, about 1-40 mg/L, about 1-30 mg/L, about 1-20 mg/L, about 1-10 mg/L, about 2-9 mg/L, about 3-8 mg/L, about 4-6 mg/L, about 5-80 mg/L, about 10-70 mg/L, or about 10-60 mg/L in the subject about 3 months after administration.

45. The method of any one of claims 1-44, wherein the serum concentration of the antibody, or antigen-binding fragment thereof, is about 1-100 mg/L, about 1-90 mg/L, about 1-80 mg/L, about 1-70 mg/L, about 1-60 mg/L, about 1-50 mg/L, about 1-40 mg/L, about 1-30 mg/L, about 1-20 mg/L, about 1-10 mg/L, about 2-9 mg/L, about 3-8 mg/L, about 4-6 mg/L, about 5-80 mg/L, about 10-70 mg/L, about 10-60 mg/L, about 5-25 mg/L, about 10-30 mg/L, about 15-25 mg/L, about 20-100 mg/L, about 30-100 mg/L, about 50-80 mg/L, or about 60-70 mg/L in the subject about 6 months after administration.

46. The method of any one of claims 1-45, wherein the serum concentration of the antibody, or antigen-binding fragment thereof, is about 0.1-30 mg/L, about 1-30 mg/L, about 1-20 mg/L, about 1- 10 mg/L, about 10-20 mg/L, about 0.1-3 mg/L, about 0.5-8 mg/L, about 0.5-10 mg/L, about 2-9 mg/L, about 5-15 mg/L, about 3-8 mg/L, or about 4-6 mg/L in the subject about 12 months after administration.

47. The method of any one of claims 1-46, wherein the clearance rate for the antibody, or antigen binding fragment thereof, is about 0.1-10 mL/d, about 0.1-5.0 mL/d, about 0.1-3.0 mL/d, about 0.5-2.5 mL/d, or about 1.0-2.0 mL/d.

48. The method of any one of claims 1-47, wherein the steady state volume of distribution for the antibody, or antigen-binding fragment thereof, is about 1-10 L, about 2-8 L, about 4-9 L, about 4-8 L, or about 5-7L.

49. The method of any one of claims 1-48, wherein the antibody, or antigen-binding fragment thereof, is administered in combination with at least one antibody selected from the group consisting of ADI-58120, ADI-58121, ADI-58122, ADI-58123, ADI-58124, ADI-58125, ADI-58126, ADI-58127, ADI-58128, ADI-58129, ADI-58130 and ADI-58131.

50. The method of any one of claims 1-49, wherein the antibody, or antigen-binding fragment thereof, is administered in combination with a vaccine.

51. The method of claim 50, wherein the antibody, or antigen-binding fragment thereof, is administered (a) concurrently with a COVID-19 vaccine; (b) after administration of a COVID-19 vaccine, or (c) prior to administration of a COVID-19 vaccine.

52. The method of any one of claims 1-51, wherein administration of the antibody, or antigen binding fragment thereof, reduces pulmonary inflammation in the subject.

53. The method of any one of claims 1-52, wherein administration of the antibody, or antigen binding fragment thereof, reduces the risk of COVID-19 hospitalization or death of the subject.

54. The method of any one of claims 1-53, wherein administration of the antibody, or antigen binding fragment thereof, reduces viral load in the subject.

55. The method of any one of claims 1-54, wherein the antibody, or antigen-binding fragment thereof, is administered to the subject within 5, 4, 3, 2 or 1 days of symptom onset.