WO2021216954A1 - Compositions and methods for treating or preventing virus infection - Google Patents

Compositions and methods for treating or preventing virus infection Download PDF

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Publication number
WO2021216954A1
WO2021216954A1 PCT/US2021/028772 US2021028772W WO2021216954A1 WO 2021216954 A1 WO2021216954 A1 WO 2021216954A1 US 2021028772 W US2021028772 W US 2021028772W WO 2021216954 A1 WO2021216954 A1 WO 2021216954A1
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antibody
integrin
integrin antagonist
fragment
derivative
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PCT/US2021/028772
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French (fr)
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David Cheresh
Sara WEIS
Stephen Mccormack
Thomas Rogers
Tami VON SCHALCHA
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Alpha Beta Holdings, Llc
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Publication of WO2021216954A1 publication Critical patent/WO2021216954A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2839—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily
    • C07K16/2848—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily against integrin beta3-subunit-containing molecules, e.g. CD41, CD51, CD61
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2839—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/53—Hinge
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/55—Fab or Fab'
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16111—Influenzavirus A, i.e. influenza A virus
    • C12N2760/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention further relates to methods of treating, reducing the severity of, or preventing RGD and/or RLD-dependent virus infections using integrin antagonists, such as antibodies or fragments or derivatives thereof, peptides, or peptidomimetics targeted to alpha V-containing integrins that recognize RGD binding motifs, integrin ⁇ M ⁇ 2 that recognizes RLD binding motifs, or integrin ⁇ v ⁇ 3 that recognizes both RGD and RLD binding motifs.
  • integrin antagonists such as antibodies or fragments or derivatives thereof, peptides, or peptidomimetics targeted to alpha V-containing integrins that recognize RGD binding motifs, integrin ⁇ M ⁇ 2 that recognizes RLD binding motifs, or integrin ⁇ v ⁇ 3 that recognizes both RGD and RLD binding motifs.
  • the invention additionally includes compositions useful for carrying out the methods of the invention.
  • SARS-CoV-2 belongs to a family of viruses that includes SARS-CoV that causes severe acute respiratory syndrome and MERS-CoV that causes Middle East respiratory syndrome, both of which are the causes of major epidemics.
  • Full-length genomic sequencing of the new SARS-CoV-2 virus reveals 79.6% sequence identity with SARS-CoV, and this study also confirmed that SARS-CoV-2 utilizes the same cell entry receptor (angiotensin converting enzyme II, ACE2) as SARS-CoV (Zhou, Yang et al.2020).
  • ACE2 angiotensin converting enzyme II
  • S proteins form a spike that the virus uses to infect host cells by binding to receptors on the surface of host cells.
  • the biological events that govern the ability of this spike protein to interact with host cells represents a potential opportunity to block virus attachment, fusion, and entry.
  • the S protein contains a receptor binding domain (RBD) in the S1 subunit that contains binding sites recognized by different receptors.
  • RBD receptor binding domain
  • SARS-CoV-2 virus that is lacking in the other SARS-like coronaviruses is the presence of a site on the S protein that can be cleaved by the enzyme furin (Coutard, Valle et al.2020). Furin is highly expressed in lungs, and its ability to cleave a site on the S protein of SARS-CoV-2 may contribute to the more aggressive pathogenicity of the new virus, since cleavage can release the S1 subunit that allows SARS-CoV-2 to bind to angiotensin converting enzyme (ACE2) more tightly than the SARS virus.
  • ACE2 angiotensin converting enzyme
  • RGD sequence Adjacent to the ACE2 binding sequence on the spike protein is an “RGD sequence” that is the minimal peptide sequence recognized by the family of alpha V integrins, cell surface receptors with diverse biological functions. Since this RGD sequence is present in SARS-CoV-2 but absent from all other coronaviruses examined, it has been suggested that the new virus may have gained the ability to utilize integrins as cell receptors to mediate virus entry (Sigrist, Bridge et al.2020). A high-throughput virtual screen was performed to search chemical libraries for agents capable of preventing the interaction of the S protein with both ACE2 and integrins, producing a list of potential drug candidates (Yan, Sun et al.2020).
  • compositions and methods of using such compositions, to treat or prevent virus infections, including in particular SARS-CoV-2 and other viruses that depend on RGD binding to mediate entry into cells.
  • virus infections including in particular SARS-CoV-2 and other viruses that depend on RGD binding to mediate entry into cells.
  • adenoviruses via an RGD adhesion sequence in their penton base coat protein
  • alpha V integrins on mammalian cells to facilitate viral uptake (Wickham, Mathias et al. 1993, Nemerow, Cheresh et al.1994, Wickham, Filardo et al.
  • the RLD motif mediates binding to only integrins ⁇ v ⁇ 3 and ⁇ M ⁇ 2 (also known as CD11b/CD18 or Mac-1). A relationship between the RLD motif and virus entry has not been recognized previously. An analysis of potential integrin binding sites in coronavirus S proteins did not identify the RLD motif (Tresoldi, Sangiuolo et al. (2020)). The RLD integrin binding motif is present in the heptad repeat 1 (HR1) domain of the S protein of all coronaviruses. The HR1 domain mediates membrane fusion. An analysis of the three-dimensional structure of the S protein of SARS- CoV-2 shows that the RGD and RLD sequences, while in different parts of the linear amino acid sequence (S1 vs.
  • integrin ⁇ v ⁇ 3 mediates entry of rotaviruses, but their entry cannot be blocked by RGD peptides (Guerrero, Méndez et al. 2000).
  • the present invention reveals that many viruses also have an RLD motif on a surface protein, including viruses that have been linked to ⁇ v ⁇ 3 for entry and internalization.
  • the RLD motif may represent an important mechanism for viral entry and internalization that functions independently or in addition to an RGD motif.
  • the RLD motif is a new target for disruption of viral entry for coronaviruses and other viruses.
  • the RLD motif is recognized by only two integrins (integrin ⁇ v ⁇ 3 and ⁇ M ⁇ 2), it represents a more selective target than the RGD motif that is recognized by many integrins, including those containing ⁇ 1 or ⁇ v (Ruoslahti 1996).
  • the present inventors have studied integrin ⁇ 3 expression, particularly ⁇ v ⁇ 3, and elucidated expression changes that may play a critical role in the sensitivity of subjects to infection by RGD and/or RLD-dependent viruses such as SARS-CoV-2. These findings also provide guidance for effective treatment of infected subjects as well as prevention of infection.
  • Subjects that are more likely to be infected and/or more likely to incur a severe infection can be identified based on integrin expression levels and conditions that are known to elevate integrin expression levels, such as tissue injury and inflammation. These identified subjects also are the ones most likely to benefit from a targeted treatment aimed at inhibiting the specific integrin(s) responsible for enhancing viral infection and its consequences.
  • One example is the relationship between the severity of COVID-19 in people with preexisting health issues and the ability of SARS-CoV-2 to enter cells. In particular, patients with cancer are more likely to be infected with COVID-19 (Leslie 2020).
  • integrin ⁇ v ⁇ 3 a driver of metastasis, stemness, and drug resistance in multiple types of solid tumors.
  • integrin ⁇ v ⁇ 3 a driver of metastasis, stemness, and drug resistance in multiple types of solid tumors.
  • An enrichment of integrin ⁇ v ⁇ 3 expression on lung cancers that had gained resistance to EGFR blockade was previously reported (Seguin, Kato et al.2014), and new data presented here reveals the induction of ⁇ 3 expression when normal or malignant epithelial cells are exposed to cellular stresses or inflammatory cytokines.
  • one aspect of the invention relates to a method of inhibiting uptake of an RGD and/or RLD-dependent virus into a cell, comprising contacting the cell with an effective amount of an integrin antagonist.
  • Another aspect of the invention relates to a method of treating, inhibiting the severity of, or preventing an RGD and/or RLD-dependent virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an integrin antagonist, thereby treating, inhibiting the severity of, or preventing RGD and/or RLD-dependent virus infection.
  • a further aspect of the invention relates to a method of treating, inhibiting the severity of, or preventing an RGD and/or RLD-dependent virus infection in a subject in need thereof, comprising the steps of: a) identifying a subject that has a condition that increases integrin expression; and b) if the subject has a condition that increases integrin expression, administering to the subject a therapeutically effective amount of an integrin antagonist, thereby treating, inhibiting the severity of, or preventing RGD and/or RLD-dependent virus infection.
  • An additional aspect of the invention relates to an integrin antagonist, e.g., one that inhibits entry of an RGD and/or RLD-dependent virus into a cell.
  • a further aspect of the invention relates to a polynucleotide encoding the integrin antagonist of the invention and a vector or host cell comprising the polynucleotide.
  • Another aspect of the invention relates to a composition, e.g., a pharmaceutical composition, comprising the integrin antagonist of the invention and a carrier.
  • An additional aspect of the invention relates to a kit comprising the integrin antagonist of the invention.
  • FIGS.1A-1B show anti- ⁇ v ⁇ 3 (mIgG1, hIgG1, or hLM609-hIgG4-S228P) blocks SARS-CoV-2 infection in human HeLa-ACE2 cells.
  • Live SARS-CoV-2 virus was added to HeLa-ACE2 cells in the presence of integrin function-blocking antibodies that recognize the ⁇ 1 integrin subunit, the ⁇ v ⁇ 3 integrin heterodimer, or the ⁇ v ⁇ 5 integrin heterodimer. After 24 h, cells were fixed, permeabilized, and stained using serum from a COVID-19 patient to identify the extent of virus infection.
  • Fig.1A Representative images and full dose range for hLM609- hIgG4-S228P are shown in Fig.1A. Immunoblot for HeLa-ACE2 and VERO cell lysates confirms integrin ⁇ 3 expression.
  • Fig.1B shows control plus three doses each for three different anti- ⁇ v ⁇ 3 antibodies (hLM609-hIgG4-S228P, hLM609-hIgG1, and LM609- mIgG1), two antibodies targeting other RGD-dependent integrins ( ⁇ v ⁇ 5 and ⁇ 1), and two peptide antagonists (cilengitide and cRGDFV).
  • FIGS.2A-2C show that integrin ⁇ 3 expression is absent on normal lung bronchial epithelium but upregulated by injury, stress, or inflammation.
  • HCC827 human lung cancer cells were grown for 24 h in the presence of vehicle control or 4 ng/ml TGF ⁇ 1. qPCR analysis for ITGB3 mRNA expression is shown as fold change relative to control (PBS). Right, H358 and HCC827 human lung cancer cells were grown in the presence of 10 ng/ml TGF ⁇ 1 for 48 h, then protein expression was analyzed by immunoblot. Graphs show mean ⁇ SD. [0025] FIG.3 shows integrin ⁇ 3 protein expression is absent on normal pancreas but upregulated in pancreatitis and cancer.
  • FIGS.4A-4D show the effect of inflammation on integrin ⁇ 3 expression in pancreatic cells.
  • A) Mouse pancreatic acinar cells were treated with vehicle control (PBS), a combination of cytokines (50 ng/ml TNF ⁇ and 50 ng/ml CCL5 for 5 days), or the pancreatitis-inducing agent caerulein (10-100nM for 48 hours). mRNA expression was analyzed by qPCR.
  • FIG.5 is a schematic showing the location of RGD and RLD integrin binding motifs in the SARS-CoV-2 S protein amino acid sequence (SEQ ID NO:16).
  • FIG.6 is a sequence alignment showing unique expression of the RGD motif on SARS-CoV-2.
  • the RGD integrin binding motif that is recognized by ⁇ v-containing integrins is present at amino acids 403-405 in the SARS-CoV-2 virus, but not found in any of the other betacoronaviruses examined.
  • FIG.7 is a sequence alignment showing the highly conserved RLD motif for betacoronaviruses.
  • the RLD integrin binding motif that is recognized by integrin ⁇ v ⁇ 3 and ⁇ M ⁇ 2 is highly conserved across betacoronaviruses except for the bat coronavirus HKU9.
  • FIG.8 shows the locations of the RGD and RLD binding motifs on a 3D structural visualization of the SARS-CoV-2 virus spike protein trimer. Top, Three RGD motifs are shown at the center of the spike.
  • RGD motif is predicted to be exposed in the up promoter, while somewhat concealed on the two down promoters, to participate in receptor binding.
  • An RLD motif located at the apex of the HR1 region is shown to act as a pedestal upon which the RBD from an adjacent down promoter sits. This region may impact the metastability of the spike before cleavage, after which the exposed RLD binding motif may interact with integrin ⁇ v ⁇ 3 to facilitate membrane fusion and/or virus internalization. Integrins are known to be robustly activated by binding to multivalent ligands, such as the conformation of RGD/RLD motifs predicted by the 3D model.
  • FIGS.9A-9B are schematics showing the implications for ⁇ v ⁇ 3 expression on susceptibility and progression of COVID-19, and the proposed effect of anti-integrin therapy on SARS-CoV-2 virus internalization.
  • integrin ⁇ v ⁇ 3 expression may already be elevated and contribute to an elevated susceptibility to infection and/or a more rapid disease progression that could be further exacerbated by the release of cytokines.
  • This scenario provides the rationale for targeting integrin ⁇ v ⁇ 3 as a novel therapeutic opportunity to protect host cells from viral infection. Such a strategy could be used in combination with other approaches to directly target the virus and/or suppress the release of cytokines.
  • the SARS-CoV-2 virus enters host cells by first engaging host cell surface receptors, including ACE2.
  • alpha V integrins bind to the virus spike proteins that each contain three RGD sequences, and this multivalent interaction promotes integrin clustering and activation.
  • SARS-CoV-2 utilizes alpha V integrins to mediate internalization into host cells.
  • An antibody, peptide, organic molecule, or other naturally agent that disrupts the ligand binding capacity of an alpha V-containing integrin, such as ⁇ v ⁇ 3, can prevent SARS-CoV-2 uptake and internalization.
  • DETAILED DESCRIPTION [0032] The present invention is explained in greater detail below. This description is not intended to be a detailed catalog of all the different ways in which the invention may be implemented, or all the features that may be added to the instant invention.
  • the term “about,” as used herein when referring to a measurable value such as an amount of a compound or agent of this invention, dose, time, temperature, and the like, is meant to encompass variations of ⁇ 10%, ⁇ 5%, ⁇ 1%, ⁇ 0.5%, or even ⁇ 0.1% of the specified amount.
  • all numbers expressing quantities of ingredients, properties such as reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about”. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and claims are approximations that can vary depending upon the desired properties sought to be obtained by the presently-disclosed subject matter.
  • ranges can be expressed as from “about” one particular value, and/or to “about” another particular value. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.
  • the term “consists essentially of” (and grammatical variants), as applied to a polynucleotide or polypeptide sequence of this invention, means a polynucleotide or polypeptide that consists of both the recited sequence (e.g., SEQ ID NO) and a total of ten or less (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) additional nucleotides or amino acids on the 5’ and/or 3’ or N-terminal and/or C-terminal ends of the recited sequence or between the two ends (e.g., between domains) such that the function of the polynucleotide or polypeptide is not materially altered.
  • SEQ ID NO a polynucleotide or polypeptide that consists of both the recited sequence (e.g., SEQ ID NO) and a total of ten or less (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) additional nucleotides or amino acids on the 5
  • polypeptide encompasses both peptides and proteins, unless indicated otherwise.
  • a “peptide” refers to a polypeptide containing less than 20 amino acid residues, e.g., less than 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10 amino acid residues, and incudes linear and cyclic peptides.
  • chimeric refers to a molecule having two or more portions that are not naturally found together in the same molecule.
  • nucleic acid or “nucleotide sequence” is a sequence of nucleotide bases, and may be RNA, DNA or DNA-RNA hybrid sequences (including both naturally occurring and non-naturally occurring nucleotide), but is preferably either single or double stranded DNA sequences.
  • isolated means a molecule, e.g., a protein, polynucleotide, or cell, separated or substantially free from at least some of the other components of the naturally occurring organism or virus, for example, the cell structural components or other polypeptides or nucleic acids commonly found associated with the molecule. The term also encompasses molecules that have been prepared synthetically.
  • treat By the terms “treat,” “treating,” or “treatment of” (or grammatically equivalent terms) it is meant that the severity of the subject's condition is reduced or at least partially improved or ameliorated and/or that some alleviation, mitigation or decrease in at least one clinical symptom is achieved and/or there is a delay in the progression of the condition.
  • the terms “prevent,” “prevents,” or “prevention” and “inhibit,” “inhibits,” or “inhibition” are not meant to imply complete abolition of disease and encompasses any type of prophylactic treatment that reduces the incidence of the condition, delays the onset of the condition, and/or reduces the symptoms associated with the condition after onset.
  • An “effective,” “prophylactically effective,” or “therapeutically effective” amount as used herein is an amount that is sufficient to provide some improvement or benefit to the subject.
  • an “effective,” “prophylactically effective,” or “therapeutically effective” amount is an amount that will provide some delay, alleviation, mitigation, or decrease in at least one clinical symptom in the subject.
  • a “prophylactically effective,” or “therapeutically effective” amount is an amount that will provide some delay, alleviation, mitigation, or decrease in at least one clinical symptom in the subject.
  • the effects need not be complete or curative, as long as some benefit is provided to the subject.
  • the term “bind specifically” or “specifically binds” in reference to an antibody or a fragment or derivative thereof of the invention means that the agent will bind with an epitope (including one or more epitopes) of a target, but does not substantially bind to other unrelated epitopes or molecules.
  • the term refers to an agent that exhibits at least about 60% binding, e.g., at least about 70%, 80%, 90%, or 95% binding, to the target epitope relative to binding to other unrelated epitopes or molecules.
  • Integrin antagonists e.g., antibodies and fragments and derivatives thereof, peptides, peptidomimetics
  • a first aspect of the invention relates to integrin antagonists (e.g., antibodies and fragments and derivatives thereof, peptides, peptidomimetics) that bind integrin and can be used in methods of inhibiting uptake of an RGD and/or RLD-dependent virus into a cell and methods of treating, inhibiting the severity of, or preventing an RGD and/or RLD-dependent virus infection in a subject.
  • an RGD and/or RLD-dependent virus is any virus that depends at least in part on the presence of an RGD sequence, an RLD sequence, or both sequences on the surface of the virus (e.g., on a structural protein) for attachment and/or entry into cells.
  • the integrin antagonist can inhibit the uptake of an RGD-dependent virus.
  • the integrin antagonist can inhibit the uptake of an RLD-dependent virus.
  • the integrin antagonist can inhibit the uptake of an RGD and RLD-dependent virus.
  • RGD and/or RLD-dependent viruses attach to a cell by binding a cell surface receptor (e.g., ACE2 for SARS-CoV-2), followed by the virus binding to integrins, causing the integrins to cluster and facilitate virus internalization (See FIG.9B).
  • a cell surface receptor e.g., ACE2 for SARS-CoV-2
  • integrin antagonists blocks virus- integrin binding to prevents internalization, even if the virus has initially attached to the cell surface receptor.
  • the integrin antagonist can be one that binds to a specific integrin or binds to a class of integrins.
  • the integrin may be any integrin that is known or later identified to mediate entry of an RGD and/or RLD-dependent virus into a cell.
  • the integrin antagonist specifically binds integrin ⁇ v.
  • the integrin antagonist specifically binds integrin ⁇ 3.
  • the integrin antagonist specifically binds a single integrin heterodimer such as ⁇ v ⁇ 3, ⁇ M ⁇ 2, or ⁇ v ⁇ 5.
  • the integrin antagonist may be any structure that is capable of binding to an integrin on the surface of a cell and inhibiting virus attachment and/or entry into the cell.
  • the integrin antagonist may be an RGD peptide or an analog or derivative thereof.
  • the integrin antagonist may be an RLD peptide or an analog or derivative thereof.
  • the integrin antagonist is a cyclic peptide, e.g., the cyclic RGD peptide cilengitide or analogs thereof. See, e.g., Meena, Singh et al. (2020), incorporated by reference herein in its entirety.
  • the cyclic peptide is an RLD version of cilengitide or analogs thereof.
  • the integrin antagonist is a peptidomimetic, e.g., of an RGD or RLD peptide.
  • the peptidomimetic may be one that has increased stability relative to a peptide, e.g., by replacing one or more peptidic bond or using one or more non-naturally occurring amino acids.
  • analog is used to refer to a peptide which differs from a disclosed peptide by modifications to the peptide, but which significantly retains a biological activity of the disclosed peptide.
  • Minor modifications include, without limitation, changes in one or a few amino acid side chains, changes to one or a few amino acids (including deletions, insertions, and substitutions), changes in stereochemistry of one or a few atoms, and minor derivatizations, including, without limitation, methylation, glycosylation, phosphorylation, acetylation, myristoylation, prenylation, palmitoylation, amidation, and addition of glycosylphosphatidyl inositol.
  • substantially retains refers to a fragment, analog, or other variant of a peptide that retains at least about 20% of the activity of the naturally occurring peptide (e.g., binding to an integrin), e.g., about 30%, 40%, 50% or more.
  • Peptides and analogs or fragments of the invention can be modified for in vivo use by the addition, at the amino- and/or carboxyl-terminal ends, of a blocking agent to facilitate survival of the relevant peptide in vivo. This can be useful in those situations in which the peptide termini tend to be degraded by proteases prior to cellular interaction or uptake.
  • blocking agents can include, without limitation, additional related or unrelated peptide sequences that can be attached to the amino and/or carboxyl terminal residues of the peptide to be administered. This can be done either chemically during the synthesis of the peptide or by recombinant DNA technology by any suitable methods. For example, one or more non- naturally occurring amino acids, such as D-alanine, can be added to the termini. Alternatively, blocking agents such as pyroglutamic acid or other molecules known in the art can be attached to the amino and/or carboxyl terminal residues, or the amino group at the amino terminus or carboxyl group at the carboxyl terminus can be replaced with a different moiety.
  • the peptide terminus can be modified, e.g., by acetylation of the N- terminus and/or amidation of the C-terminus.
  • the peptides can be covalently or noncovalently coupled to pharmaceutically acceptable “carrier” proteins prior to administration.
  • the integrin antagonist may be a small molecule, e.g., a compound having a molecular mass less than 1000 Da.
  • the integrin antagonist may be an antibody or a fragment or derivative thereof.
  • the antibody or a fragment or derivative thereof is an antibody or an antigen-binding fragment thereof.
  • the antibody or a fragment or derivative thereof comprises one or more first domains corresponding to a Fab domain. In some embodiments, the antibody or a fragment or derivative thereof further comprises one or more second domains corresponding to an Fc domain. In some embodiments, one or both domains of the antibody or a fragment or derivative thereof is a non-immunoglobulin scaffold, an aptamer, a small molecule (e.g., a receptor ligand), or other binding moiety. [0061] In certain embodiments, the first domain of the antibody or a fragment or derivative thereof is an antibody domain. In certain embodiments, the second domain of the antibody or a fragment or derivative thereof is an antibody domain. In some embodiments, both domains are antibody domains.
  • the first domain is a humanized or human antibody domain.
  • the second domain is a humanized or human antibody domain.
  • the first domain and the second domain are humanized or human antibody domains.
  • the antibody or a fragment or derivative thereof may be a bispecific antibody or a fragment or derivative thereof.
  • the bispecific antibody or a fragment or derivative thereof may bind a second antigen present on a cell comprising an integrin, e.g., another cell surface component utilized by an RGD and/or RLD-dependent virus to attach to and/or enter a cell.
  • the second antigen is ACE2.
  • the second antigen could be derived from a neutralizing or non-neutralizing antibody isolated from a patient who has recovered from COVID-19.
  • the first domain comprises, consists essentially of, or consists of a Fab domain of an antibody.
  • the Fab domain may be from any antibody isotype.
  • the first domain comprises a Fab domain of an IgG antibody, e.g., an IgG1 or IgG4 antibody.
  • the first domain comprises the amino acid sequence of the light chain of hLM609-hIgG4-S228P (SEQ ID NO:2) and the Fab portion (also known as the Fd fragment) of the heavy chain of hLM609-hIgG4-S228P (SEQ ID NO:3) or a sequence at least 90% identical thereto, e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% identical thereto.
  • the first domain comprises the amino acid sequence of a superhumanized variant of shLM609-hIgG1-WT, e.g., the LM609_7 Fab domain of heavy chain (SEQ ID NO:5) and light chain (SEQ ID NO:6) or the JC7U Fab domain of heavy chain (SEQ ID NO:7) and light chain (SEQ ID NO:8) or a sequence at least 90% identical thereto, e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% identical thereto.
  • a superhumanized variant of shLM609-hIgG1-WT e.g., the LM609_7 Fab domain of heavy chain (SEQ ID NO:5) and light chain (SEQ ID NO:6) or the JC7U Fab domain of heavy chain (SEQ ID NO:7) and light chain (SEQ ID NO:8) or a sequence at least 90% identical thereto, e.g., at
  • the first domain comprises the amino acid sequence of the light chain of hLM609-hIgG1-WT (SEQ ID NO:9) and the Fab portion of the heavy chain of hLM609-hIgG1-WT (SEQ ID NO:10) or a sequence at least 90% identical thereto, e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% identical thereto.
  • the second domain does not significantly engage natural killer (NK) cells.
  • the second domain does not significantly engage one or more types of lymphocytes, e.g., NK cells, B cells, or T cells. “Does not significantly engage,” as used herein, refers to less than 30% of the total engaged cells being the indicated cell type, e.g., less than 25%, 20%, 15%, 10%, or 5%.
  • the second domain specifically binds a protein on the surface of a myeloid-derived cell to mediate antibody-dependent cytotoxicity of cells expressing the target antigen.
  • the protein is not present or only present at low levels on other cell types, e.g., natural killer cells.
  • the second domain specifically binds to an Fc-gamma receptor.
  • the second domain specifically binds Fc-gamma receptor 1 (Fc ⁇ R1, CD64).
  • the second domain specifically binds Fc-gamma receptor IIA (Fc ⁇ RIIA, CD32) or Fc-gamma receptor IIIA (Fc ⁇ RIIIA, CD16a).
  • the second domain does not bind Fc-gamma receptor IIB (Fc ⁇ RIIB).
  • the second domain comprises, consists essentially of, or consists of a Fc domain of an antibody.
  • the Fc domain may be from any antibody isotype.
  • the first domain comprises a Fc domain of an IgG antibody, e.g., an IgG1 antibody or an IgG4 antibody.
  • the second domain comprises a Fc domain of an IgA or IgE antibody.
  • the second domain further comprises a hinge domain of an antibody.
  • the second domain comprises the amino acid sequence of the heavy chain Fc domain and hinge domain of hLM609-hIgG4-S228P (SEQ ID NO:4) or a sequence at least 90% identical thereto, e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% identical thereto.
  • the second domain comprises the amino acid sequence of the heavy chain Fc domain and hinge domain of hLM609-hIgG1-WT (SEQ ID NO:9) or a sequence at least 90% identical thereto, e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% identical thereto.
  • the antibody or a fragment or derivative thereof comprises the amino acid sequence of the hLM609-hIgG4-S228P heavy chain (SEQ ID NO:1) and light chain (SEQ ID NO:2) or a sequence at least 90% identical thereto, e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% identical thereto.
  • the antibody or a fragment or derivative thereof comprises the amino acid sequence of the hLM609-hIgG1-WT heavy chain (SEQ ID NO:9) and light chain (SEQ ID NO:10) or a sequence at least 90% identical thereto, e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% identical thereto.
  • the antibody or a fragment or derivative thereof comprises the amino acid sequence of the shLM609- hIgG1-LALA PG YTE heavy chain (SEQ ID NO:17).
  • the antibody or a fragment or derivative thereof is any antibody known to bind to one or more integrins.
  • the antibody or a fragment or derivative thereof is etaracizumab/MEDI-522 (ABEGRINTM), MEDI-523 (VITAXINTM), intetumumab/CNTO 95, or an antibody or a fragment or derivative thereof comprising a sequence at least 90% identical thereto, e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% identical thereto.
  • the antibody or a fragment or derivative thereof may include sequence modifications that are known to enhance the characteristics of an antibody, e.g., stability, or alter the binding of the antibody to Fc-gamma receptors.
  • the amino acid sequence of the antibody or a fragment or derivative thereof comprises a S228P (Eu numbering system) mutation in the hinge region.
  • the amino acid sequence comprises a mutation selected from: a) S239D/A330L/I332E; b) I332E; c) G236A/S239D/I332E; d) G236A; e) N297A/E382V/M428I; f) M252Y/S254T/T256E; g) Q295R/L328W/A330V/P331A/I332Y/E382V/M428I; h) L234A/L235A/P329G; i) M428L/N434S; j) L234A/L235A/P331S; k) L234A/L235A/P329G/M252Y/S254T/T256E;
  • antibody refers to all types of immunoglobulins, including IgG, IgM, IgA, IgD, and IgE.
  • the antibody can be monoclonal, oligoclonal, or polyclonal and can be of any species of origin, including (for example) mouse, rat, hamster, rabbit, horse, cow, goat, sheep, pig, camel, monkey, or human, or can be a chimeric or humanized antibody. See, e.g., Walker et al., Molec. Immunol.26:403 (1989).
  • the antibodies can be recombinant monoclonal antibodies produced according to the methods disclosed in U.S. Pat. No.4,474,893 or U.S. Pat. No.4,816,567.
  • the antibodies can also be chemically constructed according to the method disclosed in U.S. Pat. No.4,676,980.
  • Antibody fragments included within the scope of the present invention include, for example, Fab, Fab′, F(ab)2, and Fv fragments; domain antibodies, diabodies; vaccibodies, linear antibodies; single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.
  • Such fragments can be produced by known techniques.
  • F(ab′) 2 fragments can be produced by pepsin digestion of the antibody molecule, and Fab fragments can be generated by reducing the disulfide bridges of the F(ab′)2 fragments.
  • Fab expression libraries can be constructed to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity (Huse et al., Science 254:1275 (1989)).
  • antibody fragment may also include any protein construct that is capable of binding a target antigen.
  • Antibodies of the invention may be altered or mutated for compatibility with species other than the species in which the antibody was produced.
  • antibodies may be humanized or camelized.
  • Humanized forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab')2 or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin.
  • Humanized antibodies include human immunoglobulins (recipient antibody) in which residues from a complementarity determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity.
  • CDR complementarity determining region
  • donor antibody non-human species
  • Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues.
  • Humanized antibodies may also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences.
  • the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework (FR) regions (i.e., the sequences between the CDR regions) are those of a human immunoglobulin consensus sequence.
  • the humanized antibody can be a superhumanized antibody where only two CDRs are non-human (US Patent No.7,087,409).
  • the humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin (Jones et al., Nature 321:522 (1986); Riechmann et al., Nature, 332:323 (1988); and Presta, Curr. Op. Struct. Biol.2:593 (1992)).
  • Fc immunoglobulin constant region
  • Methods for humanizing non-human antibodies are well known in the art. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as “import” residues, which are typically taken from an “import” variable domain.
  • Humanization can essentially be performed following the method of Winter and co-workers (Jones et al., Nature 321:522 (1986); Riechmann et al., Nature 332:323 (1988); Verhoeyen et al., Science 239:1534 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such “humanized” antibodies are chimeric antibodies (U.S. Pat. No.4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non- human species.
  • humanized antibodies are typically human antibodies in which some CDR residues (e.g., all of the CDRs or a portion thereof) and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.
  • Human antibodies can also be produced using various techniques known in the art, including phage display libraries (Hoogenboom and Winter, J. Mol. Biol.227:381 (1991); Marks et al., J. Mol. Biol.222:581 (1991)). The techniques of Cole et al. and Boerner et al. are also available for the preparation of human monoclonal antibodies (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R.
  • human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Pat.
  • Recombinant or synthetic polypeptides and peptides are the preferred immunogens for the production of monoclonal or polyclonal antibodies.
  • an immunogenic polypeptide conjugate is also included as an immunogen.
  • the peptides are used either in pure, partially pure or impure form. Suitable polypeptides and epitopes for target pathogens and sperm are well known in the art. Polynucleotide and polypeptide sequences are available in public sequence databases such as GENBANK®/GENPEPT®.
  • an immunogen e.g., a purified or synthetic peptide, a peptide coupled to an appropriate carrier (e.g., glutathione-S-transferase, keyhole limpet hemocyanin, etc.), or a peptide incorporated into an immunization vector such as a recombinant vaccinia virus is optionally mixed with an adjuvant and animals are immunized with the mixture.
  • an immunogen e.g., a purified or synthetic peptide, a peptide coupled to an appropriate carrier (e.g., glutathione-S-transferase, keyhole limpet hemocyanin, etc.), or a peptide incorporated into an immunization vector such as a recombinant vaccinia virus is optionally mixed with an adjuvant and animals are immunized with the mixture.
  • the animal's immune response to the immunogen preparation is monitored by taking test bleeds and determining the titer of reactivity to
  • Antibodies including binding fragments and single chain recombinant versions thereof, against the polypeptides are raised by immunizing animals, e.g., using immunogenic conjugates comprising a polypeptide covalently attached (conjugated) to a carrier protein as described above.
  • the immunogen of interest is a polypeptide of at least about 10 amino acids, in another embodiment the polypeptide is at least about 20 amino acids in length, and in another embodiment, the fragment is at least about 30 amino acids in length.
  • the immunogenic conjugates are typically prepared by coupling the polypeptide to a carrier protein (e.g., as a fusion protein) or, alternatively, they are recombinantly expressed in an immunization vector.
  • a carrier protein e.g., as a fusion protein
  • Monoclonal antibodies are prepared from cells secreting the desired antibody. These antibodies are screened for binding to normal or modified peptides, or screened for agonistic or antagonistic activity. Specific monoclonal and polyclonal antibodies will usually bind with a KD of at least about 50 mM, e.g., at least about 1 mM, e.g., at least about 0.1 mM or better.
  • monoclonal antibodies from various mammalian hosts, such as rodents, lagomorphs, primates, humans, etc. Description of techniques for preparing such monoclonal antibodies are found in Kohler and Milstein 1975 Nature 256:495-497. Summarized briefly, this method proceeds by injecting an animal with an immunogen, e.g., an immunogenic peptide either alone or optionally linked to a carrier protein. The animal is then sacrificed, and cells taken from its spleen are fused with myeloma cells. The result is a hybrid cell or “hybridoma” that is capable of reproducing in vitro.
  • an immunogen e.g., an immunogenic peptide either alone or optionally linked to a carrier protein.
  • myeloma cells myeloma cells
  • the population of hybridomas is then screened to isolate individual clones, each of which secrete a single antibody species to the immunogen.
  • the individual antibody species obtained are the products of immortalized and cloned single B cells from the immune animal generated in response to a specific site recognized on the immunogenic substance.
  • Alternative methods of immortalization include transformation with Epstein Barr Virus, oncogenes, or retroviruses, or other methods known in the art. Colonies arising from single immortalized cells are screened for production of antibodies of the desired specificity and affinity for the antigen, and yield of the monoclonal antibodies produced by such cells is enhanced by various techniques, including injection into the peritoneal cavity of a vertebrate (preferably mammalian) host.
  • polypeptides and antibodies of the present invention are used with or without modification, and include chimeric antibodies such as humanized murine antibodies.
  • Other suitable techniques involve selection of libraries of recombinant antibodies in phage or similar vectors. See, Huse et al. 1989 Science 246:1275-1281; and Ward et al.1989 Nature 341:544-546.
  • Antibodies specific to the target polypeptide can also be obtained by phage display techniques known in the art.
  • the present invention additionally provides polynucleotides encoding the integrin antagonist (e.g., the antibody or a fragment or derivative thereof) of this invention.
  • the polynucleotides comprises a heavy chain encoding nucleotide sequence of SEQ ID NO:13 and a light chain encoding sequence of SEQ ID NO:14 or a sequence at least 90% identical thereto, e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% identical.
  • the polynucleotides comprises a heavy chain encoding nucleotide sequence of SEQ ID NO:15 and a light chain encoding sequence of SEQ ID NO:14 or a sequence at least 90% identical thereto, e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% identical.
  • a vector comprising the polynucleotide of the invention.
  • Vectors include, but are not limited to, plasmid vectors, phage vectors, virus vectors, or cosmid vectors.
  • the present invention provides a host cell comprising the polynucleotide and/or vector of this invention.
  • the host cell can be a eukaryotic or prokaryotic cell and may be used for expressing the antibody or a fragment or derivative thereof or other purposes.
  • a further aspect of the invention relates to a composition comprising the integrin antagonist (e.g., the antibody or a fragment or derivative thereof) of the invention and a carrier.
  • the composition is a pharmaceutical composition and the carrier is a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may further comprise an additional therapeutic agent, e.g., an antiviral agent.
  • Antiviral agents include, without limitation, remdesivir, gimsilumab, REGN3048, REGEN3051, Kevzara, AdCOVID, EIDD- 2801, favipiravir (Avigan), umifenovir (Arbidol), lopinavir, ritonavir, kaletra (a combination of lopinavir and ritonavir), danoprevir+ritonavir, falidesivir, oseltamivir, emtricitabine/tenofovir, nelfinavir, or darunavir.
  • the additional therapeutic agent is one that inhibits the interaction of the RGD and/or RLD-dependent virus with a cell surface receptor used for attachment.
  • the binding of SARS-CoV-2 to ACE2 or the function of ACE2 may be inhibited, e.g., using hesperidin, curcumin, brazilin, galangin, nafamostat, desmethylcurcumin, bisdesmethylcurcumin, tangeretin, hesperetin, nobiletin, naringenin, brailein, aceto cavicol acetate, rutin, diosmin, apiin, diacetyl curcumin, rescinnamine, iloprost, prazosin, posaconazole, itraconazole, sulfasalazine, azlocillin, penicillin, cefsulodin, dabigatran etexilate, licoflavonol, cos
  • kits comprising the integrin antagonist (e.g., the antibody or a fragment or derivative thereof) of the invention or cells for producing the integrin antagonist (e.g., the antibody or a fragment or derivative thereof, peptide, or peptidomimetic) of the invention.
  • the kit can include multiple integrin antagonists and/or compositions containing such agents.
  • each of the multiple integrin antagonists provided in such a kit can specifically bind to a different antigen and/or inhibit a different RGD and/or RLD-dependent virus.
  • the kit can further include an additional active agent, e.g., an antiviral agent as would be known to one of skill in the art.
  • the kit can further include additional reagents, buffers, containers, instructions, etc.
  • Another aspect of the invention relates to a method of inhibiting uptake of an RGD and/or RLD-dependent virus into a cell, comprising contacting the cell with an effective amount of an integrin antagonist (e.g., an antibody or a fragment or derivative thereof, peptide, or peptidomimetic), e.g., an integrin antagonist of the invention.
  • an integrin antagonist e.g., an antibody or a fragment or derivative thereof, peptide, or peptidomimetic
  • An additional aspect of the invention relates to a method of treating, inhibiting the severity of, or preventing an RGD and/or RLD-dependent virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an integrin antagonist (e.g., an antibody or a fragment or derivative thereof that binds integrin, peptide, or peptidomimetic), e.g., the integrin antagonist or the pharmaceutical composition of the invention, thereby treating, inhibiting the severity of, or preventing RGD and/or RLD- dependent virus infection.
  • an integrin antagonist e.g., an antibody or a fragment or derivative thereof that binds integrin, peptide, or peptidomimetic
  • the onset of infection is delayed relative to the timing in the absence of the method.
  • the severity of the infection e.g., the number of symptoms or the severity of the symptoms, is reduced relative to the level in the absence of the method.
  • the percentage of subjects exposed to the virus that actually get infected is reduced relative to the percentage in the absence of the method.
  • the recovery from the infection is faster relative to the recovery in the absence of the method.
  • the subject is one that has tested positive for an RGD and/or RLD-dependent virus infection. In some embodiments, the subject is one that has or may have been exposed to an RGD and/or RLD-dependent virus.
  • the subject is one that will potentially be exposed to an RGD and/or RLD-dependent virus, e.g., health care workers, emergency medical technicians, law enforcement officers, medical research personnel, etc.
  • the subject may be one that is at increased risk of infection with an RGD and/or RLD-dependent virus due to underlying or preexisting conditions, e.g., conditions that increase the level of integrins on cells.
  • the subject has tissue injury or tissue inflammation, e.g., epithelial tissue injury or inflammation.
  • the subject has systemic or local inflammation, which is known to increase integrin levels.
  • the subject has lung inflammation, rendering the subject more susceptible to a respiratory virus such as SARS-CoV-2.
  • the subject has a cancer, which is known to increase integrin levels.
  • Another aspect of the invention relates to a method of treating, inhibiting the severity of, or preventing an RGD and/or RLD-dependent virus infection in a subject in need thereof, comprising the steps of: a) identifying a subject that has a condition that increases integrin expression; and b) if the subject has a condition that increases integrin expression, administering to the subject a therapeutically effective amount of an integrin antagonist, thereby treating, inhibiting the severity of, or preventing RGD and/or RLD-dependent virus infection.
  • the methods of the invention may be used for whole populations of subjects, or the majority of the population, to treat and/or prevent infection. In this scenario, the methods are likely to be effective in some but not all subjects.
  • the step of identifying a subject that has a condition that increases integrin expression may be used to provide a subpopulation of subjects in which the methods of the present invention may be most effective.
  • the method advantageously may also help identify the appropriate integrin to target, e.g., if a subject has a condition known to increase ⁇ v ⁇ 3 expression, an antagonist of ⁇ v ⁇ 3 would be the most appropriate treatment.
  • the method may, e.g., prevent a subject from getting infected upon exposure to the virus, limit the infection to one that is asymptomatic or mildly symptomatic, limit the symptoms from progressing to severe levels, and/or allow a quicker recovery from the infection.
  • the method may prevent subjects from undergoing a downward spiral in which a subject has elevated integrin levels, gets infected with a virus in part because of the elevated integrin levels, the infection causes further tissue injury and/or inflammation causing integrin levels to further increase, allowing even more virus particles to enter cells, making the infection even more severe.
  • Identifying a subject that has a condition that increases integrin expression may be carried out by identifying subjects that have certain conditions that are known to increase integrin expression, such as ⁇ v ⁇ 3. These include subjects have systemic or local tissue inflammation or tissue injury, e.g., epithelial tissue inflammation or injury, e.g., in the lungs or other organs.
  • the subject may have a disease such as cancer.
  • the subject may have an acute or chronic inflammatory disease, e.g., pancreatitis.
  • the subject may have hypercytokinemia or “cytokine storm”, indicative of tissue injury and/or inflammation.
  • the subject may be exposed to noxious chemicals, such as cigarette smoke or pollutants, leading to lung injury.
  • the subject may have a lung disease that causes cellular injury and/or inflammation, such as asthma, emphysema, chronic obstructive pulmonary disorder, cystic fibrosis, etc.
  • a lung disease that causes cellular injury and/or inflammation such as asthma, emphysema, chronic obstructive pulmonary disorder, cystic fibrosis, etc.
  • Identifying a subject that has a condition that increases integrin expression may be carried out by identifying subjects that have functional limitations indicative of tissue injury or inflammation. For example, subjects may be tested for oxygen saturation, e.g., using a finger pulse oximeter or measuring arterial blood gases, as an indication of lung injury and/or inflammation. An oxygen saturation of less than 95%, e.g., less than 90% or 85%, is indicative of a subject likely to have increased integrin expression levels in the lungs.
  • the virus is one that contains at least one RGD motif. In some embodiments, the virus is one that contains at least one RLD motif. In some embodiments, the virus is one that contains both at least one RGD motif and at least one RLD motif.
  • An appropriate integrin antagonist may be selected for use in the methods of the invention based on the binding motifs present on the virus. An integrin antagonist targeted to integrins that bind the RGD motif may be used for RGD-containing viruses. An integrin antagonist targeted to integrins that bind the RLD motif may be used for RGD-containing viruses.
  • the methods of the invention may comprise using two or more integrin antagonists, including any combination of at least one targeted to RGD binding integrins and one targeted to RLD binding-integrins.
  • an integrin antagonist that targets integrins that bind both binding motifs may be used, e.g., an ⁇ v ⁇ 3 antagonist.
  • the RGD and/or RLD-dependent virus may be, without limitation, any of the virus families or viruses listed in Table 1. Table 1
  • the RGD and/or RLD-dependent virus is a coronavirus (e.g., SARS-CoV-2), adenovirus (e.g., type 2/5), human cytomegalovirus, Kaposi’s sarcoma- associated herpesvirus, Epstein-Barr virus, human immunodeficiency virus-1, HPS- associated hantavirus NY-1, Sin Nombre virus, rotavirus, echovirus type 1, echovirus type 9, foot-and-mouth disease virus, coxsackievirus A9, murine polyomavirus, vaccinia virus, West Nile virus, simian virus 40, Ross River virus, human papillomavirus, Zika virus, or Ebola virus.
  • coronavirus e.g., SARS-CoV-2
  • adenovirus e.g., type 2/5
  • human cytomegalovirus e.g., Kaposi’s sarcoma- associated herpesvirus
  • Epstein-Barr virus
  • the RGD-dependent virus is SARS-CoV-2.
  • Examples of specific integrins associated with RGD and/or RLD-dependent viruses and the role of the integrins are shown in Table 2. This information allows one of skill in the art to select the appropriate integrin to target and the appropriate integrin antagonist (e.g., antibody or fragment or derivative thereof, peptide, or peptidomimetic) to use to protect against a given virus.
  • Table 2 [0101]
  • viruses that contain RGD and/or RLD integrin binding motifs are shown in Table 3. Each of the sequences associated with the listed accession number is incorporated by reference herein in its entirety.
  • the methods of the invention may further comprise administering to the subject an additional therapeutic agent or treatment.
  • the additional therapeutic agent or treatment is an antiviral agent, e.g., remdesivir, gimsilumab, REGN3048, REGEN3051, Kevzara, AdCOVID, EIDD-2801, favipiravir (Avigan), umifenovir (Arbidol), lopinavir, ritonavir, kaletra (a combination of lopinavir and ritonavir), danoprevir+ritonavir, falidesivir, oseltamivir, emtricitabine/tenofovir, or darunavir.
  • an antiviral agent e.g., remdesivir, gimsilumab, REGN3048, REGEN3051, Kevzara, AdCOVID, EIDD-2801, favipiravir (Avigan), umifenovir (Arbidol), lopinavir, ritonavir, kal
  • the additional therapeutic agent is one that inhibits the interaction of the RGD and/or RLD-dependent virus with a cell surface receptor used for attachment.
  • the binding of SARS-CoV-2 to ACE2 or the function of ACE2 may be inhibited, e.g., using hesperidin, curcumin, brazilin, galangin, nafamostat, desmethylcurcumin, bisdesmethylcurcumin, tangeretin, hesperetin, nobiletin, naringenin, brailein, aceto cavicol acetate, rutin, diosmin, apiin, diacetyl curcumin, rescinnamine, iloprost, prazosin, posaconazole, itraconazole, sulfasalazine, azlocillin, penicillin, cefsulodin, dabigatran etexilate, licoflavonol, cos
  • integrin antagonist e.g., the antibody or a fragment or derivative thereof used in the methods of the present invention is administered directly to a subject.
  • the integrin antagonist will be suspended in a pharmaceutically-acceptable carrier (e.g., physiological saline) and administered orally or by intravenous infusion, or administered subcutaneously, intramuscularly, intrathecally, intraperitoneally, intrarectally, intravaginally, intranasally, intragastrically, intratracheally, or intrapulmonarily.
  • a pharmaceutically-acceptable carrier e.g., physiological saline
  • the intratracheal or intrapulmonary delivery can be accomplished using a standard nebulizer, jet nebulizer, wire mesh nebulizer, dry powder inhaler, or metered dose inhaler to deliver an aerosol.
  • the agents can be delivered locally, e.g., directly to the site of the disease or disorder, such as lungs, kidney, or intestines, e.g., injected in situ into or near a tumor.
  • the agents can be delivered to the mucosa.
  • the dosage required depends on the choice of the route of administration; the nature of the formulation; the nature of the patient’s illness; the subject’s size, weight, surface area, age, and sex; other drugs being administered; and the judgment of the attending physician.
  • Suitable dosages for each agent are in the range of 0.01-100 ⁇ g/kg. Wide variations in the needed dosage are to be expected in view of the variety of agents available and the differing efficiencies of various routes of administration. For example, oral administration would be expected to require higher dosages than administration by i.v. injection. Variations in these dosage levels can be adjusted using standard empirical routines for optimization as is well understood in the art. Administrations can be single or multiple (e.g., 2-, 3-, 4-, 6-, 8-, 10-; 20-, 50-, 100-, 150-, or more fold). Encapsulation of the compound in a suitable delivery vehicle (e.g., polymeric microparticles or nanoparticles or implantable devices) may increase the efficiency of delivery, particularly for oral delivery.
  • a suitable delivery vehicle e.g., polymeric microparticles or nanoparticles or implantable devices
  • compositions of the invention can optionally comprise medicinal agents, pharmaceutical agents, carriers, adjuvants, dispersing agents, diluents, and the like.
  • the integrin antagonist of the invention can be formulated for administration in a pharmaceutical carrier in accordance with known techniques. See, e.g., Remington, The Science and Practice of Pharmacy (21 * Ed.2006). In the manufacture of a pharmaceutical formulation according to the invention, the agent is typically admixed with, inter alia, an acceptable carrier.
  • the carrier can be a solid or a liquid, or both, and may be formulated with the agent as a unit-dose formulation, for example, a capsule or vial, which can contain from 0.01 or 0.5% to 95% or 99% by weight of the agent.
  • One or more agents can be incorporated in the formulations of the invention, which can be prepared by any of the well-known techniques of pharmacy.
  • the formulations of the invention include those suitable for oral, rectal, topical, buccal (e.g., sub-lingual), vaginal, parenteral (e.g., subcutaneous, intramuscular including skeletal muscle, cardiac muscle, diaphragm muscle and smooth muscle, intradermal, intravenous, intraperitoneal), topical (i.e., both skin and mucosal surfaces, including airway surfaces), intranasal, transdermal, intraarticular, intrathecal, and inhalation administration, administration to the liver by intraportal delivery, as well as direct organ injection (e.g., into the liver, into the brain for delivery to the central nervous system, or into the pancreas) or injection into a body cavity.
  • buccal e.g., sub-lingual
  • vaginal e.g., parenteral
  • parenteral e.g., subcutaneous, intramuscular including skeletal muscle, cardiac muscle, diaphragm muscle and smooth muscle, intradermal, intravenous, intraperitoneal
  • the carrier will typically be a liquid, such as sterile pyrogen-free water, pyrogen-free phosphate-buffered saline solution, bacteriostatic water, or Cremophor EL[R] (BASF, Parsippany, N.J.).
  • the carrier can be either solid or liquid.
  • the agent can be administered in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions.
  • Agents can be encapsulated in gelatin capsules together with inactive ingredients and powdered carriers, such as glucose, lactose, sucrose, mannitol, starch, cellulose or cellulose derivatives, magnesium stearate, stearic acid, sodium saccharin, talcum, magnesium carbonate and the like.
  • inactive ingredients and powdered carriers such as glucose, lactose, sucrose, mannitol, starch, cellulose or cellulose derivatives, magnesium stearate, stearic acid, sodium saccharin, talcum, magnesium carbonate and the like.
  • additional inactive ingredients that can be added to provide desirable color, taste, stability, buffering capacity, dispersion or other known desirable features are red iron oxide, silica gel, sodium lauryl sulfate, titanium dioxide, edible white ink and the like.
  • Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours.
  • Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric- coated for selective disintegration in the gastrointestinal tract.
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • Formulations suitable for buccal (sub-lingual) administration include lozenges comprising the agent in a flavored base, usually sucrose and acacia or tragacanth; and pastilles comprising the agent in an inert base such as gelatin and glycerin or sucrose and acacia.
  • Formulations of the present invention suitable for parenteral administration comprise sterile aqueous and non-aqueous injection solutions of the agent, which preparations are preferably isotonic with the blood of the intended recipient.
  • Aqueous and non-aqueous sterile suspensions can include suspending agents and thickening agents.
  • the formulations can be presented in unit/dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or water-for-injection immediately prior to use.
  • sterile liquid carrier for example, saline or water-for-injection immediately prior to use.
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described.
  • an injectable, stable, sterile composition comprising an agent of the invention, in a unit dosage form in a sealed container.
  • the agent is provided in the form of a lyophilizate which is capable of being reconstituted with a suitable pharmaceutically acceptable carrier to form a liquid composition suitable for injection thereof into a subject.
  • the unit dosage form typically comprises from about 1 mg to about 10 grams of the agent.
  • a sufficient amount of emulsifying agent which is pharmaceutically acceptable can be employed in sufficient quantity to emulsify the agent in an aqueous carrier.
  • One such useful emulsifying agent is phosphatidyl choline.
  • Formulations suitable for rectal administration are preferably presented as unit dose suppositories. These can be prepared by admixing the agent with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
  • Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which can be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.
  • Formulations suitable for transdermal administration can be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • Formulations suitable for transdermal administration can also be delivered by iontophoresis (see, for example, Tyle, Pharm. Res.3:318 (1986)) and typically take the form of an optionally buffered aqueous solution of the compounds. Suitable formulations comprise citrate or bis/tris buffer (pH 6) or ethanol/water and contain from 0.1 to 0.2M of the compound.
  • the agent can alternatively be formulated for nasal administration or otherwise administered to the lungs of a subject by any suitable means, e.g., administered by an aerosol suspension of respirable particles comprising the agent, which the subject inhales.
  • the respirable particles can be liquid or solid.
  • aerosol includes any gas-borne suspended phase, which is capable of being inhaled into the bronchioles or nasal passages.
  • aerosol includes a gas-borne suspension of droplets, as can be produced in a metered dose inhaler or nebulizer, or in a mist sprayer. Aerosol also includes a dry powder composition suspended in air or another carrier gas, which can be delivered by insufflation from an inhaler device, for example. See Ganderton & Jones, Drug Delivery to the Respiratory Tract, Ellis Horwood (1987); Gonda (1990) Critical Reviews in Therapeutic Drug Carrier Systems 6:273-313; and Raeburn et al., J. Pharmacol. Toxicol. Meth.27:143 (1992).
  • Aerosols of liquid particles comprising the agent can be produced by any suitable means, such as with a pressure-driven aerosol nebulizer or an ultrasonic nebulizer, as is known to those of skill in the art. See, e.g., U.S. Patent No.4,501,729. Aerosols of solid particles comprising the agent can likewise be produced with any solid particulate medicament aerosol generator, by techniques known in the pharmaceutical art. [0117] Alternatively, one can administer the compound in a local rather than systemic manner, for example, in a depot or sustained-release formulation. [0118] Further, the present invention provides liposomal formulations of the agents disclosed herein and salts thereof. The technology for forming liposomal suspensions is well known in the art.
  • the compound or salt thereof is an aqueous-soluble salt
  • the same can be incorporated into lipid vesicles.
  • the agent due to the water solubility of the agent, the agent will be substantially entrained within the hydrophilic center or core of the liposomes.
  • the lipid layer employed can be of any conventional composition and can either contain cholesterol or can be cholesterol-free.
  • the salt can be substantially entrained within the hydrophobic lipid bilayer which forms the structure of the liposome. In either instance, the liposomes which are produced can be reduced in size, as through the use of standard sonication and homogenization techniques.
  • the liposomal formulations containing the agent can be lyophilized to produce a lyophilizate which can be reconstituted with a pharmaceutically acceptable carrier, such as water, to regenerate a liposomal suspension.
  • a pharmaceutical composition can be prepared containing the water-insoluble agent, such as for example, in an aqueous base emulsion.
  • the composition will contain a sufficient amount of pharmaceutically acceptable emulsifying agent to emulsify the desired amount of the agent.
  • Particularly useful emulsifying agents include phosphatidyl cholines and lecithin.
  • the integrin antagonist is administered to the subject in a therapeutically effective amount, as that term is defined above.
  • Dosages of pharmaceutically active agents can be determined by methods known in the art, see, e.g., Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa).
  • the therapeutically effective dosage of any specific agent will vary somewhat from agent to agent, and patient to patient, and will depend upon the condition of the patient and the route of delivery. As a general proposition, a dosage from about 0.1 to about 50 mg/kg will have therapeutic efficacy, with all weights being calculated based upon the weight of the agent.
  • Toxicity concerns at the higher level can restrict intravenous dosages to a lower level such as up to about 10 mg/kg, with all weights being calculated based upon the weight of the agent.
  • a dosage from about 10 mg/kg to about 50 mg/kg can be employed for oral administration.
  • a dosage from about 0.5 mg/kg to 5 mg/kg can be employed for intramuscular injection.
  • Particular dosages are about 1 ⁇ mol/kg to 50 ⁇ mol/kg, and more particularly to about 22 ⁇ mol/kg and to 33 ⁇ mol/kg of the agent for intravenous or oral administration, respectively.
  • more than one administration can be employed over a variety of time intervals (e.g., hourly, daily, weekly, monthly, etc.) to achieve therapeutic effects.
  • time intervals e.g., hourly, daily, weekly, monthly, etc.
  • the present invention finds use in veterinary and medical applications. Suitable subjects include both avians and mammals, with mammals being preferred.
  • mammals include both avians and mammals, with mammals being preferred.
  • the term “mammal” as used herein includes, but is not limited to, humans, primates, bovines, ovines, caprines, equines, felines, canines, lagomorphs, etc. Human subjects include neonates, infants, juveniles, and adults.
  • the subject may be one in need of the methods of the invention, e.g., a subject that has or is suspected of having an infection or likely to be exposed to a virus.
  • the subject may be a laboratory animal, e.g., an animal model of a disease.
  • the present invention is more particularly described in the following examples that are intended as illustrative only since numerous modifications and variations therein will be apparent to those skilled in the art.
  • Example 1 [0125] The presence of an RGD sequence in the S protein of the SARS-CoV-2 virus that was not present in the closely related SARS virus raised the question of whether an alpha V integrin may participate in the attachment or entry of the SARS-CoV-2 virus (Sigrist, Bridge et al. 2020).
  • HeLa-ACE2 human cervical carcinoma cells with ectopic expression of ACE2
  • HLa-ACE2 human cervical carcinoma cells with ectopic expression of ACE2
  • viral infection was evaluated by immunostaining fixed and permeabilized cells with sera from a convalescent COVID-19 patient.
  • SARS-CoV-2 infection for HeLA-ACE2 cells with endogenous ⁇ 3 expression was dose-dependently blocked by an antibody recognizing the alpha V-containing integrin ⁇ v ⁇ 3 (FIG.1A), but not antibodies that recognize the ⁇ 1 integrin subunit or the ⁇ v ⁇ 5 integrin heterodimer (FIG.1B).
  • Integrin ⁇ v ⁇ 3 is largely absent on all cell types in the healthy adult, but its expression and function emerges during tissue remodeling events including wound healing, angiogenesis, or cancer (Weis and Cheresh 2011). There is new evidence that the severity of progression of COVID-19 may be related to a “cytokine storm” that emerges during infection (Ye, 2020). This state has been shown to arise in patients who did not show severe clinical manifestations during early stages of disease, but who rapidly and suddenly deteriorate.
  • integrin ⁇ v ⁇ 3 may be upregulated in lung epithelial cells exposed to various forms of injury or inflammatory stimuli.
  • FIG.2A For a mouse model of lung injury, there is the expected absence of integrin ⁇ 3 expression on epithelial cells in the adult mouse lung at baseline (Day 0) (FIG.2A). Analysis of lung tissue from mice two days after treatment with naphthalene showed that the injury induced a rapid gain of integrin ⁇ 3 expression (Day 2) that was then downregulated as the lung epithelium is repaired (Day 14). Similarly, primary human lung epithelial cells showed a dose-dependent increase in ITGB3 mRNA in response to serum deprivation, a form of nutrient stress (FIG.
  • integrin ⁇ 3 protein expression was examined by immunohistochemical staining for a pancreas disease spectrum microarray slide, a tissue for which the chronically inflamed state of pancreatitis represents a major risk factor for pancreatic cancer (Pierro, Minici et al.2003, DiMagno and DiMagno 2016). While undetectable in normal adult pancreatic tissues, integrin ⁇ 3 expression not only increased from mild to chronic pancreatitis, but also from low to high grade pancreatic ductal adenocarcinoma (FIG.3).
  • pancreatic epithelial cells also upregulated the integrin ⁇ 3 subunit, but not other integrin ⁇ subunits, in response to TNF ⁇ as well as dose-dependently increase ITGB3 mRNA in response to nutrient stress (FIG.4C). These results highlight how normal pancreatic cells that are negative for integrin ⁇ 3 in adult tissues gain expression of this integrin when exposed to pro-inflammatory stimuli known to enhance the emergence of pancreatic cancer.
  • pancreatic cancer cell lines with low endogenous expression of integrin ⁇ 3 also upregulated its expression after 72 hours of culture in serum-free media (FIG.4D), suggesting that multiple cell types within the pancreas, including cancer cells, respond to inflammatory cytokines or cellular stress by upregulating integrin ⁇ 3.
  • FOG.4D serum-free media
  • these examples reveal that cells from epithelial tissues such as the lung and pancreas are generally lacking in expression of integrin ⁇ v ⁇ 3 in the healthy, resting state, but that they rapidly respond to injury, inflammation, or cellular stress by upregulating mRNA expression of the ⁇ 3 subunit leading to expression of the intact avb3 heterodimer.
  • integrin alpha V While integrin alpha V is generally expressed by most cell types in the body, the modulation of ⁇ 3 expression in response to various stimuli suggests a role for ⁇ 3 integrin as a “stress- inducible” gene that when heterodimerized with alpha V can be broadly induced as a mechanism to mitigate stress by a variety of cell types.
  • cytokine storm that emerges during infection (Ye, 2020)
  • a cocktail of cytokines that includes those highly enriched in COVID-19 patients (including INF ⁇ , TNF ⁇ , and IL-6)
  • cytokines that includes those highly enriched in COVID-19 patients (including INF ⁇ , TNF ⁇ , and IL-6)
  • INF ⁇ , TNF ⁇ , and IL-6 those highly enriched in COVID-19 patients
  • integrin ⁇ 3 expression that serves as an internalization receptor for viral infection.
  • Patients with underlying health conditions especially those that involve elevated cytokines or lung inflammation, may be especially susceptible to SARS-CoV-2 infection and/or at high risk for severe disease progression.
  • Integrins are cell surface receptors that interact with a variety of ligands via binding to specific sequences or motifs found on extracellular matrix proteins, such as the Arg-Gly- Asp (RGD) motif recognized by alpha V-containing integrins (Ruoslahti and Pierschbacher 1987). Aside from their role as cell-matrix receptors, integrins can also bind to non-matrix ligands to mediate cell-cell interactions or to serve as receptors for soluble factors including growth factors or hormones (LaFoya, Munroe et al.2018).
  • integrins Some functions of integrins have also been exploited by cancer cells to mitigate environmental stresses, immune surveillance, and to escape the effects of cancer therapy (Seguin, Desgrosellier et al.2015), and by bacteria and viruses to support various aspects of infection (LaFoya, Munroe et al.2018).
  • the alpha V containing integrins ⁇ v ⁇ 3 and ⁇ v ⁇ 5 were discovered to promote adenovirus internalization, but not virus attachment (Wickham, Mathias et al.1993, Nemerow, Cheresh et al.1994, Wickham, Filardo et al.1994).
  • viruses utilize a variety of integrins for cell attachment, entry, or both (Hussein, Walker et al. 2015). While many viruses contain one or more RGD motifs that serve as integrin- binding sites, disrupting RGD binding can prevent infection of certain viruses but not others. Examples of viruses that utilize integrin ⁇ v ⁇ 3 for internalization but do not rely on RGD binding include the hantaviruses NY-1 and Sin Nombre Virus (Grajovskaya, Shepley et al. 1998) and rotaviruses (Guerrero, Méndez et al.2000). [0133] Integrins recognize certain binding motifs to achieve receptor-ligand specificity.
  • integrin ⁇ v ⁇ 3 the receptor that this invention links to both cytokine storm and SARS-CoV-2 infection.
  • integrin ⁇ v ⁇ 3 was shown to recognize two motifs, Arg-Gly-Asp (RGD) and Arg- Leu-Asp (RLD) (Ruoslahti 1996). While, the RGD motif is recognized by a variety of ⁇ v and ⁇ 1 containing integrins, the RLD and KRLDGS motifs are recognized by only two integrins, ⁇ v ⁇ 3 and ⁇ M ⁇ 2 (Ruoslahti 1996).
  • ⁇ v ⁇ 3 and ⁇ M ⁇ 2 are the only integrins that bind to fibrinogen, and this occurs through recognition of an RLD motif (Altieri, Plescia et al. 1993).
  • An RGD motif has been identified in the SARS-CoV-2 S protein that was not present in other coronaviruses including SARS, but there have been opposing views on whether this motif enhances or prevents viral infection (Luan, Lu et al.2020, Sigrist, Bridge et al. 2020).
  • the Leu-Asp-Ile (LDI) motif is present in the S proteins of both SARS-CoV-2 and SARS (Tresoldi, Sangiuolo et al.).
  • FIG.5 shows the existence of an RLD motif in the SARS-CoV-2 S protein at amino acids 983-985.
  • the RGD sequence is located on the S1 subunit within the receptor binding domain (RBD)
  • the RLD sequence is located within the heptad repeat 1 (HR1) domain of the S2 subunit that participates in membrane fusion.
  • the RGD motif is a unique sequence found in SARS-CoV-2 that is not present in other betacoronavirus family members (FIG.6).
  • the RLD motif is highly conserved across betacoronavirus S proteins, except for one exception (the bat coronavirus HKU9) (FIG.7).
  • This particular region of the HR1 that contains the RLD motif is highly conserved among coronaviruses from diverse species, as well as sequences from many individuals with COVID-19 (Xia, Liu et al.2020). If viruses generally utilize an RLD motif for fusion or internalization, agents targeting this mechanism may have broad applications across many viral families.
  • the combination of both RGD and RLD motifs may provide a mechanistic explanation for the aggressive nature of SARS-CoV-2. [0135] 3D structural analysis of the SARS-CoV-2 virus (FIG.8) reveals that one RGD motif is be exposed in the up promoter, while somewhat concealed on the two down promoters, to participate in receptor binding.
  • RLD motif located at the apex of the HR1 region may act as a pedestal upon which the RBD from an adjacent down promoter sits. This region could impact the metastability of the spike protein.
  • the exposed RLD binding motif may interact with integrin ⁇ v ⁇ 3 to facilitate membrane fusion and/or virus internalization.
  • integrins are known to be robustly activated by binding to multivalent ligands, such as the conformation of RGD/RLD motifs predicted by the 3D model. Integrin ⁇ v ⁇ 3 may be particularly important for SARS-CoV-2 viral infection by virtue of its ability to recognize both the RGD and RLD binding motifs.
  • an alpha V integrin such as integrin ⁇ v ⁇ 3 can become activated and clustered when the SARS-CoV-2 or another RGD and/or RLD-dependent virus engages receptors such as ACE2 that mediates initial virus attachment.
  • An activated alpha V integrin would then facilitate virus internalization to enable viral replication.
  • the right side of FIG.9B provides a potential therapeutic intervention using an integrin antagonizing peptide, organic molecule, or function-blocking antibody to block the interaction between the virus and integrin, thereby preventing viral entry.
  • integrin ⁇ v ⁇ 3 blockade using a humanized monoclonal antibody is able to block viral infection of cultured human cells.
  • the structural motif glycine 190-valine 202 of the fibrinogen gamma chain interacts with CD11b/CD18 integrin (alpha M beta 2, Mac-1) and promotes leukocyte adhesion.” Journal of Biological Chemistry 268(3): 1847-1853. Chen, C. A., J. M. Chang, E. E. Chang, H. C. Chen and Y. L. Yang (2016). "TGF- ⁇ 1 modulates podocyte migration by regulating the expression of integrin- ⁇ 1 and - ⁇ 3 through different signaling pathways.” Biomed Pharmacother 105: 974-980. Coutard, B., C. Valle, X. de Lamballerie, B. Canard, N. G. Seidah and E.
  • hLM609-hIgG4-S228P (humanized LM609) Heavy chain (SEQ ID NO:1) Light chain (SEQ ID NO:2) Fab domain of heavy chain (SEQ ID NO:3) Fc and hinge domain of heavy chain (SEQ ID NO:4) shLM609-hIgG1-WT (super-humanized LM609_7) Fab domain of heavy chain (SEQ ID NO:5) Light chain (SEQ ID NO:6) shLM609-hIgG1-WT (super-humanized JC7U) Fab domain of heavy chain (SEQ ID NO:7) Light chain (SEQ ID NO:8) hLM609-hIgG1-WT (humanized LM609) Heavy chain (SEQ ID NO:9) Light chain (SEQ ID NO:10) mAb LM609-mIgG1-kappa Heavy chain (SEQ ID NO:11) Light chain (SEQ ID NO:12) hLM609-hIgG4-S228

Abstract

The present invention relates to methods of inhibiting viruses that depend on RGD and/or RLD integrin binding motifs on the virus structural proteins for entry into cells. The invention further relates to methods of treating, reducing the severity of, or preventing RGD and/or RLD-dependent virus infections using integrin antagonists such as antibodies or fragments or derivatives thereof, peptides, or peptidomimetics targeted to alpha V integrins that recognize RGD binding motifs, integrin αMβ2 that recognizes RLD binding motifs, or integrin αvβ3 that recognizes both RGD and RLD binding motifs. The invention additionally includes compositions useful for carrying out the methods of the invention.

Description

COMPOSITIONS AND METHODS FOR TREATING OR PREVENTING VIRUS INFECTION STATEMENT OF PRIORITY [0001] This application claims the benefit of U.S. Provisional Application Serial No. 63/014,658, filed April 23, 2020, and U.S. Provisional Application Serial No. 63/023,140, filed May 11, 2020, the entire contents of each of which are incorporated by reference herein. FIELD OF THE INVENTION [0002] The present invention relates to methods of inhibiting viruses that depend on an RGD and/or RLD sequence on the virus structural proteins for entry into cells. The invention further relates to methods of treating, reducing the severity of, or preventing RGD and/or RLD-dependent virus infections using integrin antagonists, such as antibodies or fragments or derivatives thereof, peptides, or peptidomimetics targeted to alpha V-containing integrins that recognize RGD binding motifs, integrin αMβ2 that recognizes RLD binding motifs, or integrin αvβ3 that recognizes both RGD and RLD binding motifs. The invention additionally includes compositions useful for carrying out the methods of the invention. BACKGROUND [0003] There is an urgent unmet need to develop therapeutic strategies to prevent infection of the novel coronavirus SARS-CoV-2 and to slow progression of its associated disease, COVID-19. SARS-CoV-2 belongs to a family of viruses that includes SARS-CoV that causes severe acute respiratory syndrome and MERS-CoV that causes Middle East respiratory syndrome, both of which are the causes of major epidemics. Full-length genomic sequencing of the new SARS-CoV-2 virus reveals 79.6% sequence identity with SARS-CoV, and this study also confirmed that SARS-CoV-2 utilizes the same cell entry receptor (angiotensin converting enzyme II, ACE2) as SARS-CoV (Zhou, Yang et al.2020). [0004] Despite these similarities between SARS and the new SARS-CoV-2, a number of unique aspects have also been reported. Whereas all coronaviruses share a general structure, there are key differences in a few proteins that alter viral entry into host species. In particular, three “S proteins” form a spike that the virus uses to infect host cells by binding to receptors on the surface of host cells. The biological events that govern the ability of this spike protein to interact with host cells represents a potential opportunity to block virus attachment, fusion, and entry. The S protein contains a receptor binding domain (RBD) in the S1 subunit that contains binding sites recognized by different receptors. The RBD for SARS-CoV-2 has been compared to other coronavirus family members, and a number of important differences have been identified (Tai, He et al.2020). [0005] One aspect of the SARS-CoV-2 virus that is lacking in the other SARS-like coronaviruses is the presence of a site on the S protein that can be cleaved by the enzyme furin (Coutard, Valle et al.2020). Furin is highly expressed in lungs, and its ability to cleave a site on the S protein of SARS-CoV-2 may contribute to the more aggressive pathogenicity of the new virus, since cleavage can release the S1 subunit that allows SARS-CoV-2 to bind to angiotensin converting enzyme (ACE2) more tightly than the SARS virus. [0006] Adjacent to the ACE2 binding sequence on the spike protein is an “RGD sequence” that is the minimal peptide sequence recognized by the family of alpha V integrins, cell surface receptors with diverse biological functions. Since this RGD sequence is present in SARS-CoV-2 but absent from all other coronaviruses examined, it has been suggested that the new virus may have gained the ability to utilize integrins as cell receptors to mediate virus entry (Sigrist, Bridge et al.2020). A high-throughput virtual screen was performed to search chemical libraries for agents capable of preventing the interaction of the S protein with both ACE2 and integrins, producing a list of potential drug candidates (Yan, Sun et al.2020). [0007] Thus, there is a need for new compositions, and methods of using such compositions, to treat or prevent virus infections, including in particular SARS-CoV-2 and other viruses that depend on RGD binding to mediate entry into cells. SUMMARY OF THE DISCLOSURE [0008] The present invention is based in part on an understanding of the role that integrins play in viral infection. It was previously reported that adenoviruses (via an RGD adhesion sequence in their penton base coat protein) interact with alpha V integrins on mammalian cells to facilitate viral uptake (Wickham, Mathias et al. 1993, Nemerow, Cheresh et al.1994, Wickham, Filardo et al. 1994, Li, Stupack et al.1998, Wang, Guan et al.2000, Li, Brown et al.2001). Since that time, various investigators have identified a similar entry mechanism for additional viruses, indicating this is a reasonably conserved mechanism of viral uptake (Stewart and Nemerow 2007). [0009] It was recently determined that integrin αvβ5 is critically involved in Zika virus uptake into glioblastoma stem cells, and it was demonstrated that αvβ5 integrin antagonists are able to prevent Zika virus infection in preclinical models of glioblastoma (Zhu, Mesci et al.2019). Interestingly, infection with the Zika virus increases the expression of both subunits for αvβ5, ITGAV and ITGB5. Integrin αvβ3 is required for viral entry of dengue virus serotype 2, and infection induces an upregulation of β3 expression (Zhang, Wang et al. 2007). Classical swine fever virus also induces β3 expression, which significantly enhances virus infection and proliferation (Li, Wang et al.2014). These studies provide several examples of how a virus may potentiate infection by upregulating expression of an integrin that can function as an internalizing receptor. [0010] While it is known that some viruses contain RGD sequences on their surface proteins and some of those viruses utilize integrin binding as part of the entry mechanism, it cannot be predicted a priori which integrins are involved. Further, it cannot be predicted whether modulation of integrin expression before and/or during virus infection plays a significant role in the infection process. In fact, it has been suggested that integrin binding to the S protein of SARS-CoV-2 would inhibit virus entry (Luan, Lu et al.2020). [0011] The present invention is further based on the discovery of an RLD integrin binding motif in the S protein of coronaviruses and other viruses. The RLD motif mediates binding to only integrins αvβ3 and αMβ2 (also known as CD11b/CD18 or Mac-1). A relationship between the RLD motif and virus entry has not been recognized previously. An analysis of potential integrin binding sites in coronavirus S proteins did not identify the RLD motif (Tresoldi, Sangiuolo et al. (2020)). The RLD integrin binding motif is present in the heptad repeat 1 (HR1) domain of the S protein of all coronaviruses. The HR1 domain mediates membrane fusion. An analysis of the three-dimensional structure of the S protein of SARS- CoV-2 shows that the RGD and RLD sequences, while in different parts of the linear amino acid sequence (S1 vs. S2), are both located toward the inner surface of the receptor binding pocket of the spike protein (FIG.8). In the trimeric spike formed from three S proteins, the 3 RGD motifs and 3 RLD motifs alternate to generate a hexamer within the binding pocket. The presence of 6 integrin binding motifs may enhance integrin clustering, thereby enhancing virus entry. [0012] While αvβ3 is known to modulate entry in some viruses, in some cases the modulation has been reported to be RGD-independent. For example, β3 integrins mediate the cellular entry of hantaviruses NY-1 and Sin Nombre Virus, but entry is not blocked by RGD peptides (Gavrilovskaya, Shepley et al.1998). Similarly, integrin αvβ3 mediates entry of rotaviruses, but their entry cannot be blocked by RGD peptides (Guerrero, Méndez et al. 2000). The present invention reveals that many viruses also have an RLD motif on a surface protein, including viruses that have been linked to αvβ3 for entry and internalization. The RLD motif may represent an important mechanism for viral entry and internalization that functions independently or in addition to an RGD motif. Thus, the RLD motif is a new target for disruption of viral entry for coronaviruses and other viruses. Additionally, as the RLD motif is recognized by only two integrins (integrin αvβ3 and αMβ2), it represents a more selective target than the RGD motif that is recognized by many integrins, including those containing β1 or αv (Ruoslahti 1996). [0013] The present inventors have studied integrin β3 expression, particularly αvβ3, and elucidated expression changes that may play a critical role in the sensitivity of subjects to infection by RGD and/or RLD-dependent viruses such as SARS-CoV-2. These findings also provide guidance for effective treatment of infected subjects as well as prevention of infection. Subjects that are more likely to be infected and/or more likely to incur a severe infection can be identified based on integrin expression levels and conditions that are known to elevate integrin expression levels, such as tissue injury and inflammation. These identified subjects also are the ones most likely to benefit from a targeted treatment aimed at inhibiting the specific integrin(s) responsible for enhancing viral infection and its consequences. [0014] One example is the relationship between the severity of COVID-19 in people with preexisting health issues and the ability of SARS-CoV-2 to enter cells. In particular, patients with cancer are more likely to be infected with COVID-19 (Leslie 2020). It may be beneficial to block the activity of certain factors that may contribute to the progression of cancer as well as susceptibility to viral infection, such as integrin αvβ3, a driver of metastasis, stemness, and drug resistance in multiple types of solid tumors (Seguin, Desgrosellier et al. 2015). An enrichment of integrin αvβ3 expression on lung cancers that had gained resistance to EGFR blockade was previously reported (Seguin, Kato et al.2014), and new data presented here reveals the induction of β3 expression when normal or malignant epithelial cells are exposed to cellular stresses or inflammatory cytokines. Thus, patients with pre- existing lung inflammation or cancer may be much more susceptible to infection with SARS- CoV-2 by virtue of elevated integrin αvβ3 expression on their lung epithelial cells. If so, an integrin αvβ3 antagonist that competes for ligand binding, e.g., formulated for local delivery to the lung using an aerosol delivery vehicle, represents a novel strategy to prevent virus uptake and slow the progression of COVID-19. [0015] Thus, one aspect of the invention relates to a method of inhibiting uptake of an RGD and/or RLD-dependent virus into a cell, comprising contacting the cell with an effective amount of an integrin antagonist. [0016] Another aspect of the invention relates to a method of treating, inhibiting the severity of, or preventing an RGD and/or RLD-dependent virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an integrin antagonist, thereby treating, inhibiting the severity of, or preventing RGD and/or RLD-dependent virus infection. [0017] A further aspect of the invention relates to a method of treating, inhibiting the severity of, or preventing an RGD and/or RLD-dependent virus infection in a subject in need thereof, comprising the steps of: a) identifying a subject that has a condition that increases integrin expression; and b) if the subject has a condition that increases integrin expression, administering to the subject a therapeutically effective amount of an integrin antagonist, thereby treating, inhibiting the severity of, or preventing RGD and/or RLD-dependent virus infection. [0018] An additional aspect of the invention relates to an integrin antagonist, e.g., one that inhibits entry of an RGD and/or RLD-dependent virus into a cell. [0019] A further aspect of the invention relates to a polynucleotide encoding the integrin antagonist of the invention and a vector or host cell comprising the polynucleotide. [0020] Another aspect of the invention relates to a composition, e.g., a pharmaceutical composition, comprising the integrin antagonist of the invention and a carrier. [0021] An additional aspect of the invention relates to a kit comprising the integrin antagonist of the invention. [0022] These and other aspects of the invention are set forth in more detail in the description of the invention below. BRIEF DESCRIPTION OF THE DRAWINGS [0023] FIGS.1A-1B show anti-αvβ3 (mIgG1, hIgG1, or hLM609-hIgG4-S228P) blocks SARS-CoV-2 infection in human HeLa-ACE2 cells. Live SARS-CoV-2 virus was added to HeLa-ACE2 cells in the presence of integrin function-blocking antibodies that recognize the β1 integrin subunit, the αvβ3 integrin heterodimer, or the αvβ5 integrin heterodimer. After 24 h, cells were fixed, permeabilized, and stained using serum from a COVID-19 patient to identify the extent of virus infection. Representative images and full dose range for hLM609- hIgG4-S228P are shown in Fig.1A. Immunoblot for HeLa-ACE2 and VERO cell lysates confirms integrin β3 expression. Fig.1B shows control plus three doses each for three different anti-αvβ3 antibodies (hLM609-hIgG4-S228P, hLM609-hIgG1, and LM609- mIgG1), two antibodies targeting other RGD-dependent integrins (αvβ5 and β1), and two peptide antagonists (cilengitide and cRGDFV). Each of the three forms of anti-αvβ3 dose- dependently blocked the level of SARS-CoV-2 infection after 24 hours, providing proof of concept that a monoclonal anti-αvβ3 integrin antibody is able to prevent the binding of integrin αvβ3 to SARS-CoV-2 virus to prevent uptake/internalization. In comparison, neither the αvβ5/β1 antibodies nor the peptide inhibitors were able to achieve a substantial blockade of viral infection. [0024] FIGS.2A-2C show that integrin β3 expression is absent on normal lung bronchial epithelium but upregulated by injury, stress, or inflammation. A) Adult mice were subject to inhalation of naphthalene to injure the bronchial epithelium. Lungs were immunostained for integrin β3 (brown) and hematoxylin (blue), and analyzed for β3 IHC staining intensity on a scale from 1 to 3 at timepoints before naphthalene (Day 0), during the early stages of tissue repair (Day 2), and after the epithelial layer has been completely restored (Day 14). Bar graph shows mean ± SD IHC score for β3 expression on a scale from 0 (lowest) to 3 (highest), for n=4 mice per group. Asterisks indicate P<0.05 compared to Day 0 and bracket shown compares Day 2 vs. Day 14. B) Left, Primary human lung epithelial cells were grown for 72 hours in media containing indicated % serum. qPCR analysis for ITGB3 mRNA expression is shown as fold change relative to control (10% serum). Graph shows mean ± SD. Right, Primary human bronchial epithelial, umbilical vein endothelial, or dermal fibroblast cells were treated with PBS control or a cocktail of inflammatory cytokines (INFγ, TNFα, IL-6) to mimic a “cytokine storm” that is observed in COVID-19 patients. Immunoblot for integrin β3 or loading control (β-actin) shows low expression of β3 in unstimulated cells, with a significant increase in β3 levels in cells exposed to cytokines. C) Left, HCC827 human lung cancer cells were grown for 24 h in the presence of vehicle control or 4 ng/ml TGFβ1. qPCR analysis for ITGB3 mRNA expression is shown as fold change relative to control (PBS). Right, H358 and HCC827 human lung cancer cells were grown in the presence of 10 ng/ml TGFβ1 for 48 h, then protein expression was analyzed by immunoblot. Graphs show mean ± SD. [0025] FIG.3 shows integrin β3 protein expression is absent on normal pancreas but upregulated in pancreatitis and cancer. A pancreas disease spectrum tissue microarray slide (Biomax PA2081) was stained for β3 protein (brown) and expression scored by blinded observers as being positive or negative for each tissue core. The graph displays the number and percent of cores from each group with visibly positive exocrine cells. [0026] FIGS.4A-4D show the effect of inflammation on integrin β3 expression in pancreatic cells. A) Mouse pancreatic acinar cells were treated with vehicle control (PBS), a combination of cytokines (50 ng/ml TNFα and 50 ng/ml CCL5 for 5 days), or the pancreatitis-inducing agent caerulein (10-100nM for 48 hours). mRNA expression was analyzed by qPCR. Graph shows the log2-fold change in the expression of mouse β3 (Itgb3) and other markers for cells treated with cytokines vs. cells treated with PBS. Integrin β3 protein expression was assessed using immunoblot and densitometry used for quantification compared to β-actin as a loading control. Bars represent mean ± SD for n = 3 independent experiments. B) Human pancreatic stellate cells were treated with the cytokines shown for 48 or 72 hours, and mRNA expression was analyzed by qPCR. Graph shows the log2-fold change in human β3 (ITGB3) expression vs. cells treated with PBS. Bars represent mean ± SD for n = 3 independent experiments. C) Human pancreatic epithelial cells were treated with 50 ng/ml TNFα or serum deprivation as indicated. mRNA expression was analyzed by qPCR. Graph shows fold change for indicated integrin expression relative to control. D) Human pancreatic carcinoma cell lines were cultured in 0% or 10% serum for 72 hours. ITGB3 mRNA expression was analyzed by qPCR. Graph shows fold change for β3 (ITGB3) relative to control (10% serum). [0027] FIG.5 is a schematic showing the location of RGD and RLD integrin binding motifs in the SARS-CoV-2 S protein amino acid sequence (SEQ ID NO:16). The Arg-Gly- Asp (RGD) motif is located at 403-405, within the receptor binding domain (RBD) that mediates virus attachment to ACE2. The Arg-Leu-Asp (RLD) motif is located at 983-985 within the HR1 domain that mediates fusion of the viral and host cell membranes. [0028] FIG.6 is a sequence alignment showing unique expression of the RGD motif on SARS-CoV-2. The RGD integrin binding motif that is recognized by αv-containing integrins is present at amino acids 403-405 in the SARS-CoV-2 virus, but not found in any of the other betacoronaviruses examined. A KGD motif that is recognized by αIIbβ3, αVβ5, αVβ6, and αVβ8 integrins is present at the same location in 11 of the other betacoronaviruses. [0029] FIG.7 is a sequence alignment showing the highly conserved RLD motif for betacoronaviruses. The RLD integrin binding motif that is recognized by integrin αvβ3 and αMβ2 is highly conserved across betacoronaviruses except for the bat coronavirus HKU9. [0030] FIG.8 shows the locations of the RGD and RLD binding motifs on a 3D structural visualization of the SARS-CoV-2 virus spike protein trimer. Top, Three RGD motifs are shown at the center of the spike. One RGD motif is predicted to be exposed in the up promoter, while somewhat concealed on the two down promoters, to participate in receptor binding. Bottom, An RLD motif located at the apex of the HR1 region is shown to act as a pedestal upon which the RBD from an adjacent down promoter sits. This region may impact the metastability of the spike before cleavage, after which the exposed RLD binding motif may interact with integrin αvβ3 to facilitate membrane fusion and/or virus internalization. Integrins are known to be robustly activated by binding to multivalent ligands, such as the conformation of RGD/RLD motifs predicted by the 3D model. [0031] FIGS.9A-9B are schematics showing the implications for αvβ3 expression on susceptibility and progression of COVID-19, and the proposed effect of anti-integrin therapy on SARS-CoV-2 virus internalization. A) Individuals without underlying health conditions are expected to have low expression of integrin αvβ3, which may contribute to a relatively lower susceptibility to viral infection and/or more mild symptoms. In some patients, a cytokine storm suddenly arises that could enhance αvβ3 expression and thereby contribute to the progression of severe disease. For individuals with pre-existing underlying health conditions, including those associated with chronic inflammation, integrin αvβ3 expression may already be elevated and contribute to an elevated susceptibility to infection and/or a more rapid disease progression that could be further exacerbated by the release of cytokines. This scenario provides the rationale for targeting integrin αvβ3 as a novel therapeutic opportunity to protect host cells from viral infection. Such a strategy could be used in combination with other approaches to directly target the virus and/or suppress the release of cytokines. B) The SARS-CoV-2 virus enters host cells by first engaging host cell surface receptors, including ACE2. After initial virus attachment, alpha V integrins bind to the virus spike proteins that each contain three RGD sequences, and this multivalent interaction promotes integrin clustering and activation. SARS-CoV-2 utilizes alpha V integrins to mediate internalization into host cells. An antibody, peptide, organic molecule, or other naturally agent that disrupts the ligand binding capacity of an alpha V-containing integrin, such as αvβ3, can prevent SARS-CoV-2 uptake and internalization. DETAILED DESCRIPTION [0032] The present invention is explained in greater detail below. This description is not intended to be a detailed catalog of all the different ways in which the invention may be implemented, or all the features that may be added to the instant invention. For example, features illustrated with respect to one embodiment may be incorporated into other embodiments, and features illustrated with respect to a particular embodiment may be deleted from that embodiment. In addition, numerous variations and additions to the various embodiments suggested herein will be apparent to those skilled in the art in light of the instant disclosure which do not depart from the instant invention. Hence, the following specification is intended to illustrate some particular embodiments of the invention, and not to exhaustively specify all permutations, combinations and variations thereof. [0033] Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination. Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted. To illustrate, if the specification states that a complex comprises components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed singularly or in any combination. [0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. [0035] Except as otherwise indicated, standard methods known to those skilled in the art may be used for production of recombinant and synthetic polypeptides, antibodies or antigen- binding fragments thereof, manipulation of nucleic acid sequences, and production of transformed cells. Such techniques are known to those skilled in the art. See, e.g., SAMBROOK et al., MOLECULAR CLONING: A LABORATORY MANUAL 4th Ed. (Cold Spring Harbor, N.Y., 2012); F. M. AUSUBEL et al. CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (Green Publishing Associates, Inc. and John Wiley & Sons, Inc., New York). [0036] All publications, patent applications, patents, nucleotide sequences, amino acid sequences and other references mentioned herein are incorporated by reference in their entirety. Definitions [0037] As used in the description of the invention and the appended claims, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. [0038] As used herein, “and/or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”). [0039] Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted. [0040] Furthermore, the term “about,” as used herein when referring to a measurable value such as an amount of a compound or agent of this invention, dose, time, temperature, and the like, is meant to encompass variations of ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of the specified amount. [0041] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about”. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and claims are approximations that can vary depending upon the desired properties sought to be obtained by the presently-disclosed subject matter. [0042] As used herein, ranges can be expressed as from “about” one particular value, and/or to “about” another particular value. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed. [0043] The transitional phrase “consisting essentially of” means that the scope of a claim is to be interpreted to encompass the specified materials or steps recited in the claim, and those that do not materially affect the basic and novel characteristic(s) of the claimed invention. [0044] The term “consists essentially of” (and grammatical variants), as applied to a polynucleotide or polypeptide sequence of this invention, means a polynucleotide or polypeptide that consists of both the recited sequence (e.g., SEQ ID NO) and a total of ten or less (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) additional nucleotides or amino acids on the 5’ and/or 3’ or N-terminal and/or C-terminal ends of the recited sequence or between the two ends (e.g., between domains) such that the function of the polynucleotide or polypeptide is not materially altered. The total of ten or less additional nucleotides or amino acids includes the total number of additional nucleotides or amino acids added together. [0045] As used herein, the term “polypeptide” encompasses both peptides and proteins, unless indicated otherwise. A “peptide” refers to a polypeptide containing less than 20 amino acid residues, e.g., less than 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10 amino acid residues, and incudes linear and cyclic peptides. [0046] The term “chimeric” refers to a molecule having two or more portions that are not naturally found together in the same molecule. [0047] A “nucleic acid” or “nucleotide sequence” is a sequence of nucleotide bases, and may be RNA, DNA or DNA-RNA hybrid sequences (including both naturally occurring and non-naturally occurring nucleotide), but is preferably either single or double stranded DNA sequences. [0048] As used herein, the term “isolated” means a molecule, e.g., a protein, polynucleotide, or cell, separated or substantially free from at least some of the other components of the naturally occurring organism or virus, for example, the cell structural components or other polypeptides or nucleic acids commonly found associated with the molecule. The term also encompasses molecules that have been prepared synthetically. [0049] By the terms “treat,” “treating,” or “treatment of” (or grammatically equivalent terms) it is meant that the severity of the subject's condition is reduced or at least partially improved or ameliorated and/or that some alleviation, mitigation or decrease in at least one clinical symptom is achieved and/or there is a delay in the progression of the condition. [0050] As used herein, the terms “prevent,” “prevents,” or “prevention” and “inhibit,” “inhibits,” or “inhibition” (and grammatical equivalents thereof) are not meant to imply complete abolition of disease and encompasses any type of prophylactic treatment that reduces the incidence of the condition, delays the onset of the condition, and/or reduces the symptoms associated with the condition after onset. [0051] An “effective,” “prophylactically effective,” or “therapeutically effective” amount as used herein is an amount that is sufficient to provide some improvement or benefit to the subject. Alternatively stated, an “effective,” “prophylactically effective,” or “therapeutically effective” amount is an amount that will provide some delay, alleviation, mitigation, or decrease in at least one clinical symptom in the subject. Those skilled in the art will appreciate that the effects need not be complete or curative, as long as some benefit is provided to the subject. [0052] As used herein, the term “bind specifically” or “specifically binds” in reference to an antibody or a fragment or derivative thereof of the invention means that the agent will bind with an epitope (including one or more epitopes) of a target, but does not substantially bind to other unrelated epitopes or molecules. In certain embodiments, the term refers to an agent that exhibits at least about 60% binding, e.g., at least about 70%, 80%, 90%, or 95% binding, to the target epitope relative to binding to other unrelated epitopes or molecules. Integrin antagonists [0053] A first aspect of the invention relates to integrin antagonists (e.g., antibodies and fragments and derivatives thereof, peptides, peptidomimetics) that bind integrin and can be used in methods of inhibiting uptake of an RGD and/or RLD-dependent virus into a cell and methods of treating, inhibiting the severity of, or preventing an RGD and/or RLD-dependent virus infection in a subject. An RGD and/or RLD-dependent virus, as used herein, is any virus that depends at least in part on the presence of an RGD sequence, an RLD sequence, or both sequences on the surface of the virus (e.g., on a structural protein) for attachment and/or entry into cells. In some embodiments, the integrin antagonist can inhibit the uptake of an RGD-dependent virus. In some embodiments, the integrin antagonist can inhibit the uptake of an RLD-dependent virus. In some embodiments, the integrin antagonist can inhibit the uptake of an RGD and RLD-dependent virus. [0054] Without being bound by theory, it is thought that RGD and/or RLD-dependent viruses attach to a cell by binding a cell surface receptor (e.g., ACE2 for SARS-CoV-2), followed by the virus binding to integrins, causing the integrins to cluster and facilitate virus internalization (See FIG.9B). Contacting cells with integrin antagonists blocks virus- integrin binding to prevents internalization, even if the virus has initially attached to the cell surface receptor. [0055] The integrin antagonist can be one that binds to a specific integrin or binds to a class of integrins. The integrin may be any integrin that is known or later identified to mediate entry of an RGD and/or RLD-dependent virus into a cell. In some embodiments, the integrin antagonist specifically binds integrin αv. In some embodiments, the integrin antagonist specifically binds integrin β3. In some embodiments, the integrin antagonist specifically binds a single integrin heterodimer such as αvβ3, αMβ2, or αvβ5. [0056] The integrin antagonist may be any structure that is capable of binding to an integrin on the surface of a cell and inhibiting virus attachment and/or entry into the cell. In some embodiments, the integrin antagonist may be an RGD peptide or an analog or derivative thereof. In some embodiments, the integrin antagonist may be an RLD peptide or an analog or derivative thereof. In some embodiments, the integrin antagonist is a cyclic peptide, e.g., the cyclic RGD peptide cilengitide or analogs thereof. See, e.g., Meena, Singh et al. (2020), incorporated by reference herein in its entirety. In some embodiments, the cyclic peptide is an RLD version of cilengitide or analogs thereof. In some embodiments, the integrin antagonist is a peptidomimetic, e.g., of an RGD or RLD peptide. The peptidomimetic may be one that has increased stability relative to a peptide, e.g., by replacing one or more peptidic bond or using one or more non-naturally occurring amino acids. [0057] As used herein, the term “analog” is used to refer to a peptide which differs from a disclosed peptide by modifications to the peptide, but which significantly retains a biological activity of the disclosed peptide. Minor modifications include, without limitation, changes in one or a few amino acid side chains, changes to one or a few amino acids (including deletions, insertions, and substitutions), changes in stereochemistry of one or a few atoms, and minor derivatizations, including, without limitation, methylation, glycosylation, phosphorylation, acetylation, myristoylation, prenylation, palmitoylation, amidation, and addition of glycosylphosphatidyl inositol. The term “substantially retains,” as used herein, refers to a fragment, analog, or other variant of a peptide that retains at least about 20% of the activity of the naturally occurring peptide (e.g., binding to an integrin), e.g., about 30%, 40%, 50% or more. [0058] Peptides and analogs or fragments of the invention can be modified for in vivo use by the addition, at the amino- and/or carboxyl-terminal ends, of a blocking agent to facilitate survival of the relevant peptide in vivo. This can be useful in those situations in which the peptide termini tend to be degraded by proteases prior to cellular interaction or uptake. Such blocking agents can include, without limitation, additional related or unrelated peptide sequences that can be attached to the amino and/or carboxyl terminal residues of the peptide to be administered. This can be done either chemically during the synthesis of the peptide or by recombinant DNA technology by any suitable methods. For example, one or more non- naturally occurring amino acids, such as D-alanine, can be added to the termini. Alternatively, blocking agents such as pyroglutamic acid or other molecules known in the art can be attached to the amino and/or carboxyl terminal residues, or the amino group at the amino terminus or carboxyl group at the carboxyl terminus can be replaced with a different moiety. Additionally, the peptide terminus can be modified, e.g., by acetylation of the N- terminus and/or amidation of the C-terminus. Likewise, the peptides can be covalently or noncovalently coupled to pharmaceutically acceptable “carrier” proteins prior to administration. [0059] In some embodiments, the integrin antagonist may be a small molecule, e.g., a compound having a molecular mass less than 1000 Da. [0060] In some embodiments, the integrin antagonist may be an antibody or a fragment or derivative thereof. In some embodiments, the antibody or a fragment or derivative thereof is an antibody or an antigen-binding fragment thereof. In some embodiments, the antibody or a fragment or derivative thereof comprises one or more first domains corresponding to a Fab domain. In some embodiments, the antibody or a fragment or derivative thereof further comprises one or more second domains corresponding to an Fc domain. In some embodiments, one or both domains of the antibody or a fragment or derivative thereof is a non-immunoglobulin scaffold, an aptamer, a small molecule (e.g., a receptor ligand), or other binding moiety. [0061] In certain embodiments, the first domain of the antibody or a fragment or derivative thereof is an antibody domain. In certain embodiments, the second domain of the antibody or a fragment or derivative thereof is an antibody domain. In some embodiments, both domains are antibody domains. In some embodiments, the first domain is a humanized or human antibody domain. In some embodiments, the second domain is a humanized or human antibody domain. In some embodiments, the first domain and the second domain are humanized or human antibody domains. [0062] In some embodiments, the antibody or a fragment or derivative thereof may be a bispecific antibody or a fragment or derivative thereof. The bispecific antibody or a fragment or derivative thereof may bind a second antigen present on a cell comprising an integrin, e.g., another cell surface component utilized by an RGD and/or RLD-dependent virus to attach to and/or enter a cell. In some embodiments, the second antigen is ACE2. In some embodiments, the second antigen could be derived from a neutralizing or non-neutralizing antibody isolated from a patient who has recovered from COVID-19. [0063] In certain embodiments, the first domain comprises, consists essentially of, or consists of a Fab domain of an antibody. The Fab domain may be from any antibody isotype. In some embodiments, the first domain comprises a Fab domain of an IgG antibody, e.g., an IgG1 or IgG4 antibody. In some embodiments, the first domain comprises the amino acid sequence of the light chain of hLM609-hIgG4-S228P (SEQ ID NO:2) and the Fab portion (also known as the Fd fragment) of the heavy chain of hLM609-hIgG4-S228P (SEQ ID NO:3) or a sequence at least 90% identical thereto, e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% identical thereto. In some embodiments, the first domain comprises the amino acid sequence of a superhumanized variant of shLM609-hIgG1-WT, e.g., the LM609_7 Fab domain of heavy chain (SEQ ID NO:5) and light chain (SEQ ID NO:6) or the JC7U Fab domain of heavy chain (SEQ ID NO:7) and light chain (SEQ ID NO:8) or a sequence at least 90% identical thereto, e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% identical thereto. In some embodiments, the first domain comprises the amino acid sequence of the light chain of hLM609-hIgG1-WT (SEQ ID NO:9) and the Fab portion of the heavy chain of hLM609-hIgG1-WT (SEQ ID NO:10) or a sequence at least 90% identical thereto, e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% identical thereto. [0064] In some circumstances, it may be advantageous for the antibody or a fragment or derivative thereof to not bind significantly to one or more classes of immune cells that could act as effector cells known to mediate antibody-dependent cytotoxicity. Avoiding such an interaction will permit more of the antibody to be available to bind the desired target, i.e., the virus. In certain embodiments, the second domain does not significantly engage natural killer (NK) cells. In certain embodiments, the second domain does not significantly engage one or more types of lymphocytes, e.g., NK cells, B cells, or T cells. “Does not significantly engage,” as used herein, refers to less than 30% of the total engaged cells being the indicated cell type, e.g., less than 25%, 20%, 15%, 10%, or 5%. [0065] In some embodiments, the second domain (the Fc domain) specifically binds a protein on the surface of a myeloid-derived cell to mediate antibody-dependent cytotoxicity of cells expressing the target antigen. In some embodiments, the protein is not present or only present at low levels on other cell types, e.g., natural killer cells. In some embodiments, the second domain specifically binds to an Fc-gamma receptor. In some embodiments, the second domain specifically binds Fc-gamma receptor 1 (FcγR1, CD64). In some embodiments, the second domain specifically binds Fc-gamma receptor IIA (FcγRIIA, CD32) or Fc-gamma receptor IIIA (FcγRIIIA, CD16a). In some embodiments, the second domain does not bind Fc-gamma receptor IIB (FcγRIIB). [0066] In certain embodiments, the second domain comprises, consists essentially of, or consists of a Fc domain of an antibody. The Fc domain may be from any antibody isotype. In some embodiments, the first domain comprises a Fc domain of an IgG antibody, e.g., an IgG1 antibody or an IgG4 antibody. In some embodiments, the second domain comprises a Fc domain of an IgA or IgE antibody. In certain embodiments, the second domain further comprises a hinge domain of an antibody. In some embodiments, the second domain comprises the amino acid sequence of the heavy chain Fc domain and hinge domain of hLM609-hIgG4-S228P (SEQ ID NO:4) or a sequence at least 90% identical thereto, e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% identical thereto. In some embodiments, the second domain comprises the amino acid sequence of the heavy chain Fc domain and hinge domain of hLM609-hIgG1-WT (SEQ ID NO:9) or a sequence at least 90% identical thereto, e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% identical thereto. [0067] In certain embodiments, the antibody or a fragment or derivative thereof comprises the amino acid sequence of the hLM609-hIgG4-S228P heavy chain (SEQ ID NO:1) and light chain (SEQ ID NO:2) or a sequence at least 90% identical thereto, e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% identical thereto. In certain embodiments, the antibody or a fragment or derivative thereof comprises the amino acid sequence of the hLM609-hIgG1-WT heavy chain (SEQ ID NO:9) and light chain (SEQ ID NO:10) or a sequence at least 90% identical thereto, e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% identical thereto. In some embodiments, the antibody or a fragment or derivative thereof comprises the amino acid sequence of the shLM609- hIgG1-LALA PG YTE heavy chain (SEQ ID NO:17). [0068] In certain embodiments, the antibody or a fragment or derivative thereof is any antibody known to bind to one or more integrins. In some embodiments, the antibody or a fragment or derivative thereof is etaracizumab/MEDI-522 (ABEGRIN™), MEDI-523 (VITAXIN™), intetumumab/CNTO 95, or an antibody or a fragment or derivative thereof comprising a sequence at least 90% identical thereto, e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% identical thereto. [0069] The antibody or a fragment or derivative thereof may include sequence modifications that are known to enhance the characteristics of an antibody, e.g., stability, or alter the binding of the antibody to Fc-gamma receptors. In some embodiments, the amino acid sequence of the antibody or a fragment or derivative thereof comprises a S228P (Eu numbering system) mutation in the hinge region. In some embodiments, the amino acid sequence comprises a mutation selected from: a) S239D/A330L/I332E; b) I332E; c) G236A/S239D/I332E; d) G236A; e) N297A/E382V/M428I; f) M252Y/S254T/T256E; g) Q295R/L328W/A330V/P331A/I332Y/E382V/M428I; h) L234A/L235A/P329G; i) M428L/N434S; j) L234A/L235A/P331S; k) L234A/L235A/P329G/M252Y/S254T/T256E; l) S298A/E333A/K334/A; m) S239D/I332E; n) G236A/S239D/A330L/I332E; o) S239D/I332E/G236A; p) L234Y/G236W/S298A; q) F243L/R292P/Y300L/V305I/P396L; r) K326W/E333S; s) K326A/E333A; t) K326M/E333S; u) C221D/D222C; v) S267E/H268F/S324W; w) H268F/S324W; x) E345R y) R435H; z) N434A; aa) M252Y/S254T/T256E; ab) M428L/N434S; ac) T252L/T/253S/T254F; ad) E294delta/T307P/N434Y; ae) T256N/A378V/S383N/N434Y; af) E294delta ag) L235E; ah) L234A/L235A; ai) S228P/L235E; aj) P331S/L234E/L225F; ak) D265A; al) G237A; am) E318A; an) E233P; ao) G236R/L328R; ap) H268Q/V309L/A330S/P331S; aq) L234A/L235A/G237A/P238S/H268A/A330S/P331S; ar) A330L; as) D270A; at) K322A; au) P329A; av) P331A; aw V264A; ax) F241A; ay) N297A or G or N az) S228P/F234A/L235A; or ba) any combination of a) to az); (Eu numbering system) with or without the S228P mutation. See, e.g., Saunders, Front. Immunol.10:1296 (2019), incorporated by reference herein in its entirety. [0070] The following discussion is presented as a general overview of the techniques available for the production of antibodies; however, one of skill in the art will recognize that many variations upon the following methods are known. [0071] The term “antibody” or “antibodies” as used herein refers to all types of immunoglobulins, including IgG, IgM, IgA, IgD, and IgE. The antibody can be monoclonal, oligoclonal, or polyclonal and can be of any species of origin, including (for example) mouse, rat, hamster, rabbit, horse, cow, goat, sheep, pig, camel, monkey, or human, or can be a chimeric or humanized antibody. See, e.g., Walker et al., Molec. Immunol.26:403 (1989). The antibodies can be recombinant monoclonal antibodies produced according to the methods disclosed in U.S. Pat. No.4,474,893 or U.S. Pat. No.4,816,567. The antibodies can also be chemically constructed according to the method disclosed in U.S. Pat. No.4,676,980. [0072] Antibody fragments included within the scope of the present invention include, for example, Fab, Fab′, F(ab)2, and Fv fragments; domain antibodies, diabodies; vaccibodies, linear antibodies; single-chain antibody molecules; and multispecific antibodies formed from antibody fragments. Such fragments can be produced by known techniques. For example, F(ab′)2 fragments can be produced by pepsin digestion of the antibody molecule, and Fab fragments can be generated by reducing the disulfide bridges of the F(ab′)2 fragments. Alternatively, Fab expression libraries can be constructed to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity (Huse et al., Science 254:1275 (1989)). In some embodiments, the term “antibody fragment” as used herein may also include any protein construct that is capable of binding a target antigen. [0073] Antibodies of the invention may be altered or mutated for compatibility with species other than the species in which the antibody was produced. For example, antibodies may be humanized or camelized. Humanized forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab')2 or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin. Humanized antibodies include human immunoglobulins (recipient antibody) in which residues from a complementarity determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity. In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies may also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework (FR) regions (i.e., the sequences between the CDR regions) are those of a human immunoglobulin consensus sequence. The humanized antibody can be a superhumanized antibody where only two CDRs are non-human (US Patent No.7,087,409). The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin (Jones et al., Nature 321:522 (1986); Riechmann et al., Nature, 332:323 (1988); and Presta, Curr. Op. Struct. Biol.2:593 (1992)). [0074] Methods for humanizing non-human antibodies are well known in the art. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as “import” residues, which are typically taken from an “import” variable domain. Humanization can essentially be performed following the method of Winter and co-workers (Jones et al., Nature 321:522 (1986); Riechmann et al., Nature 332:323 (1988); Verhoeyen et al., Science 239:1534 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such “humanized” antibodies are chimeric antibodies (U.S. Pat. No.4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non- human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues (e.g., all of the CDRs or a portion thereof) and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies. [0075] Human antibodies can also be produced using various techniques known in the art, including phage display libraries (Hoogenboom and Winter, J. Mol. Biol.227:381 (1991); Marks et al., J. Mol. Biol.222:581 (1991)). The techniques of Cole et al. and Boerner et al. are also available for the preparation of human monoclonal antibodies (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p.77 (1985) and Boerner et al., J. Immunol.147:86 (1991)). Similarly, human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Pat. Nos.5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in the following scientific publications: Marks et al., Bio/Technology 10:779 (1992); Lonberg et al., Nature 368:856 (1994); Morrison, Nature 368:812 (1994); Fishwild et al., Nature Biotechnol.14:845 (1996); Neuberger, Nature Biotechnol.14:826 (1996); Lonberg and Huszar, Intern. Rev. Immunol.13:65 (1995). [0076] Immunogens (antigens) are used to produce antibodies specifically reactive with target polypeptides. Recombinant or synthetic polypeptides and peptides, e.g., of at least 5 (e.g., at least 7 or 10) amino acids in length, or greater, are the preferred immunogens for the production of monoclonal or polyclonal antibodies. In one embodiment, an immunogenic polypeptide conjugate is also included as an immunogen. The peptides are used either in pure, partially pure or impure form. Suitable polypeptides and epitopes for target pathogens and sperm are well known in the art. Polynucleotide and polypeptide sequences are available in public sequence databases such as GENBANK®/GENPEPT®. Large numbers of antibodies that specifically bind to target cancer cell antigens have been described in the art and can be used as starting material to prepare the antibodies of the present invention. Alternatively, new antibodies can be raised against target antigens using the techniques described herein and well known in the art. [0077] Recombinant polypeptides are expressed in eukaryotic or prokaryotic cells and purified using standard techniques. The polypeptide, or a synthetic version thereof, is then injected into an animal capable of producing antibodies. Either monoclonal or polyclonal antibodies can be generated for subsequent use in immunoassays to measure the presence and quantity of the polypeptide. [0078] Methods of producing polyclonal antibodies are known to those of skill in the art. In brief, an immunogen, e.g., a purified or synthetic peptide, a peptide coupled to an appropriate carrier (e.g., glutathione-S-transferase, keyhole limpet hemocyanin, etc.), or a peptide incorporated into an immunization vector such as a recombinant vaccinia virus is optionally mixed with an adjuvant and animals are immunized with the mixture. The animal's immune response to the immunogen preparation is monitored by taking test bleeds and determining the titer of reactivity to the peptide of interest. When appropriately high titers of antibody to the immunogen are obtained, blood is collected from the animal and antisera are prepared. Further fractionation of the antisera to enrich for antibodies reactive to the peptide is performed where desired. Antibodies, including binding fragments and single chain recombinant versions thereof, against the polypeptides are raised by immunizing animals, e.g., using immunogenic conjugates comprising a polypeptide covalently attached (conjugated) to a carrier protein as described above. Typically, the immunogen of interest is a polypeptide of at least about 10 amino acids, in another embodiment the polypeptide is at least about 20 amino acids in length, and in another embodiment, the fragment is at least about 30 amino acids in length. The immunogenic conjugates are typically prepared by coupling the polypeptide to a carrier protein (e.g., as a fusion protein) or, alternatively, they are recombinantly expressed in an immunization vector. [0079] Monoclonal antibodies are prepared from cells secreting the desired antibody. These antibodies are screened for binding to normal or modified peptides, or screened for agonistic or antagonistic activity. Specific monoclonal and polyclonal antibodies will usually bind with a KD of at least about 50 mM, e.g., at least about 1 mM, e.g., at least about 0.1 mM or better. In some instances, it is desirable to prepare monoclonal antibodies from various mammalian hosts, such as rodents, lagomorphs, primates, humans, etc. Description of techniques for preparing such monoclonal antibodies are found in Kohler and Milstein 1975 Nature 256:495-497. Summarized briefly, this method proceeds by injecting an animal with an immunogen, e.g., an immunogenic peptide either alone or optionally linked to a carrier protein. The animal is then sacrificed, and cells taken from its spleen are fused with myeloma cells. The result is a hybrid cell or “hybridoma” that is capable of reproducing in vitro. The population of hybridomas is then screened to isolate individual clones, each of which secrete a single antibody species to the immunogen. In this manner, the individual antibody species obtained are the products of immortalized and cloned single B cells from the immune animal generated in response to a specific site recognized on the immunogenic substance. [0080] Alternative methods of immortalization include transformation with Epstein Barr Virus, oncogenes, or retroviruses, or other methods known in the art. Colonies arising from single immortalized cells are screened for production of antibodies of the desired specificity and affinity for the antigen, and yield of the monoclonal antibodies produced by such cells is enhanced by various techniques, including injection into the peritoneal cavity of a vertebrate (preferably mammalian) host. The polypeptides and antibodies of the present invention are used with or without modification, and include chimeric antibodies such as humanized murine antibodies. Other suitable techniques involve selection of libraries of recombinant antibodies in phage or similar vectors. See, Huse et al. 1989 Science 246:1275-1281; and Ward et al.1989 Nature 341:544-546. [0081] Antibodies specific to the target polypeptide can also be obtained by phage display techniques known in the art. [0082] The present invention additionally provides polynucleotides encoding the integrin antagonist (e.g., the antibody or a fragment or derivative thereof) of this invention. In some embodiments, the polynucleotides comprises a heavy chain encoding nucleotide sequence of SEQ ID NO:13 and a light chain encoding sequence of SEQ ID NO:14 or a sequence at least 90% identical thereto, e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% identical. In some embodiments, the polynucleotides comprises a heavy chain encoding nucleotide sequence of SEQ ID NO:15 and a light chain encoding sequence of SEQ ID NO:14 or a sequence at least 90% identical thereto, e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% identical. [0083] Further provided herein is a vector comprising the polynucleotide of the invention. Vectors include, but are not limited to, plasmid vectors, phage vectors, virus vectors, or cosmid vectors. [0084] In some embodiments, the present invention provides a host cell comprising the polynucleotide and/or vector of this invention. The host cell can be a eukaryotic or prokaryotic cell and may be used for expressing the antibody or a fragment or derivative thereof or other purposes. [0085] A further aspect of the invention relates to a composition comprising the integrin antagonist (e.g., the antibody or a fragment or derivative thereof) of the invention and a carrier. In some embodiments, the composition is a pharmaceutical composition and the carrier is a pharmaceutically acceptable carrier. [0086] In some embodiments, the pharmaceutical composition may further comprise an additional therapeutic agent, e.g., an antiviral agent. Antiviral agents include, without limitation, remdesivir, gimsilumab, REGN3048, REGEN3051, Kevzara, AdCOVID, EIDD- 2801, favipiravir (Avigan), umifenovir (Arbidol), lopinavir, ritonavir, kaletra (a combination of lopinavir and ritonavir), danoprevir+ritonavir, falidesivir, oseltamivir, emtricitabine/tenofovir, nelfinavir, or darunavir. In some embodiments, the additional therapeutic agent is one that inhibits the interaction of the RGD and/or RLD-dependent virus with a cell surface receptor used for attachment. For example, the binding of SARS-CoV-2 to ACE2 or the function of ACE2 may be inhibited, e.g., using hesperidin, curcumin, brazilin, galangin, nafamostat, desmethylcurcumin, bisdesmethylcurcumin, tangeretin, hesperetin, nobiletin, naringenin, brailein, aceto cavicol acetate, rutin, diosmin, apiin, diacetyl curcumin, rescinnamine, iloprost, prazosin, posaconazole, itraconazole, sulfasalazine, azlocillin, penicillin, cefsulodin, dabigatran etexilate, licoflavonol, cosmosiin, neohesperidin, mangostin, kouitchenside D, excoecariatoxin, phyllaemblicin G7, piceatannol, (E)-1-(2- hydroxy-4-methoxyphenyl)-3[3-[(E)-3-(2-hydroxy-4-methoxyphenyl)-3-oxoprop-1- enyl]phenyl]prop-2-en-1-one, and beta,beta'-(4-methoxy-1,3-phenylene)bis(2'-hydroxy-4',6'- dimethoxyacrylophenone. [0087] An additional aspect of the invention relates to a kit comprising the integrin antagonist (e.g., the antibody or a fragment or derivative thereof) of the invention or cells for producing the integrin antagonist (e.g., the antibody or a fragment or derivative thereof, peptide, or peptidomimetic) of the invention. In some embodiments, the kit can include multiple integrin antagonists and/or compositions containing such agents. In some embodiments, each of the multiple integrin antagonists provided in such a kit can specifically bind to a different antigen and/or inhibit a different RGD and/or RLD-dependent virus. In some embodiments, the kit can further include an additional active agent, e.g., an antiviral agent as would be known to one of skill in the art. In some embodiments, the kit can further include additional reagents, buffers, containers, instructions, etc. [0088] Another aspect of the invention relates to a method of inhibiting uptake of an RGD and/or RLD-dependent virus into a cell, comprising contacting the cell with an effective amount of an integrin antagonist (e.g., an antibody or a fragment or derivative thereof, peptide, or peptidomimetic), e.g., an integrin antagonist of the invention. In some embodiments, uptake of the virus is inhibited by at least 50%, 60%, 70%, 80%, 90%, 95%, or 99%. [0089] An additional aspect of the invention relates to a method of treating, inhibiting the severity of, or preventing an RGD and/or RLD-dependent virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an integrin antagonist (e.g., an antibody or a fragment or derivative thereof that binds integrin, peptide, or peptidomimetic), e.g., the integrin antagonist or the pharmaceutical composition of the invention, thereby treating, inhibiting the severity of, or preventing RGD and/or RLD- dependent virus infection. In some embodiments, the onset of infection is delayed relative to the timing in the absence of the method. In some embodiments, the severity of the infection, e.g., the number of symptoms or the severity of the symptoms, is reduced relative to the level in the absence of the method. In some embodiments, the percentage of subjects exposed to the virus that actually get infected is reduced relative to the percentage in the absence of the method. In some embodiments, the recovery from the infection is faster relative to the recovery in the absence of the method. [0090] In some embodiments, the subject is one that has tested positive for an RGD and/or RLD-dependent virus infection. In some embodiments, the subject is one that has or may have been exposed to an RGD and/or RLD-dependent virus. In some embodiments, the subject is one that will potentially be exposed to an RGD and/or RLD-dependent virus, e.g., health care workers, emergency medical technicians, law enforcement officers, medical research personnel, etc. [0091] In some embodiments, the subject may be one that is at increased risk of infection with an RGD and/or RLD-dependent virus due to underlying or preexisting conditions, e.g., conditions that increase the level of integrins on cells. In some embodiments, the subject has tissue injury or tissue inflammation, e.g., epithelial tissue injury or inflammation. In some embodiments, the subject has systemic or local inflammation, which is known to increase integrin levels. In one embodiment, the subject has lung inflammation, rendering the subject more susceptible to a respiratory virus such as SARS-CoV-2. In some embodiments, the subject has a cancer, which is known to increase integrin levels. [0092] Another aspect of the invention relates to a method of treating, inhibiting the severity of, or preventing an RGD and/or RLD-dependent virus infection in a subject in need thereof, comprising the steps of: a) identifying a subject that has a condition that increases integrin expression; and b) if the subject has a condition that increases integrin expression, administering to the subject a therapeutically effective amount of an integrin antagonist, thereby treating, inhibiting the severity of, or preventing RGD and/or RLD-dependent virus infection. [0093] The methods of the invention may be used for whole populations of subjects, or the majority of the population, to treat and/or prevent infection. In this scenario, the methods are likely to be effective in some but not all subjects. Alternatively, the step of identifying a subject that has a condition that increases integrin expression may be used to provide a subpopulation of subjects in which the methods of the present invention may be most effective. The method advantageously may also help identify the appropriate integrin to target, e.g., if a subject has a condition known to increase αvβ3 expression, an antagonist of αvβ3 would be the most appropriate treatment. [0094] The method may, e.g., prevent a subject from getting infected upon exposure to the virus, limit the infection to one that is asymptomatic or mildly symptomatic, limit the symptoms from progressing to severe levels, and/or allow a quicker recovery from the infection. In one embodiment, the method may prevent subjects from undergoing a downward spiral in which a subject has elevated integrin levels, gets infected with a virus in part because of the elevated integrin levels, the infection causes further tissue injury and/or inflammation causing integrin levels to further increase, allowing even more virus particles to enter cells, making the infection even more severe. [0095] Identifying a subject that has a condition that increases integrin expression may be carried out by identifying subjects that have certain conditions that are known to increase integrin expression, such as αvβ3. These include subjects have systemic or local tissue inflammation or tissue injury, e.g., epithelial tissue inflammation or injury, e.g., in the lungs or other organs. The subject may have a disease such as cancer. The subject may have an acute or chronic inflammatory disease, e.g., pancreatitis. The subject may have hypercytokinemia or “cytokine storm”, indicative of tissue injury and/or inflammation. For the lungs, the subject may be exposed to noxious chemicals, such as cigarette smoke or pollutants, leading to lung injury. The subject may have a lung disease that causes cellular injury and/or inflammation, such as asthma, emphysema, chronic obstructive pulmonary disorder, cystic fibrosis, etc. [0096] Identifying a subject that has a condition that increases integrin expression may be carried out by identifying subjects that have functional limitations indicative of tissue injury or inflammation. For example, subjects may be tested for oxygen saturation, e.g., using a finger pulse oximeter or measuring arterial blood gases, as an indication of lung injury and/or inflammation. An oxygen saturation of less than 95%, e.g., less than 90% or 85%, is indicative of a subject likely to have increased integrin expression levels in the lungs. [0097] In some embodiments, the virus is one that contains at least one RGD motif. In some embodiments, the virus is one that contains at least one RLD motif. In some embodiments, the virus is one that contains both at least one RGD motif and at least one RLD motif. An appropriate integrin antagonist may be selected for use in the methods of the invention based on the binding motifs present on the virus. An integrin antagonist targeted to integrins that bind the RGD motif may be used for RGD-containing viruses. An integrin antagonist targeted to integrins that bind the RLD motif may be used for RGD-containing viruses. If the virus contains two or more binding motifs, the methods of the invention may comprise using two or more integrin antagonists, including any combination of at least one targeted to RGD binding integrins and one targeted to RLD binding-integrins. For all viruses, an integrin antagonist that targets integrins that bind both binding motifs may be used, e.g., an αvβ3 antagonist. [0098] The RGD and/or RLD-dependent virus may be, without limitation, any of the virus families or viruses listed in Table 1. Table 1
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000028_0002
Figure imgf000028_0003
Figure imgf000028_0004
[0099] In some embodiments, the RGD and/or RLD-dependent virus is a coronavirus (e.g., SARS-CoV-2), adenovirus (e.g., type 2/5), human cytomegalovirus, Kaposi’s sarcoma- associated herpesvirus, Epstein-Barr virus, human immunodeficiency virus-1, HPS- associated hantavirus NY-1, Sin Nombre virus, rotavirus, echovirus type 1, echovirus type 9, foot-and-mouth disease virus, coxsackievirus A9, murine polyomavirus, vaccinia virus, West Nile virus, simian virus 40, Ross River virus, human papillomavirus, Zika virus, or Ebola virus. In one embodiment, the RGD-dependent virus is SARS-CoV-2. [0100] Examples of specific integrins associated with RGD and/or RLD-dependent viruses and the role of the integrins are shown in Table 2. This information allows one of skill in the art to select the appropriate integrin to target and the appropriate integrin antagonist (e.g., antibody or fragment or derivative thereof, peptide, or peptidomimetic) to use to protect against a given virus. Table 2
Figure imgf000029_0001
[0101] Additionally, viruses that contain RGD and/or RLD integrin binding motifs are shown in Table 3. Each of the sequences associated with the listed accession number is incorporated by reference herein in its entirety. It is notable that viruses containing both RGD and RLD motifs tend to be more severe, supporting the idea that increased integrin binding sites leads to increased avidity. Table 3
Figure imgf000030_0001
[0102] In certain embodiments, the methods of the invention may further comprise administering to the subject an additional therapeutic agent or treatment. In some embodiments, the additional therapeutic agent or treatment is an antiviral agent, e.g., remdesivir, gimsilumab, REGN3048, REGEN3051, Kevzara, AdCOVID, EIDD-2801, favipiravir (Avigan), umifenovir (Arbidol), lopinavir, ritonavir, kaletra (a combination of lopinavir and ritonavir), danoprevir+ritonavir, falidesivir, oseltamivir, emtricitabine/tenofovir, or darunavir. In some embodiments, the additional therapeutic agent is one that inhibits the interaction of the RGD and/or RLD-dependent virus with a cell surface receptor used for attachment. For example, the binding of SARS-CoV-2 to ACE2 or the function of ACE2 may be inhibited, e.g., using hesperidin, curcumin, brazilin, galangin, nafamostat, desmethylcurcumin, bisdesmethylcurcumin, tangeretin, hesperetin, nobiletin, naringenin, brailein, aceto cavicol acetate, rutin, diosmin, apiin, diacetyl curcumin, rescinnamine, iloprost, prazosin, posaconazole, itraconazole, sulfasalazine, azlocillin, penicillin, cefsulodin, dabigatran etexilate, licoflavonol, cosmosiin, neohesperidin, mangostin, kouitchenside D, excoecariatoxin, phyllaemblicin G7, piceatannol, (E)-1-(2- hydroxy-4-methoxyphenyl)-3[3-[(E)-3-(2-hydroxy-4-methoxyphenyl)-3-oxoprop-1- enyl]phenyl]prop-2-en-1-one, and beta,beta'-(4-methoxy-1,3-phenylene)bis(2'-hydroxy-4',6'- dimethoxyacrylophenone. [0103] In certain embodiments, integrin antagonist (e.g., the antibody or a fragment or derivative thereof) used in the methods of the present invention is administered directly to a subject. In some embodiments, the integrin antagonist will be suspended in a pharmaceutically-acceptable carrier (e.g., physiological saline) and administered orally or by intravenous infusion, or administered subcutaneously, intramuscularly, intrathecally, intraperitoneally, intrarectally, intravaginally, intranasally, intragastrically, intratracheally, or intrapulmonarily. In another embodiment, the intratracheal or intrapulmonary delivery can be accomplished using a standard nebulizer, jet nebulizer, wire mesh nebulizer, dry powder inhaler, or metered dose inhaler to deliver an aerosol. The agents can be delivered locally, e.g., directly to the site of the disease or disorder, such as lungs, kidney, or intestines, e.g., injected in situ into or near a tumor. The agents can be delivered to the mucosa. The dosage required depends on the choice of the route of administration; the nature of the formulation; the nature of the patient’s illness; the subject’s size, weight, surface area, age, and sex; other drugs being administered; and the judgment of the attending physician. Suitable dosages for each agent are in the range of 0.01-100 μg/kg. Wide variations in the needed dosage are to be expected in view of the variety of agents available and the differing efficiencies of various routes of administration. For example, oral administration would be expected to require higher dosages than administration by i.v. injection. Variations in these dosage levels can be adjusted using standard empirical routines for optimization as is well understood in the art. Administrations can be single or multiple (e.g., 2-, 3-, 4-, 6-, 8-, 10-; 20-, 50-, 100-, 150-, or more fold). Encapsulation of the compound in a suitable delivery vehicle (e.g., polymeric microparticles or nanoparticles or implantable devices) may increase the efficiency of delivery, particularly for oral delivery. [0104] By “pharmaceutically acceptable” it is meant a material that is not biologically or otherwise undesirable, i.e., the material can be administered to a subject without causing any undesirable biological effects such as toxicity. [0105] The formulations of the invention can optionally comprise medicinal agents, pharmaceutical agents, carriers, adjuvants, dispersing agents, diluents, and the like. [0106] The integrin antagonist of the invention can be formulated for administration in a pharmaceutical carrier in accordance with known techniques. See, e.g., Remington, The Science and Practice of Pharmacy (21* Ed.2006). In the manufacture of a pharmaceutical formulation according to the invention, the agent is typically admixed with, inter alia, an acceptable carrier. The carrier can be a solid or a liquid, or both, and may be formulated with the agent as a unit-dose formulation, for example, a capsule or vial, which can contain from 0.01 or 0.5% to 95% or 99% by weight of the agent. One or more agents can be incorporated in the formulations of the invention, which can be prepared by any of the well-known techniques of pharmacy. [0107] The formulations of the invention include those suitable for oral, rectal, topical, buccal (e.g., sub-lingual), vaginal, parenteral (e.g., subcutaneous, intramuscular including skeletal muscle, cardiac muscle, diaphragm muscle and smooth muscle, intradermal, intravenous, intraperitoneal), topical (i.e., both skin and mucosal surfaces, including airway surfaces), intranasal, transdermal, intraarticular, intrathecal, and inhalation administration, administration to the liver by intraportal delivery, as well as direct organ injection (e.g., into the liver, into the brain for delivery to the central nervous system, or into the pancreas) or injection into a body cavity. The most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular agent which is being used. [0108] For injection, the carrier will typically be a liquid, such as sterile pyrogen-free water, pyrogen-free phosphate-buffered saline solution, bacteriostatic water, or Cremophor EL[R] (BASF, Parsippany, N.J.). For other methods of administration, the carrier can be either solid or liquid. [0109] For oral administration, the agent can be administered in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. Agents can be encapsulated in gelatin capsules together with inactive ingredients and powdered carriers, such as glucose, lactose, sucrose, mannitol, starch, cellulose or cellulose derivatives, magnesium stearate, stearic acid, sodium saccharin, talcum, magnesium carbonate and the like. Examples of additional inactive ingredients that can be added to provide desirable color, taste, stability, buffering capacity, dispersion or other known desirable features are red iron oxide, silica gel, sodium lauryl sulfate, titanium dioxide, edible white ink and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric- coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. [0110] Formulations suitable for buccal (sub-lingual) administration include lozenges comprising the agent in a flavored base, usually sucrose and acacia or tragacanth; and pastilles comprising the agent in an inert base such as gelatin and glycerin or sucrose and acacia. [0111] Formulations of the present invention suitable for parenteral administration comprise sterile aqueous and non-aqueous injection solutions of the agent, which preparations are preferably isotonic with the blood of the intended recipient. These preparations can contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient. Aqueous and non-aqueous sterile suspensions can include suspending agents and thickening agents. The formulations can be presented in unit/dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or water-for-injection immediately prior to use. [0112] Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described. For example, in one aspect of the present invention, there is provided an injectable, stable, sterile composition comprising an agent of the invention, in a unit dosage form in a sealed container. The agent is provided in the form of a lyophilizate which is capable of being reconstituted with a suitable pharmaceutically acceptable carrier to form a liquid composition suitable for injection thereof into a subject. The unit dosage form typically comprises from about 1 mg to about 10 grams of the agent. When the agent is substantially water-insoluble, a sufficient amount of emulsifying agent which is pharmaceutically acceptable can be employed in sufficient quantity to emulsify the agent in an aqueous carrier. One such useful emulsifying agent is phosphatidyl choline. [0113] Formulations suitable for rectal administration are preferably presented as unit dose suppositories. These can be prepared by admixing the agent with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture. [0114] Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which can be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof. [0115] Formulations suitable for transdermal administration can be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration can also be delivered by iontophoresis (see, for example, Tyle, Pharm. Res.3:318 (1986)) and typically take the form of an optionally buffered aqueous solution of the compounds. Suitable formulations comprise citrate or bis/tris buffer (pH 6) or ethanol/water and contain from 0.1 to 0.2M of the compound. [0116] The agent can alternatively be formulated for nasal administration or otherwise administered to the lungs of a subject by any suitable means, e.g., administered by an aerosol suspension of respirable particles comprising the agent, which the subject inhales. The respirable particles can be liquid or solid. The term “aerosol” includes any gas-borne suspended phase, which is capable of being inhaled into the bronchioles or nasal passages. Specifically, aerosol includes a gas-borne suspension of droplets, as can be produced in a metered dose inhaler or nebulizer, or in a mist sprayer. Aerosol also includes a dry powder composition suspended in air or another carrier gas, which can be delivered by insufflation from an inhaler device, for example. See Ganderton & Jones, Drug Delivery to the Respiratory Tract, Ellis Horwood (1987); Gonda (1990) Critical Reviews in Therapeutic Drug Carrier Systems 6:273-313; and Raeburn et al., J. Pharmacol. Toxicol. Meth.27:143 (1992). Aerosols of liquid particles comprising the agent can be produced by any suitable means, such as with a pressure-driven aerosol nebulizer or an ultrasonic nebulizer, as is known to those of skill in the art. See, e.g., U.S. Patent No.4,501,729. Aerosols of solid particles comprising the agent can likewise be produced with any solid particulate medicament aerosol generator, by techniques known in the pharmaceutical art. [0117] Alternatively, one can administer the compound in a local rather than systemic manner, for example, in a depot or sustained-release formulation. [0118] Further, the present invention provides liposomal formulations of the agents disclosed herein and salts thereof. The technology for forming liposomal suspensions is well known in the art. When the compound or salt thereof is an aqueous-soluble salt, using conventional liposome technology, the same can be incorporated into lipid vesicles. In such an instance, due to the water solubility of the agent, the agent will be substantially entrained within the hydrophilic center or core of the liposomes. The lipid layer employed can be of any conventional composition and can either contain cholesterol or can be cholesterol-free. When the compound or salt of interest is water-insoluble, again employing conventional liposome formation technology, the salt can be substantially entrained within the hydrophobic lipid bilayer which forms the structure of the liposome. In either instance, the liposomes which are produced can be reduced in size, as through the use of standard sonication and homogenization techniques. [0119] The liposomal formulations containing the agent can be lyophilized to produce a lyophilizate which can be reconstituted with a pharmaceutically acceptable carrier, such as water, to regenerate a liposomal suspension. [0120] In the case of water-insoluble agents, a pharmaceutical composition can be prepared containing the water-insoluble agent, such as for example, in an aqueous base emulsion. In such an instance, the composition will contain a sufficient amount of pharmaceutically acceptable emulsifying agent to emulsify the desired amount of the agent. Particularly useful emulsifying agents include phosphatidyl cholines and lecithin. [0121] In particular embodiments, the integrin antagonist is administered to the subject in a therapeutically effective amount, as that term is defined above. Dosages of pharmaceutically active agents can be determined by methods known in the art, see, e.g., Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa). The therapeutically effective dosage of any specific agent will vary somewhat from agent to agent, and patient to patient, and will depend upon the condition of the patient and the route of delivery. As a general proposition, a dosage from about 0.1 to about 50 mg/kg will have therapeutic efficacy, with all weights being calculated based upon the weight of the agent. Toxicity concerns at the higher level can restrict intravenous dosages to a lower level such as up to about 10 mg/kg, with all weights being calculated based upon the weight of the agent. A dosage from about 10 mg/kg to about 50 mg/kg can be employed for oral administration. Typically, a dosage from about 0.5 mg/kg to 5 mg/kg can be employed for intramuscular injection. Particular dosages are about 1 ^mol/kg to 50 ^mol/kg, and more particularly to about 22 ^mol/kg and to 33 ^mol/kg of the agent for intravenous or oral administration, respectively. [0122] In particular embodiments of the invention, more than one administration (e.g., two, three, four, or more administrations) can be employed over a variety of time intervals (e.g., hourly, daily, weekly, monthly, etc.) to achieve therapeutic effects. [0123] The present invention finds use in veterinary and medical applications. Suitable subjects include both avians and mammals, with mammals being preferred. The term “mammal” as used herein includes, but is not limited to, humans, primates, bovines, ovines, caprines, equines, felines, canines, lagomorphs, etc. Human subjects include neonates, infants, juveniles, and adults. The subject may be one in need of the methods of the invention, e.g., a subject that has or is suspected of having an infection or likely to be exposed to a virus. The subject may be a laboratory animal, e.g., an animal model of a disease. [0124] The present invention is more particularly described in the following examples that are intended as illustrative only since numerous modifications and variations therein will be apparent to those skilled in the art. Example 1 [0125] The presence of an RGD sequence in the S protein of the SARS-CoV-2 virus that was not present in the closely related SARS virus raised the question of whether an alpha V integrin may participate in the attachment or entry of the SARS-CoV-2 virus (Sigrist, Bridge et al. 2020). However, this same sequence has also been suggested to play a potential inhibitory role for virus uptake (Luan, Lu et al.2020). While modeling predicts that the RGD sequence in SARS-CoV-2 and KGD sequences in other coronaviruses including SARS is expected to be accessible to integrins, there is also a KGD sequence on ACE2. As a consequence, it has been suggested that integrin binding to RGD/KGD on the virus and integrin binding to KDG on ACE2 would interfere with ACE2-mediated virus entry (Luan, Lu et al.2020). To test this directly, human cervical carcinoma cells with ectopic expression of ACE2 (HeLa-ACE2) were exposed to live SARS-CoV-2 virus for 24 hours in the presence of vehicle control or increasing concentrations of various anti-integrin antibodies, and viral infection was evaluated by immunostaining fixed and permeabilized cells with sera from a convalescent COVID-19 patient. Using this assay, SARS-CoV-2 infection for HeLA-ACE2 cells with endogenous β3 expression was dose-dependently blocked by an antibody recognizing the alpha V-containing integrin αvβ3 (FIG.1A), but not antibodies that recognize the β1 integrin subunit or the αvβ5 integrin heterodimer (FIG.1B). These findings suggest that integrin αvβ3 (which recognizes both RGD and RLD motifs such as those within the SARS-CoV-2 S protein) contributes to at least one step of the viral infection process in human cells. In HeLa-ACE2 cells, the antibodies targeting integrins αvβ5 or β1 showed relatively lower activity over the same dose range. Interestingly, the peptide antagonists showed only moderate inhibition even at relatively high doses, suggesting that the role of integrin αvβ3 in SARS-CoV-2 entry may be RGD-independent. Together, these findings provide proof of principle that antibodies, including those that target integrin αvβ3, may provide a therapeutic opportunity to halt or lessen disease progression in a patient who is exposed to SARS-CoV-2. Considering that this approach targets the host cell rather than the virus, it is likely that the role of αvβ3 in viral entry and its value as a therapeutic target will depend on the level of integrin αvβ3 expression on a given host cell. Example 2 [0126] Integrin αvβ3 is largely absent on all cell types in the healthy adult, but its expression and function emerges during tissue remodeling events including wound healing, angiogenesis, or cancer (Weis and Cheresh 2011). There is new evidence that the severity of progression of COVID-19 may be related to a “cytokine storm” that emerges during infection (Ye, 2020). This state has been shown to arise in patients who did not show severe clinical manifestations during early stages of disease, but who rapidly and suddenly deteriorate. It was therefore considered whether the expression of integrin αvβ3 may be upregulated in lung epithelial cells exposed to various forms of injury or inflammatory stimuli. [0127] For a mouse model of lung injury, there is the expected absence of integrin β3 expression on epithelial cells in the adult mouse lung at baseline (Day 0) (FIG.2A). Analysis of lung tissue from mice two days after treatment with naphthalene showed that the injury induced a rapid gain of integrin β3 expression (Day 2) that was then downregulated as the lung epithelium is repaired (Day 14). Similarly, primary human lung epithelial cells showed a dose-dependent increase in ITGB3 mRNA in response to serum deprivation, a form of nutrient stress (FIG. 2B). Finally, integrin β3 was upregulated in human transformed lung cells exposed to the inflammatory cytokine TGFβ1 (FIG.2C). Taken together, these findings suggest that normal or transformed lung epithelial cells that lack integrin αvβ3 expression in the resting state have the capacity to rapidly gain expression of this integrin in response to injury, cellular stress, or inflammatory cytokines such as TGFβ1. [0128] It was next considered whether the upregulation of β3 expression in response to stress or inflammatory stimuli may occur in another tissue type. Therefore, integrin β3 protein expression was examined by immunohistochemical staining for a pancreas disease spectrum microarray slide, a tissue for which the chronically inflamed state of pancreatitis represents a major risk factor for pancreatic cancer (Pierro, Minici et al.2003, DiMagno and DiMagno 2016). While undetectable in normal adult pancreatic tissues, integrin β3 expression not only increased from mild to chronic pancreatitis, but also from low to high grade pancreatic ductal adenocarcinoma (FIG.3). [0129] For primary mouse pancreatic acinar grown in vitro, treatment with cytokines TNFα + CCL5 induced the expression of Itgb3 mRNA and protein expression along with a loss of acinar markers (FIG 4A, left panel), a reprogramming feature linked to the formation of precancerous PanINs and a risk factor for pancreatic cancer (Wang, Xie et al.2019). Mouse acinar cells also upregulated integrin β3 and downregulate acinar markers following exposure to caerulein (FIG.4A, right panel), an experimental agent used to induce pancreatitis in mice. [0130] Next, primary human pancreatic stellate cells were treated with a variety of inflammatory cytokines and analyzed for ITGB3 mRNA expression after 48 and 72 hours. For this model, the largest increases in ITGB3 expression were observed for IL-1β as well as TGFβ (FIG.4B), a cytokine known to induce β3 expression in a variety of cell types (Pierro, Minici et al.2003, Mori, Kodaira et al.2015, Chen, Chang et al.2018). Primary human pancreatic epithelial cells also upregulated the integrin β3 subunit, but not other integrin β subunits, in response to TNFα as well as dose-dependently increase ITGB3 mRNA in response to nutrient stress (FIG.4C). These results highlight how normal pancreatic cells that are negative for integrin β3 in adult tissues gain expression of this integrin when exposed to pro-inflammatory stimuli known to enhance the emergence of pancreatic cancer. In fact, pancreatic cancer cell lines with low endogenous expression of integrin β3 also upregulated its expression after 72 hours of culture in serum-free media (FIG.4D), suggesting that multiple cell types within the pancreas, including cancer cells, respond to inflammatory cytokines or cellular stress by upregulating integrin β3. [0131] Taken together, these examples reveal that cells from epithelial tissues such as the lung and pancreas are generally lacking in expression of integrin αvβ3 in the healthy, resting state, but that they rapidly respond to injury, inflammation, or cellular stress by upregulating mRNA expression of the β3 subunit leading to expression of the intact avb3 heterodimer. While integrin alpha V is generally expressed by most cell types in the body, the modulation of β3 expression in response to various stimuli suggests a role for β3 integrin as a “stress- inducible” gene that when heterodimerized with alpha V can be broadly induced as a mechanism to mitigate stress by a variety of cell types. Considering the “cytokine storm” that emerges during infection (Ye, 2020), and the response of primary human lung epithelial cells, endothelial cells, and fibroblasts to upregulate ITGB3 expression in response to a cocktail of cytokines that includes those highly enriched in COVID-19 patients (including INFγ, TNFα, and IL-6), it is possible that early stages of SARS-CoV-2 infection trigger the upregulation of integrin β3 expression that serves as an internalization receptor for viral infection. Patients with underlying health conditions, especially those that involve elevated cytokines or lung inflammation, may be especially susceptible to SARS-CoV-2 infection and/or at high risk for severe disease progression. Example 3 [0132] Integrins are cell surface receptors that interact with a variety of ligands via binding to specific sequences or motifs found on extracellular matrix proteins, such as the Arg-Gly- Asp (RGD) motif recognized by alpha V-containing integrins (Ruoslahti and Pierschbacher 1987). Aside from their role as cell-matrix receptors, integrins can also bind to non-matrix ligands to mediate cell-cell interactions or to serve as receptors for soluble factors including growth factors or hormones (LaFoya, Munroe et al.2018). Some functions of integrins have also been exploited by cancer cells to mitigate environmental stresses, immune surveillance, and to escape the effects of cancer therapy (Seguin, Desgrosellier et al.2015), and by bacteria and viruses to support various aspects of infection (LaFoya, Munroe et al.2018). In particular, the alpha V containing integrins αvβ3 and αvβ5 were discovered to promote adenovirus internalization, but not virus attachment (Wickham, Mathias et al.1993, Nemerow, Cheresh et al.1994, Wickham, Filardo et al.1994). Subsequent work revealed that viruses utilize a variety of integrins for cell attachment, entry, or both (Hussein, Walker et al. 2015). While many viruses contain one or more RGD motifs that serve as integrin- binding sites, disrupting RGD binding can prevent infection of certain viruses but not others. Examples of viruses that utilize integrin αvβ3 for internalization but do not rely on RGD binding include the hantaviruses NY-1 and Sin Nombre Virus (Gavrilovskaya, Shepley et al. 1998) and rotaviruses (Guerrero, Méndez et al.2000). [0133] Integrins recognize certain binding motifs to achieve receptor-ligand specificity. Of particular interest are the binding motifs recognized by integrin αvβ3, the receptor that this invention links to both cytokine storm and SARS-CoV-2 infection. By screening phage libraries, integrin αvβ3 was shown to recognize two motifs, Arg-Gly-Asp (RGD) and Arg- Leu-Asp (RLD) (Ruoslahti 1996). While, the RGD motif is recognized by a variety of αv and β1 containing integrins, the RLD and KRLDGS motifs are recognized by only two integrins, αvβ3 and αMβ2 (Ruoslahti 1996). αvβ3 and αMβ2 are the only integrins that bind to fibrinogen, and this occurs through recognition of an RLD motif (Altieri, Plescia et al. 1993). [0133] An RGD motif has been identified in the SARS-CoV-2 S protein that was not present in other coronaviruses including SARS, but there have been opposing views on whether this motif enhances or prevents viral infection (Luan, Lu et al.2020, Sigrist, Bridge et al. 2020). In addition, the Leu-Asp-Ile (LDI) motif is present in the S proteins of both SARS-CoV-2 and SARS (Tresoldi, Sangiuolo et al.). FIG.5 shows the existence of an RLD motif in the SARS-CoV-2 S protein at amino acids 983-985. Whereas the RGD sequence is located on the S1 subunit within the receptor binding domain (RBD), the RLD sequence is located within the heptad repeat 1 (HR1) domain of the S2 subunit that participates in membrane fusion. [0134] The RGD motif is a unique sequence found in SARS-CoV-2 that is not present in other betacoronavirus family members (FIG.6). In contrast, the RLD motif is highly conserved across betacoronavirus S proteins, except for one exception (the bat coronavirus HKU9) (FIG.7). This particular region of the HR1 that contains the RLD motif is highly conserved among coronaviruses from diverse species, as well as sequences from many individuals with COVID-19 (Xia, Liu et al.2020). If viruses generally utilize an RLD motif for fusion or internalization, agents targeting this mechanism may have broad applications across many viral families. The combination of both RGD and RLD motifs may provide a mechanistic explanation for the aggressive nature of SARS-CoV-2. [0135] 3D structural analysis of the SARS-CoV-2 virus (FIG.8) reveals that one RGD motif is be exposed in the up promoter, while somewhat concealed on the two down promoters, to participate in receptor binding. An RLD motif located at the apex of the HR1 region may act as a pedestal upon which the RBD from an adjacent down promoter sits. This region could impact the metastability of the spike protein. Once the S1/S2 subunits are cleaved, the exposed RLD binding motif may interact with integrin αvβ3 to facilitate membrane fusion and/or virus internalization. Indeed, integrins are known to be robustly activated by binding to multivalent ligands, such as the conformation of RGD/RLD motifs predicted by the 3D model. Integrin αvβ3 may be particularly important for SARS-CoV-2 viral infection by virtue of its ability to recognize both the RGD and RLD binding motifs. [0136] In the context of COVID-19, the cytokine storm and excessive inflammatory state of the lung that occurs in some patients with rapidly progressing disease may exacerbate viral infection by placing integrin αvβ3 on the surface of cells lining the lung or other organs to render them highly susceptible to infection. For patients with chronic lung or pancreatic inflammatory conditions, these findings suggest that expression of integrin αvβ3 may increase the risk and severity of infection with the SARS-CoV-2 virus that utilizes integrin αvβ3 for viral internalization (FIG. 9A). As shown in FIG.9B, an alpha V integrin such as integrin αvβ3 can become activated and clustered when the SARS-CoV-2 or another RGD and/or RLD-dependent virus engages receptors such as ACE2 that mediates initial virus attachment. An activated alpha V integrin would then facilitate virus internalization to enable viral replication. The right side of FIG.9B provides a potential therapeutic intervention using an integrin antagonizing peptide, organic molecule, or function-blocking antibody to block the interaction between the virus and integrin, thereby preventing viral entry. We have provided evidence that integrin αvβ3 blockade using a humanized monoclonal antibody is able to block viral infection of cultured human cells. This work provides a strong rationale for further testing and development of integrin antagonists as anti-viral agents. Such an approach may have particular efficacy in patients with pre-existing or COVID-19-induced inflammation or tissue injury that is expected to enrich for integrin αvβ3 expression. [0136] The foregoing is illustrative of the present invention, and is not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein. References: Altieri, D. C., J. Plescia and E. F. Plow (1993). "The structural motif glycine 190-valine 202 of the fibrinogen gamma chain interacts with CD11b/CD18 integrin (alpha M beta 2, Mac-1) and promotes leukocyte adhesion." Journal of Biological Chemistry 268(3): 1847-1853. Chen, C. A., J. M. Chang, E. E. Chang, H. C. Chen and Y. L. Yang (2018). "TGF-β1 modulates podocyte migration by regulating the expression of integrin-β1 and -β3 through different signaling pathways." Biomed Pharmacother 105: 974-980. Coutard, B., C. Valle, X. de Lamballerie, B. Canard, N. G. Seidah and E. Decroly (2020). "The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade." Antiviral Res 176: 104742. DiMagno, E. P. and M. J. DiMagno (2016). "Chronic Pancreatitis: Landmark Papers, Management Decisions, and Future." Pancreas 45(5): 641-650. Gavrilovskaya, I. N., M. Shepley, R. Shaw, M. H. Ginsberg and E. R. Mackow (1998). "β<sub>3</sub> integrins mediate the cellular entry of hantaviruses that cause respiratory failure." Proceedings of the National Academy of Sciences 95(12): 7074-7079. Guerrero, C. A., E. Méndez, S. Zárate, P. Isa, S. López and C. F. Arias (2000). "Integrin α<sub>v</sub>β<sub>3</sub> mediates rotavirus cell entry." Proceedings of the National Academy of Sciences 97(26): 14644-14649. Hussein, H. A., L. R. Walker, U. M. Abdel-Raouf, S. A. Desouky, A. K. Montasser and S. M. Akula (2015). "Beyond RGD: virus interactions with integrins." Arch Virol 160(11): 2669- 2681. LaFoya, B., J. A. Munroe, A. Miyamoto, M. A. Detweiler, J. J. Crow, T. Gazdik and A. R. Albig (2018). "Beyond the Matrix: The Many Non-ECM Ligands for Integrins." Int J Mol Sci 19(2). Leslie, M. (2020). "COVID-19 More Frequent, Severe in Cancer Patients." Cancer Discovery Advance Online April 20, 2020. Li, E., S. L. Brown, D. G. Stupack, X. S. Puente, D. A. Cheresh and G. R. Nemerow (2001). "Integrin alpha(v)beta1 is an adenovirus coreceptor." J Virol 75(11): 5405-5409. Li, E., D. Stupack, R. Klemke, D. A. Cheresh and G. R. Nemerow (1998). "Adenovirus endocytosis via alpha(v) integrins requires phosphoinositide-3-OH kinase." J Virol 72(3): 2055-2061. Li, W., G. Wang, W. Liang, K. Kang, K. Guo and Y. Zhang (2014). "Integrin β3 is required in infection and proliferation of classical swine fever virus." PLoS One 9(10): e110911. Luan, J., Y. Lu, S. Gao and L. Zhang (2020). "A potential inhibitory role for integrin in the receptor targeting of SARS-CoV-2." Journal of Infection. Mori, S., M. Kodaira, A. Ito, M. Okazaki, N. Kawaguchi, Y. Hamada, Y. Takada and N. Matsuura (2015). "Enhanced Expression of Integrin alphavbeta3 Induced by TGF-beta Is Required for the Enhancing Effect of Fibroblast Growth Factor 1 (FGF1) in TGF-beta- Induced Epithelial-Mesenchymal Transition (EMT) in Mammary Epithelial Cells." PLoS One 10(9): e0137486. Nemerow, G. R., D. A. Cheresh and T. J. Wickham (1994). "Adenovirus entry into host cells: a role for alpha(v) integrins." Trends Cell Biol 4(2): 52-55. Pierro, E., F. Minici, O. Alesiani, L. D. Monica, M. M. Anna, S. Muncuso and A. Lanzone (2003). "In vitro regulation of beta1 and beta3 integrin subunits in endometrial epithelial cells from normal endometrium." Am J Reprod Immunol 49(6): 373-376. Ruoslahti, E. (1996). "RGD and other recognition sequences for integrins." Annu Rev Cell Dev Biol 12: 697-715. Ruoslahti, E. and M. D. Pierschbacher (1987). "New perspectives in cell adhesion: RGD and integrins." Science 238(4826): 491-497. Seguin, L., J. S. Desgrosellier, S. M. Weis and D. A. Cheresh (2015). "Integrins and cancer: regulators of cancer stemness, metastasis, and drug resistance." Trends Cell Biol 25(4): 234- 240. Seguin, L., S. Kato, A. Franovic, M. F. Camargo, J. Lesperance, K. C. Elliott, M. Yebra, A. Mielgo, A. M. Lowy, H. Husain, T. Cascone, L. Diao, J. Wang, I. I. Wistuba, J. V. Heymach, S. M. Lippman, J. S. Desgrosellier, S. Anand, S. M. Weis and D. A. Cheresh (2014). "An integrin beta(3)-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition." Nat Cell Biol 16(5): 457-468. Sigrist, C. J. A., A. Bridge and P. Le Mercier (2020). "A potential role for integrins in host cell entry by SARS-CoV-2." Antiviral Research 177: 104759. Stewart, P. L. and G. R. Nemerow (2007). "Cell integrins: commonly used receptors for diverse viral pathogens." Trends in Microbiology 15(11): 500-507. Tai, W., L. He, X. Zhang, J. Pu, D. Voronin, S. Jiang, Y. Zhou and L. Du (2020). "Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine." Cell Mol Immunol. Tresoldi, I., C. F. Sangiuolo, V. Manzari and A. Modesti (2020). "SARS-COV-2 and infectivity: Possible increase in infectivity associated to integrin motif expression." Journal of Medical Virology n/a(n/a). Wang, K., T. Guan, D. A. Cheresh and G. R. Nemerow (2000). "Regulation of adenovirus membrane penetration by the cytoplasmic tail of integrin beta5." J Virol 74(6): 2731-2739. Wang, L., D. Xie and D. Wei (2019). "Pancreatic Acinar-to-Ductal Metaplasia and Pancreatic Cancer." Methods Mol Biol 1882: 299-308. Weis, S. M. and D. A. Cheresh (2011). "αv Integrins in Angiogenesis and Cancer." Cold Spring Harbor Perspectives in Medicine 1(1). Wickham, T. J., E. J. Filardo, D. A. Cheresh and G. R. Nemerow (1994). "Integrin alpha v beta 5 selectively promotes adenovirus mediated cell membrane permeabilization." J Cell Biol 127(1): 257-264. Wickham, T. J., P. Mathias, D. A. Cheresh and G. R. Nemerow (1993). "Integrins alpha v beta 3 and alpha v beta 5 promote adenovirus internalization but not virus attachment." Cell 73(2): 309-319. Xia, S., M. Liu, C. Wang, W. Xu, Q. Lan, S. Feng, F. Qi, L. Bao, L. Du, S. Liu, C. Qin, F. Sun, Z. Shi, Y. Zhu, S. Jiang and L. Lu (2020). "Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion." Cell Research 30(4): 343- 355. Yan, S., H. Sun, X. Bu and G. Wan (2020). "An Evolutionary RGD Motif in the Spike Protein of SARS-CoV-2 may Serve as a Potential High Risk Factor for Virus Infection?" Preprints 2020020447. Zhang, J. L., J. L. Wang, N. Gao, Z. T. Chen, Y. P. Tian and J. An (2007). "Up-regulated expression of beta3 integrin induced by dengue virus serotype 2 infection associated with virus entry into human dermal microvascular endothelial cells." Biochem Biophys Res Commun 356(3): 763-768. Zhou, P., X.-L. Yang, X.-G. Wang, B. Hu, L. Zhang, W. Zhang, H.-R. Si, Y. Zhu, B. Li, C.- L. Huang, H.-D. Chen, J. Chen, Y. Luo, H. Guo, R.-D. Jiang, M.-Q. Liu, Y. Chen, X.-R. Shen, X. Wang, X.-S. Zheng, K. Zhao, Q.-J. Chen, F. Deng, L.-L. Liu, B. Yan, F.-X. Zhan, Y.-Y. Wang, G.-F. Xiao and Z.-L. Shi (2020). "A pneumonia outbreak associated with a new coronavirus of probable bat origin." Nature 579(7798): 270-273. Zhu, Z., P. Mesci, J. A. Bernatchez, R. C. Gimple, X. Wang, S. T. Schafer, H. I. Wettersten, S. Beck, A. E. Clark, Q. Wu, B. C. Prager, L. J. Y. Kim, R. Dhanwani, S. Sharma, A. Garancher, S. M. Weis, S. C. Mack, P. D. Negraes, C. A. Trujillo, L. O. Penalva, J. Feng, Z. Lan, R. Zhang, A. W. Wessel, S. Dhawan, M. S. Diamond, C. C. Chen, R. J. Wechsler-Reya, F. H. Gage, H. Hu, J. L. Siqueira-Neto, A. R. Muotri, D. A. Cheresh and J. N. Rich (2019). "Zika Virus Targets Glioblastoma Stem Cells through a SOX2-Integrin α(v)β(5) Axis." Cell stem cell: S1934-5909(1919)30471-30470. Sequences: hLM609-hIgG4-S228P (humanized LM609) Heavy chain (SEQ ID NO:1)
Figure imgf000044_0001
Light chain (SEQ ID NO:2)
Figure imgf000044_0002
Fab domain of heavy chain (SEQ ID NO:3)
Figure imgf000044_0003
Fc and hinge domain of heavy chain (SEQ ID NO:4)
Figure imgf000045_0001
shLM609-hIgG1-WT (super-humanized LM609_7) Fab domain of heavy chain (SEQ ID NO:5)
Figure imgf000045_0002
Light chain (SEQ ID NO:6)
Figure imgf000045_0003
shLM609-hIgG1-WT (super-humanized JC7U) Fab domain of heavy chain (SEQ ID NO:7)
Figure imgf000045_0004
Light chain (SEQ ID NO:8)
Figure imgf000045_0005
hLM609-hIgG1-WT (humanized LM609) Heavy chain (SEQ ID NO:9)
Figure imgf000045_0006
Figure imgf000046_0001
Light chain (SEQ ID NO:10)
Figure imgf000046_0002
mAb LM609-mIgG1-kappa Heavy chain (SEQ ID NO:11)
Figure imgf000046_0003
Light chain (SEQ ID NO:12)
Figure imgf000046_0004
hLM609-hIgG4-S228P (humanized LM609) Heavy chain encoding sequence (SEQ ID NO:13)
Figure imgf000046_0005
Figure imgf000047_0001
Light chain encoding sequence (SEQ ID NO:14)
Figure imgf000047_0002
hLM609-hIgG1-WT (humanized LM609) Heavy chain encoding sequence (SEQ ID NO:15)
Figure imgf000047_0003
Figure imgf000048_0001
SARS-CoV-2 S protein (SEQ ID NO:16)
Figure imgf000048_0002
shLM609-hIgG1-LALA PG YTE heavy chain (SEQ ID NO:17)
Figure imgf000048_0003
Figure imgf000049_0001

Claims

CLAIMS What is claimed is: 1. A method of inhibiting uptake of an RGD and/or RLD-dependent virus into a cell, comprising contacting the cell with an effective amount of an integrin antagonist that binds integrin and inhibits uptake of an RGD and/or RLD-dependent virus into a cell.
2. The method of claim 1, wherein uptake of the virus is inhibited by at least 50%, 60%, 70%, 80%, 90%, 95%, or 99%.
3. A method of treating, inhibiting the severity of, or preventing an RGD and/or RLD- dependent virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an integrin antagonist that binds integrin and inhibits uptake of an RGD and/or RLD-dependent virus into a cell, thereby treating, inhibiting the severity of, or preventing RGD and/or RLD-dependent virus infection.
4. The method of claim 3, wherein the subject has a condition that increases integrin expression.
5. The method of claim 4, wherein the subject has tissue injury or tissue inflammation.
6. The method of claim 5, wherein the subject has systemic or local inflammation.
7. The method of claim 6, wherein the subject has lung inflammation.
8. A method of treating, inhibiting the severity of, or preventing an RGD and/or RLD- dependent virus infection in a subject in need thereof, comprising the steps of: a) identifying a subject that has a condition that increases integrin expression; and b) if the subject has a condition that increases integrin expression, administering to the subject a therapeutically effective amount of an integrin antagonist, thereby treating, inhibiting the severity of, or preventing RGD and/or RLD-dependent virus infection.
9. The method of any one of claims 3-8, wherein the subject has tested positive for an RGD and/or RLD-dependent virus infection.
10. The method of any one of claims 3-8, wherein the subject has or may have been exposed to an RGD and/or RLD-dependent virus.
11. The method of any one of claims 3-8, wherein the subject will potentially be exposed to an RGD and/or RLD-dependent virus.
12. The method of any one of claims 3-11, wherein the integrin antagonist is administered systemically.
13. The method of claim 12, wherein the integrin antagonist is administered intravenously or subcutaneously.
14. The method of any one of claims 3-11, wherein the integrin antagonist is administered locally.
15. The method of claim 14, wherein the integrin antagonist is administered to the lungs.
16. The method of claim 15, wherein the integrin antagonist is administered to the lungs by aerosol delivery.
17. The method of claim 14, wherein the integrin antagonist is administered to the mucosa.
18. The method of claim 17, wherein the integrin antagonist is administered intranasally.
19. The method of any one of claims 3-18, further comprising administering to the subject an additional therapeutic agent or treatment.
20. The method of claim 19, wherein the additional therapeutic agent or treatment is an antiviral agent.
21. The method of claim 20, wherein the antiviral agent is remdesivir, gimsilumab, REGN3048, REGEN3051, Kevzara, AdCOVID, EIDD-2801, favipiravir (Avigan), umifenovir (Arbidol), lopinavir, ritonavir, kaletra (a combination of lopinavir and ritonavir), danoprevir+ritonavir, falidesivir, oseltamivir, emtricitabine/tenofovir, darunavir, hesperidin, curcumin, brazilin, galangin, nafamostat, desmethylcurcumin, bisdesmethylcurcumin, tangeretin, hesperetin, nobiletin, naringenin, brailein, aceto cavicol acetate, rutin, diosmin, apiin, diacetyl curcumin, rescinnamine, iloprost, prazosin, posaconazole, itraconazole, sulfasalazine, azlocillin, penicillin, cefsulodin, dabigatran etexilate, licoflavonol, cosmosiin, neohesperidin, mangostin, kouitchenside D, excoecariatoxin, phyllaemblicin G7, piceatannol, (E)-1-(2-hydroxy-4-methoxyphenyl)-3[3-[(E)-3-(2-hydroxy-4-methoxyphenyl)-3-oxoprop-1- enyl]phenyl]prop-2-en-1-one, or beta,beta'-(4-methoxy-1,3-phenylene)bis(2'-hydroxy-4',6'- dimethoxyacrylophenone.
22. The method of any one of claims 3-21, wherein the subject is a human.
23. The method of any one of claims 1-22, wherein the RGD and/or RLD-dependent virus is a coronavirus, adenovirus, human cytomegalovirus, Kaposi’s sarcoma-associated herpesvirus, Epstein-Barr virus, human immunodeficiency virus-1, HPS-associated hantavirus NY-1, Sin Nombre virus, rotavirus, echovirus type 1, echovirus type 9, foot-and- mouth disease virus, coxsackievirus A9, murine polyomavirus, vaccinia virus, West Nile virus, Japanese encephalitis virus, Tick-borne encephalitis virus, Yellow fever virus, Dengue fever virus, simian virus 40, Ross River virus, human papillomavirus, Zika virus, or Ebola virus.
24. The method of claim 23, wherein the coronavirus is SARS-CoV-2, SARS-CoV, or MERS-CoV.
25. The method of any one of claims 1-24, wherein the integrin antagonist binds any integrin.
26. The method of any one of claims 1-24, wherein the integrin antagonist specifically binds integrin αv.
27. The method of any one of claims 1-24, wherein the integrin antagonist specifically binds integrin β3.
28. The method of any one of claims 1-24, wherein the integrin antagonist specifically binds integrin αvβ3.
29. The method of any one of claims 1-24, wherein the integrin antagonist specifically binds integrin αvβ5.
30. The method of any one of claims 1-24, wherein the integrin antagonist specifically binds integrin αMβ2.
31. The method of any one of claims 1-24, wherein the integrin antagonist specifically binds integrin αIIbβ3,
32. The method of any one of claims 1-31, wherein the integrin antagonist is a peptide, a cyclic peptide, a peptide analog, or a peptidomimetic.
33. The method of any one of claims 1-31, wherein the integrin antagonist is an antibody or a fragment or derivative thereof.
34. The method of claim 33, wherein the antibody or a fragment or derivative thereof is a chimeric antibody or a fragment or derivative thereof.
35. The method of claim 33, wherein the antibody or a fragment or derivative thereof is a humanized antibody or a fragment or derivative thereof.
36. The method of any one of claims 33-35, wherein the antibody or a fragment or derivative thereof is a bispecific antibody or a fragment or derivative thereof.
37. The method of claim 36, wherein the bispecific antibody or a fragment or derivative thereof binds a second antigen present on a cell comprising an integrin.
38. The method of claim 37, wherein the second antigen is angiotensin converting enzyme 2 (ACE2) or an antigen derived from a neutralizing or non-neutralizing antibody isolated from a patient who has recovered from COVID-19.
39. The method of any one of claims 33-38, wherein the antibody or a fragment or derivative thereof comprises a Fab domain of an IgG antibody.
40. The method of claim 39, wherein the antibody or a fragment or derivative thereof comprises a Fab domain of an IgG4 antibody.
41. The method of claim 40, wherein the Fab domain comprises the amino acid sequence of the light chain of hLM609-hIgG4-S228P (SEQ ID NO:2) and the Fab portion of the heavy chain of hLM609-hIgG4-S228P (SEQ ID NO:3) or a sequence at least 90% identical thereto.
42. The method of claim 40, wherein the Fab domain comprises the amino acid sequence of the Fab portion of the heavy chain of LM609_7 (SEQ ID NO:5) and the light chain of LM609_7 (SEQ ID NO:6), the Fab portion of the heavy chain of JC7U (SEQ ID NO:7) and the light chain of JC7U (SEQ ID NO:8), or a sequence at least 90% identical thereto.
43. The method of any one of claims 33-42, wherein the antibody or a fragment or derivative thereof comprises a Fc domain that does not significantly engage natural killer cells.
44. The method of any one of claims 33-43, wherein the Fc domain does not significantly engage lymphocytes.
45. The method of any one of claims 33-44, wherein the Fc domain specifically binds an Fc-gamma receptor.
46. The method of claim 45, wherein the Fc domain specifically binds Fc-gamma receptor I (FcγRI, CD64).
47. The method of claim 45, wherein the Fc domain specifically binds Fc-gamma receptor IIA (FcγRIIA, CD32) or Fc-gamma receptor IIIA (FcγRIIIA, CD16a).
48. The method of any one of claims 33-47, wherein the Fc domain does not bind Fc- gamma receptor IIB (FcγRIIB).
49. The method of any one of claims 33-48, wherein the antibody or a fragment or derivative thereof comprises an Fc domain of an IgG antibody.
50. The method of claim 49, wherein the antibody or a fragment or derivative thereof comprises an Fc domain of an IgG1 antibody.
51. The method of claim 49, wherein the antibody or a fragment or derivative thereof comprises an Fc domain of an IgG4 antibody.
52. The method of any one of claims 33-48, wherein the antibody or a fragment or derivative thereof comprises an Fc domain of an IgA or IgE antibody.
53. The method of any one of claims 33-52, wherein the Fc domain is linked a hinge domain of an antibody.
54. The method of claim 53, wherein the antibody or a fragment or derivative thereof comprises the amino acid sequence of the heavy chain Fc domain and hinge domain of hLM609-hIgG4-S228P (SEQ ID NO:4) or a sequence at least 90% identical thereto.
55. The method of any one of claims 33-54, wherein the antibody or a fragment or derivative thereof comprises a S228P mutation (Eu numbering system) in the hinge region.
56. The method of claim 55, wherein the antibody or a fragment or derivative thereof comprises the amino acid sequence of the hLM609-hIgG4-S228P heavy chain (SEQ ID NO:1) and light chain (SEQ ID NO:2) or a sequence at least 90% identical thereto.
57. The method of any one of claims 33-56, wherein the antibody or a fragment or derivative thereof is etaracizumab/MEDI-522 (ABEGRIN™), MEDI-523 (VITAXIN™), intetumumab/CNTO 95, or an antibody or a fragment or derivative thereof comprising a sequence at least 90% identical thereto.
58. The method of any one of claims 33-57, wherein the antibody or a fragment or derivative thereof comprises a mutation selected from: a) S239D/A330L/I332E; b) I332E; c) G236A/S239D/I332E; d) G236A; e) N297A/E382V/M428I; f) M252Y/S254T/T256E; g) Q295R/L328W/A330V/P331A/I332Y/E382V/M428I; h) L234A/L235A/P329G; i) M428L/N434S; j) L234A/L235A/P331S; k) L234A/L235A/P329G/M252Y/S254T/T256E; l) S298A/E333A/K334/A; m) S239D/I332E; n) G236A/S239D/A330L/I332E; o) S239D/I332E/G236A; p) L234Y/G236W/S298A; q) F243L/R292P/Y300L/V305I/P396L; r) K326W/E333S; s) K326A/E333A; t) K326M/E333S; u) C221D/D222C; v) S267E/H268F/S324W; w) H268F/S324W; x) E345R y) R435H; z) N434A; aa) M252Y/S254T/T256E; ab) M428L/N434S; ac) T252L/T/253S/T254F; ad) E294delta/T307P/N434Y; ae) T256N/A378V/S383N/N434Y; af) E294delta ag) L235E; ah) L234A/L235A; ai) S228P/L235E; aj) P331S/L234E/L225F; ak) D265A; al) G237A; am) E318A; an) E233P; ao) G236R/L328R; ap) H268Q/V309L/A330S/P331S; aq) L234A/L235A/G237A/P238S/H268A/A330S/P331S; ar) A330L; as) D270A; at) K322A; au) P329A; av) P331A; aw V264A; ax) F241A; ay) N297A or G or N az) S228P/F234A/L235A; or ba) any combination of a) to az); (Eu numbering system).
59. An integrin antagonist that binds integrin and inhibits uptake of an RGD and/or RLD- dependent virus into a cell.
60. The integrin antagonist of claim 59, wherein the integrin antagonist specifically binds integrin αv.
61. The integrin antagonist of claim 59, wherein the integrin antagonist specifically binds integrin β3.
62. The integrin antagonist of claim 59, wherein the integrin antagonist specifically binds integrin αvβ3.
63. The integrin antagonist of claim 59, wherein the integrin antagonist specifically binds integrin αvβ5.
64. The integrin antagonist of claim 59, wherein the integrin antagonist specifically binds integrin αMβ2.
65. The integrin antagonist of claim 59, wherein the integrin antagonist specifically binds integrin αIIbβ3,
66. The integrin antagonist of any one of claims 59-65, wherein the integrin antagonist is a peptide, a cyclic peptide, a peptide analog, or a peptidomimetic.
67. The integrin antagonist of any one of claims 59-65, wherein the integrin antagonist is an antibody or a fragment or derivative thereof.
68. The integrin antagonist of claim 67, wherein the antibody or a fragment or derivative thereof is a chimeric antibody or a fragment or derivative thereof.
69. The integrin antagonist of claim 67 or 68, wherein the antibody or a fragment or derivative thereof is a humanized antibody or a fragment or derivative thereof.
70. The integrin antagonist of any one of claims 67-69, wherein the antibody or a fragment or derivative thereof is a bispecific antibody or a fragment or derivative thereof.
71. The integrin antagonist of claim 70, wherein the bispecific antibody or a fragment or derivative thereof binds a second antigen present on a cell comprising an integrin.
72. The integrin antagonist of claim 71, wherein the second antigen is angiotensin converting enzyme 2 (ACE2) or an antigen derived from a neutralizing or non-neutralizing antibody isolated from a patient who has recovered from COVID-19.
73. The integrin antagonist of any one of claims 67-72, wherein the antibody or a fragment or derivative thereof comprises a Fab domain of an IgG antibody.
74. The integrin antagonist of claim 73, wherein the antibody or a fragment or derivative thereof comprises a Fab domain of an IgG4 antibody.
75. The integrin antagonist of claim 74, wherein the Fab domain comprises the amino acid sequence of the light chain of hLM609-hIgG4-S228P (SEQ ID NO:2) and the Fab portion of the heavy chain of hLM609-hIgG4-S228P (SEQ ID NO:3) or a sequence at least 90% identical thereto.
76. The integrin antagonist of claim 74, wherein the Fab domain comprises the amino acid sequence of the Fab portion of the heavy chain of LM609_7 (SEQ ID NO:5) and the light chain of LM609_7 (SEQ ID NO:6), the Fab portion of the heavy chain of JC7U (SEQ ID NO:7) and the light chain of JC7U (SEQ ID NO:8), or a sequence at least 90% identical thereto.
77. The integrin antagonist of any one of claims 67-76, wherein the antibody or a fragment or derivative thereof comprises a Fc domain that does not significantly engage natural killer cells.
78. The integrin antagonist of any one of claims 67-77, wherein the Fc domain does not significantly engage lymphocytes.
79. The integrin antagonist of any one of claims 67-78, wherein the Fc domain specifically binds an Fc-gamma receptor.
80. The integrin antagonist of claim 79, wherein the Fc domain specifically binds Fc- gamma receptor I (FcγRI, CD64).
81. The integrin antagonist of claim 79, wherein the Fc domain specifically binds Fc- gamma receptor IIA (FcγRIIA, CD32) or Fc-gamma receptor IIIA (FcγRIIIA, CD16a).
82. The integrin antagonist of any one of claims 67-81, wherein the Fc domain does not bind Fc-gamma receptor IIB (FcγRIIB).
83. The integrin antagonist of any one of claims 67-82, wherein the antibody or a fragment or derivative thereof comprises an Fc domain of an IgG antibody.
84. The integrin antagonist of claim 83, wherein the antibody or a fragment or derivative thereof comprises an Fc domain of an IgG1 antibody.
85. The integrin antagonist of claim 83, wherein the antibody or a fragment or derivative thereof comprises an Fc domain of an IgG4 antibody.
86. The integrin antagonist of any one of claims 67-82, wherein the antibody or a fragment or derivative thereof comprises an Fc domain of an IgA or IgE antibody.
87. The integrin antagonist of any one of claims 67-86, wherein the Fc domain is linked a hinge domain of an antibody.
88. The integrin antagonist of claim 87, wherein the antibody or a fragment or derivative thereof comprises the amino acid sequence of the heavy chain Fc domain and hinge domain of hLM609-hIgG4-S228P (SEQ ID NO:4) or a sequence at least 90% identical thereto.
89. The integrin antagonist of any one of claims 67-88, wherein the antibody or a fragment or derivative thereof comprises a S228P mutation (Eu numbering system) in the hinge region.
90. The integrin antagonist of claim 89, wherein the antibody or a fragment or derivative thereof comprises the amino acid sequence of the hLM609-hIgG4-S228P heavy chain (SEQ ID NO:1) and light chain (SEQ ID NO:2) or a sequence at least 90% identical thereto.
91. The integrin antagonist of any one of claims 67-90, wherein the antibody or a fragment or derivative thereof is etaracizumab/MEDI-522 (ABEGRIN™), MEDI-523 (VITAXIN™), intetumumab/CNTO 95, or an antibody or a fragment or derivative thereof comprising a sequence at least 90% identical thereto.
92. The integrin antagonist of any one of claims 67-91, wherein the antibody or a fragment or derivative thereof comprises a mutation selected from: a) S239D/A330L/I332E; b) I332E; c) G236A/S239D/I332E; d) G236A; e) N297A/E382V/M428I; f) M252Y/S254T/T256E; g) Q295R/L328W/A330V/P331A/I332Y/E382V/M428I; h) L234A/L235A/P329G; i) M428L/N434S; j) L234A/L235A/P331S; k) L234A/L235A/P329G/M252Y/S254T/T256E; l) S298A/E333A/K334/A; m) S239D/I332E; n) G236A/S239D/A330L/I332E; o) S239D/I332E/G236A; p) L234Y/G236W/S298A; q) F243L/R292P/Y300L/V305I/P396L; r) K326W/E333S; s) K326A/E333A; t) K326M/E333S; u) C221D/D222C; v) S267E/H268F/S324W; w) H268F/S324W; x) E345R y) R435H; z) N434A; aa) M252Y/S254T/T256E; ab) M428L/N434S; ac) T252L/T/253S/T254F; ad) E294delta/T307P/N434Y; ae) T256N/A378V/S383N/N434Y; af) E294delta ag) L235E; ah) L234A/L235A; ai) S228P/L235E; aj) P331S/L234E/L225F; ak) D265A; al) G237A; am) E318A; an) E233P; ao) G236R/L328R; ap) H268Q/V309L/A330S/P331S; aq) L234A/L235A/G237A/P238S/H268A/A330S/P331S; ar) A330L; as) D270A; at) K322A; au) P329A; av) P331A; aw V264A; ax) F241A; ay) N297A or G or N az) S228P/F234A/L235A; or ba) any combination of a) to az); (Eu numbering system).
93. A polynucleotide encoding the integrin antagonist of any one of claims 67-92.
94. A vector comprising the polynucleotide of claim 93.
95. A host cell comprising the polynucleotide of claim 93 or the vector of claim 94.
96. A composition comprising the integrin antagonist of any one of claims 67-92 and a carrier.
97. A pharmaceutical composition comprising the integrin antagonist of any one of claims 67-96 and a pharmaceutically acceptable carrier.
98. The pharmaceutical composition of claim 97, which is suitable for systemic delivery to a subject.
99. The pharmaceutical composition of claim 98, which is suitable for intravenous or subcutaneous delivery.
100. The pharmaceutical composition of claim 97, which is suitable for local delivery to a subject.
101. The pharmaceutical composition of claim 100, which is suitable for delivery to the lungs.
102. The pharmaceutical composition of claim 101, which is an aerosol.
103. The pharmaceutical composition of claim 102, wherein the aerosol comprises liquid particles or solid particles.
104. The pharmaceutical composition of claim 100, which is suitable for mucosal delivery.
105. The pharmaceutical composition of claim 100, which is suitable for intranasal delivery.
106. The pharmaceutical composition of any one of claims 97-105, further comprising an additional therapeutic agent.
107. The pharmaceutical composition of claim 106, wherein the additional therapeutic agent is an antiviral agent.
108. The pharmaceutical composition of claim 107, wherein the antiviral agent is remdesivir, gimsilumab, REGN3048, REGEN3051, Kevzara, AdCOVID, EIDD-2801, favipiravir (Avigan), umifenovir (Arbidol), lopinavir, ritonavir, kaletra (a combination of lopinavir and ritonavir), danoprevir+ritonavir, falidesivir, oseltamivir, emtricitabine/tenofovir, darunavir, hesperidin, curcumin, brazilin, galangin, nafamostat, desmethylcurcumin, bisdesmethylcurcumin, tangeretin, hesperetin, nobiletin, naringenin, brailein, aceto cavicol acetate, rutin, diosmin, apiin, diacetyl curcumin, rescinnamine, iloprost, prazosin, posaconazole, itraconazole, sulfasalazine, azlocillin, penicillin, cefsulodin, dabigatran etexilate, licoflavonol, cosmosiin, neohesperidin, mangostin, kouitchenside D, excoecariatoxin, phyllaemblicin G7, piceatannol, (E)-1-(2-hydroxy-4-methoxyphenyl)-3[3- [(E)-3-(2-hydroxy-4-methoxyphenyl)-3-oxoprop-1-enyl]phenyl]prop-2-en-1-one, or beta,beta'-(4-methoxy-1,3-phenylene)bis(2'-hydroxy-4',6'-dimethoxyacrylophenone.
109. A kit comprising the integrin antagonist of any one of claims 67-92.
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