WO2021226560A1 - Antibodies against sars-cov-2 - Google Patents
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
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- 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
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
- C07K16/1002—Coronaviridae
- C07K16/1003—Severe acute respiratory syndrome coronavirus 2 [SARS‐CoV‐2 or Covid-19]
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- 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
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- 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
- A61K2039/507—Comprising a combination of two or more separate antibodies
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
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- 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
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
- C07K2317/41—Glycosylation, sialylation, or fucosylation
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- 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'
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
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- 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
- C07K2317/72—Increased effector function due to an Fc-modification
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Definitions
- Figures 3A-3F show results from neutralization of infection assays using certain antibodies against SARS-CoV-2 pseudotyped virus. Monoclonal antibodies isolated from patients who recovered from SARS-CoV-2 infection were expressed recombinantly and tested in neutralization assays against murine leukemia virus (MLV) pseudotyped with SARS-CoV-2 Spike protein.
- Figure 3 A shows results for three antibodies.
- Figures 3B-3F each show results for four antibodies. Antibodies were tested at concentrations indicated in the x-axis. Boxes on the right side of each figure, where present, indicate the calculated IC50 for the indicated antibody.
- MMV murine leukemia virus
- Antibodies were tested in neutralization assays against murine leukemia virus (MLV) pseudotyped with SARS-CoV-2 Spike protein.
- Figure 11 A shows results for monoclonal antibodies S2X193 and S2X195.
- Figure 1 IB shows results for monoclonal antibodies S2X219 and S2X244.
- Figure 11C shows results for monoclonal antibodies S2X246 and S2X256.
- Figure 1 ID shows results for monoclonal antibody S2X278.
- the x-axis shows the total concentration of antibody. Calculated IC50, IC80, and IC90 values (expressed as ng/ml) are shown in the box on the right side of each figure.
- Figures 19A-19E show results from neutralization of infection assays using certain monoclonal antibodies. Antibodies were tested in neutralization assays against murine leukemia virus (MLV) pseudotyped with SARS-CoV-2 Spike protein.
- Figure 19A shows results for monoclonal antibodies S2X149 and S2X179.
- Figure 19B shows results for monoclonal antibody S2D65.
- Figure 19C shows results for monoclonal antibody S2D97.
- Figure 19D shows results for monoclonal antibody S2D106.
- Figure 19E shows results for monoclonal antibody S2H101. The x-axis shows the total concentration of antibody.
- Figures 20A and 20B show binding of human monoclonal antibody S2X149 and comparator antibody S309-v2 LS (VH amino acid sequence of SEQ ID NO.:342, VL amino acid sequence of SEQ ID NO.:346; CDRH1-H3 and L1-L3 as set forth in SEQ ID NOs.:343-345 and 347-349, respectively; expressed as rlgGl with M428L and N434S Fc mutations) to SARS-CoV-1 Spike protein, SARS-CoV-1 Spike protein RBD, and SARS-CoV-2 Spike protein RBD.
- Figures 28A and 28B show activation of FcyRIIIa (V158 allele) ( Figure 28A) and FcyRIIa (H131 allele) ( Figure 28B) by certain monoclonal antibodies. Data show experiments using CHO target cells expressing SARS CoV2 S protein.
- Figures 30A and 30B show binding of certain antibodies against SARS-CoV-2 RBD, SARS-CoV-2 S protein, and SARS-CoV-1 RBD.
- Figures 31A and 31B show binding of antibody S2D106 to SARS-CoV-2 RBD in the presence of different concentrations of AAPH (2,2'-azobis(2-amidinopropane) dihydrochloride) or after UV irradiation. Both AAPH and UV radiation are used to induce oxidation stress in the antibody.
- Figure 31 A shows binding of S2D106 to RBD as measured by indirect ELISA.
- Figures 32A-32C show neutralization of infection (pseudovirus particles) by S2E12 and engineered variants thereof (see Table 22 in Example 9 for VH and VL sequences of S2E12 antibodies).
- Figure 32A and Figure 32B show results from two repetitions of the same experiment.
- Figure 32C shows results for a third experiment using S2E12 and other variants thereof.
- Figure 47 shows live SARS-CoV-2 infection levels in wild-type HEK293T cells and in HEK293T cells engineered to overexpress DC-SIGN, L-SIGN, SIGLEC-1, or ACE2. Infection was determined using a recombinant S protein with luciferase reporter. See Example 14.
- Figure 49 shows neutralization by monoclonal antibody S2E12-LS (VH of SEQ ID NO.:399, VL of SEQ ID NO.:403n M428L/N434S Fc mutations) oflive SARS- CoV-2 infection in HEK293T cells engineered to overexpress DC-SIGN, L-SIGN, SIGLEC-1, or ACE2.
- antibody S2E12 includes M428L and N434S Fc mutations. See Example 14.
- Figures 50A and 50B shows expression analysis of receptor proteins including CD209 (DC-SIGN) and SIGLEC proteins in several cell types. Size of dot correlates with the percentage of cells of the indicated type that express the protein, and intensity of dot shading correlates with the expression level of the protein. See Example 14.
- Figure 52 shows infection by SARS-CoV-2 pseudotyped VSV in HEK293T cells, HeLa cells, and MRC5 cells transiently transduced with lentivirus to express DC- SIGN, L-SIGN, SIGLEC-1, or ACE2. Uninfected cells are shown as negative control. See Example 14.
- Figure 53 shows neutralization of infection by S2E12.
- Figure 54 shows neutralization of infection by S2E12.
- a panel of 7 cell lines (HeLa, 293T (wt), Vero E6, Huh7, 293T ACE2, MRC 5 - ACE2-TMPRS S2, A549- ACE2-TMPRSS2 clone 5, A549-ACE2-TMPRSS2 clone 10) were infected with VSV pseudotyped with the SARS-CoV-2 spike protein in the presence of S2E12-LS. Luciferase signal was quantified 24h post infection.
- Figure 55 shows binding of purified, fluorescently-labeled SARS-CoV-2 spike protein binding to each of 7 cell lines as quantified by flow cytometry.
- HeLa and 239T WT cells had he lowest MFIs, followed by Huh7 and VeroE6 cells.
- Figures 56A and 56B show that both S309 (VH SEQ ID NO : 139; VL SEQ ID NO. : 143) or the combination of S309 and S2E12-LS provide robust in vivo protection against SARS-CoV-2 challenge.
- Syrian hamsters were injected with the indicated amount of mAh 48 hours before intra-nasal challenge with SARS-CoV-2.
- Fig. 56A top row, shows quantification of viral RNA in the lungs 4 days post-infection.
- Fig 56A, middle row shows quantification of replicating virus in lung homogenates harvested 4 days post infection using a TCID50 assay.
- Fig 56A, bottom row shows histological score of the lung tissue assessed 4 days post infection.
- Fig. 56B shows that the concentration of mAbs measured in the serum before infection (day 0) inversely correlates with the viral RNA load in the lung 4 days post infection. See Example 14.
- Figure 64 shows the distribution and expression of ACE2, DC-SIGN (CD209), L-SIGN (CLEC4M), and SIGLEC1 in the human lung cell atlas.
- Figure 66 shows analysis of major cell types with detectable SARS-CoV-2 genome in bronchoalveolar lavage fluid or sputum of severe COVID-19 patients. The cumulative fraction of cells (y-axis) with detected viral RNA per cell up to the corresponding logCPM (log(counts per million); x-axis) is shown for each of the indicated cell types.
- Figure 68 shows the correlation of receptor transcript counts (y-axis of each plot) with SARS-CoV-2 RNA counts (x-axis of each plot) in macrophages and in secretory cells. Correlation is based on counts before log transformation from Ren et al.
- Figure 70 shows the results of trans-infection, where VSV-SARS-CoV-2 viral adsorption was performed in the presence or absence of an anti-SIGLECl blocking antibody.
- Figure 71 shows neutralization of SARS-CoV-2 infection of Vero-E6 cells by antibodies S309, S2E12-LS, and S2X33.
- S2E12-LS comprises the VH sequence of SEQ ID NO:399 and the VL sequence of SEQ ID NO:403, and M428L/N434S in Fc.
- Figure 73 shows quantification of binding of purified, fluorescently-labeled SARS-CoV-2 spike protein or RBD to the indicated cell lines, as measured by flow cytometry.
- A indicates cell line overexpressing ACE2;
- T indicates cell line overexpressing TMPRSS2.
- Figure 74 shows quantification of cellular ACE2 and TMPRSS2 transcripts in the indicated cell lines, as measured by RT-qPCR.
- A indicates cell line overexpressing ACE2;
- T indicates cell line overexpressing TMPRSS2.
- Figure 75 shows neutralization of SARS-CoV-2-Nluc infection by antibodies S309, S2E12-LS, or S2X333. Each of the seven cell lines indicated was tested. Luciferase signal was quantified 24 hours post infection.
- Figure 76 shows neutralization of VSV-SARS-CoV-2 pseudovirus infection by antibodies S309, S2E12-LS, or S2X333. Each of the seven cell lines indicated was tested. Luciferase signal was quantified 24 hours post infection.
- Figure 77 shows cell-cell fusion of CHO cells expressing SARS-CoV-2 S protein (CHO-S) on the plasma membrane in the absence (top panels) or presence (bottom panels) of 5 ⁇ g/ml of antibody S2E12-LS, as measured by immune- fluorescence. Nuclei were stained with Hoechst dye; cytoplasm was stained with CellTracker Green.
- Figure 78 shows CHO-S cell-cell fusion mediated by different spike-specific antibodies. Fusion was quantified using the Cytation 5 Imager (BioTek) and an object detection protocol that detected nuclei as objects and measured their size. The area of the objects in fused cells divided by the total area of all the objects multiplied by 100 provides the percentage of fused cells.
- Figure 87 shows analysis of binding of antibodies targeting DC/L-SIGN, DC- SIGN, SIGLEC1, or ACE2 on HEK293T cells stably over-expressing the respective attachment receptor, as measured by immunofluorescence.
- Figure 93 shows analysis of the protective effect of antibody S309 (left panels) or a combination of antibodies S309 and S2E12-LS (right panels) against SARS-CoV-2 challenge in Syrian hamsters. Top panels show histopathological score of lung tissue assessed four days post infection. Bottom panels show efficacy plots based on the correlation between the level of serum antibody measured at the time of infection (x- axis) and the level of SARS-CoV-2 viral RNA measured in lungs (y-axis) on day four after infection. The dotted lines represent the EC50 and EC90 for viral reduction.
- Figure 95 shows analysis of the role of host effector function in SARS-CoV-2 challenge.
- Syrian hamsters were injected with the indicated amount (mg/kg) of hamster IgG2a S309, either wt or Fc silenced (S309-N297A).
- Top panel shows quantification of viral RNA in the lung 4 days post infection.
- Center panel shows quantification of replicating virus in the lung 4 days post infection.
- Bottom panel shows histopathological score in the lung 4 days post infection.
- Control animals (white symbols) were injected with 4 mg/kg unrelated control isotype antibody.
- SARS-CoV-2 also referred to herein as "Wuhan seafood market phenomia virus", or “Wuhan coronavirus” or “Wuhan CoV”, or “novel CoV”, or “nCoV”, or “2019 nCoV”, or “Wuhan nCoV” is a betacoronavirus believed to be of lineage B (sarbecovirus).
- SARS-CoV-2 was first identified in Wuhan, Hubei province, China, in late 2019 and spread within China and to other parts of the world by early 2020. Symptoms of SARS-CoV-2 infection include fever, dry cough, and dyspnea.
- SARS-CoV-2 comprises a "spike” or surface (“S") type I transmembrane glycoprotein containing a receptor binding domain (RBD).
- SARS-CoV-2 comprises a "spike” or surface (“S") type I transmembrane glycoprotein containing a receptor binding domain (RBD).
- RBD is believed to mediate entry of the lineage B SARS coronavirus to respiratory epithelial cells by binding to the cell surface receptor angiotensin-converting enzyme 2 (ACE2).
- ACE2 cell surface receptor angiotensin-converting enzyme 2
- RBM receptor binding motif
- B.1.351 also include two other mutations in the RBD domain of SARS-CoV2 spike protein, K417N and E484K (Tegally, H., et al., Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. medRxiv, 2020: p. 2020.12.21.20248640).
- SARS-CoV-2 variants include the Lineage B.1.1.28, which was first reported in Brazil; the Variant P.1, lineage B.1.1.28 (also known as 20J/501Y.V3), which was first reported in Japan; Variant L452R, which was first reported in California in the United States (Pan American Health Organization, Epidemiological update: Occurrence of variants of SARS-CoV-2 in the Americas, January 20, 2021, available at reliefweb.int/sites/reliefweb.int/files/resources/2021-jan-20-phe-epi-update-SARS- CoV-2.pdf).
- SARS-CoV-2 variants include a SARS CoV-2 of clade 19A; SARS CoV-2 of clade 19B; a SARS CoV-2 of clade 20A; a SARS CoV-2 of clade 20B; a SARS CoV-2 of clade 20C; a SARS CoV-2 of clade 20D; a SARS CoV-2 of clade 20E (EU1); a SARS CoV-2 of clade 20F; a SARS CoV-2 of clade 20G; and SARS CoV-2 Bl.1.207; and other SARS CoV-2 lineages described in Rambaut, A., et al ., A dynamic nomenclature proposal for SARS-CoV-2 lineages to assist genomic epidemiology.
- any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.
- any number range recited herein relating to any physical feature, such as polymer subunits, size or thickness are to be understood to include any integer within the recited range, unless otherwise indicated.
- the term “about” means ⁇ 20% of the indicated range, value, or structure, unless otherwise indicated. It should be understood that the terms “a” and “an” as used herein refer to “one or more" of the enumerated components. The use of the alternative (e.g.
- a protein domain, region, or module e.g., a binding domain
- a protein "consists essentially of a particular amino acid sequence when the amino acid sequence of a domain, region, module, or protein includes extensions, deletions, mutations, or a combination thereof (e.g., amino acids at the amino- or carboxy -terminus or between domains) that, in combination, contribute to at most 20% (e.g., at most 15%, 10%, 8%, 6%, 5%, 4%, 3%, 2% or 1%) of the length of a domain, region, module, or protein and do not substantially affect (i.e., do not reduce the activity by more than 50%, such as no more than 40%, 30%, 25%, 20%, 15%, 10%, 5%, or 1%) the activity of the domain(s), region(s
- Amino acid analogs refer to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a-carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g, homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g, norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid.
- Amino acid mimetics refer to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid.
- variant proteins, peptides, and polypeptides comprise or consist of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identical to an amino acid sequence of a defined or reference amino acid sequence as described herein.
- Nucleic acid molecules include polyribonucleic acid (RNA), which includes mRNA, microRNA, siRNA, viral genomic RNA, and synthetic RNA, and polydeoxyribonucleic acid (DNA), which includes cDNA, genomic DNA, and synthetic DNA, either of which may be single or double stranded. If single-stranded, the nucleic acid molecule may be the coding strand or non-coding (anti-sense) strand.
- a nucleic acid molecule encoding an amino acid sequence includes all nucleotide sequences that encode the same amino acid sequence. Some versions of the nucleotide sequences may also include intron(s) to the extent that the intron(s) would be removed through co- or post-transcriptional mechanisms. In other words, different nucleotide sequences may encode the same amino acid sequence as the result of the redundancy or degeneracy of the genetic code, or by splicing.
- Variants of nucleic acid molecules of this disclosure are also contemplated. Variant nucleic acid molecules are at least 70%, 75%, 80%, 85%, 90%, and are preferably 95%, 96%, 97%, 98%, 99%, or 99.9% identical a nucleic acid molecule of a defined or reference polynucleotide as described herein, or that hybridize to a polynucleotide under stringent hybridization conditions of 0.015M sodium chloride, 0.0015M sodium citrate at about 65-68°C or 0.015M sodium chloride, 0.0015M sodium citrate, and 50% formamide at about 42°C. Nucleic acid molecule variants retain the capacity to encode a binding domain thereof having a functionality described herein, such as binding a target molecule.
- Percent sequence identity refers to a relationship between two or more sequences, as determined by comparing the sequences. Preferred methods to determine sequence identity are designed to give the best match between the sequences being compared. For example, the sequences are aligned for optimal comparison purposes (e.g ., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment). Further, non-homologous sequences may be disregarded for comparison purposes. The percent sequence identity referenced herein is calculated over the length of the reference sequence, unless indicated otherwise. Methods to determine sequence identity and similarity can be found in publicly available computer programs.
- isolated means that the material is removed from its original environment (e.g, the natural environment if it is naturally occurring).
- a naturally occurring nucleic acid or polypeptide present in a living animal is not isolated, but the same nucleic acid or polypeptide, separated from some or all of the co-existing materials in the natural system, is isolated.
- nucleic acid could be part of a vector and/or such nucleic acid or polypeptide could be part of a composition (e.g, a cell lysate), and still be isolated in that such vector or composition is not part of the natural environment for the nucleic acid or polypeptide.
- gene means the segment of DNA or RNA involved in producing a polypeptide chain; in certain contexts, it includes regions preceding and following the coding region (e.g ., 5’ untranslated region (UTR) and 3’ UTR) as well as intervening sequences (introns) between individual coding segments (exons).
- regions preceding and following the coding region e.g ., 5’ untranslated region (UTR) and 3’ UTR
- intervening sequences introns between individual coding segments (exons).
- a functional variant of a polypeptide or encoded polypeptide of this disclosure has "similar binding,” “similar affinity” or “similar activity” when the functional variant displays no more than a 50% reduction in performance in a selected assay as compared to the parent or reference polypeptide, such as an assay for measuring binding affinity (e.g., Biacore® or tetramer staining measuring an association (Ka) or a dissociation (KD) constant).
- binding affinity e.g., Biacore® or tetramer staining measuring an association (Ka) or a dissociation (KD) constant.
- the term "engineered,” “recombinant,” or “non-natural” refers to an organism, microorganism, cell, nucleic acid molecule, or vector that includes at least one genetic alteration or has been modified by introduction of an exogenous or heterologous nucleic acid molecule, wherein such alterations or modifications are introduced by genetic engineering (i.e., human intervention).
- Genetic alterations include, for example, modifications introducing expressible nucleic acid molecules encoding functional RNA, proteins, fusion proteins or enzymes, or other nucleic acid molecule additions, deletions, substitutions, or other functional disruption of a cell’s genetic material. Additional modifications include, for example, non-coding regulatory regions in which the modifications alter expression of a polynucleotide, gene, or operon.
- heterologous or non-endogenous or exogenous refers to any gene, protein, compound, nucleic acid molecule, or activity that is not native to a host cell or a subject, or any gene, protein, compound, nucleic acid molecule, or activity native to a host cell or a subject that has been altered.
- Heterologous, non-endogenous, or exogenous includes genes, proteins, compounds, or nucleic acid molecules that have been mutated or otherwise altered such that the structure, activity, or both is different as between the native and altered genes, proteins, compounds, or nucleic acid molecules.
- a nucleic acid molecule or portion thereof native to a host cell will be considered heterologous to the host cell if it has been altered or mutated, or a nucleic acid molecule native to a host cell may be considered heterologous if it has been altered with a heterologous expression control sequence or has been altered with an endogenous expression control sequence not normally associated with the nucleic acid molecule native to a host cell.
- heterologous can refer to a biological activity that is different, altered, or not endogenous to a host cell.
- operably linked refers to the association of two or more nucleic acid molecules on a single nucleic acid fragment so that the function of one is affected by the other.
- a promoter is operably linked with a coding sequence when it is capable of affecting the expression of that coding sequence (i.e., the coding sequence is under the transcriptional control of the promoter).
- Unlinked means that the associated genetic elements are not closely associated with one another and the function of one does not affect the other.
- construct refers to any polynucleotide that contains a recombinant nucleic acid molecule (or, when the context clearly indicates, a fusion protein of the present disclosure).
- a (polynucleotide) construct may be present in a vector (e.g., a bacterial vector, a viral vector) or may be integrated into a genome.
- a "vector” is a nucleic acid molecule that is capable of transporting another nucleic acid molecule.
- Exemplary vectors are those capable of autonomous replication (episomal vector), capable of delivering a polynucleotide to a cell genome (e.g., viral vector), or capable of expressing nucleic acid molecules to which they are linked (expression vectors).
- expression vector refers to a DNA construct containing a nucleic acid molecule that is operably linked to a suitable control sequence capable of effecting the expression of the nucleic acid molecule in a suitable host.
- control sequences include a promoter to effect transcription, an optional operator sequence to control such transcription, a sequence encoding suitable mRNA ribosome binding sites, and sequences which control termination of transcription and translation.
- the vector may be a plasmid, a phage particle, a virus, or simply a potential genomic insert.
- the term "introduced” in the context of inserting a nucleic acid molecule into a cell means “transfection", “transformation,” or “transduction” and includes reference to the incorporation of a nucleic acid molecule into a eukaryotic or prokaryotic cell wherein the nucleic acid molecule may be incorporated into the genome of a cell (e.g ., chromosome, plasmid, plastid, or mitochondrial DNA), converted into an autonomous replicon, or transiently expressed (e.g., transfected mRNA).
- a cell e.g ., chromosome, plasmid, plastid, or mitochondrial DNA
- transiently expressed e.g., transfected mRNA
- polynucleotides of the present disclosure may be operatively linked to certain elements of a vector.
- polynucleotide sequences that are needed to effect the expression and processing of coding sequences to which they are ligated may be operatively linked.
- Expression control sequences may include appropriate transcription initiation, termination, promoter, and enhancer sequences; efficient RNA processing signals such as splicing and polyadenylation signals; sequences that stabilize cytoplasmic mRNA; sequences that enhance translation efficiency (i.e., Kozak consensus sequences); sequences that enhance protein stability; and possibly sequences that enhance protein secretion.
- Expression control sequences may be operatively linked if they are contiguous with the gene of interest and expression control sequences that act in trans or at a distance to control the gene of interest.
- the vector comprises a plasmid vector or a viral vector (e.g, a lentiviral vector or a g-retroviral vector).
- Viral vectors include retrovirus, adenovirus, parvovirus (e.g ., adeno-associated viruses), coronavirus, negative strand RNA viruses such as ortho-myxovirus (e.g., influenza virus), rhabdovirus (e.g, rabies and vesicular stomatitis virus), paramyxovirus (e.g, measles and Sendai), positive strand RNA viruses such as picornavirus and alphavirus, and double-stranded DNA viruses including adenovirus, herpesvirus (e.g, Herpes Simplex virus types 1 and 2, Epstein-Barr virus, cytomegalovirus), and poxvirus (e.g, vaccinia, fowlpox, and canarypox).
- herpesvirus e.g, Herpe
- viruses include, for example, Norwalk virus, togavirus, flavivirus, reoviruses, papovavirus, hepadnavirus, and hepatitis virus.
- retroviruses include avian leukosis-sarcoma, mammalian C-type, B-type viruses, D type viruses, HTLV-BLV group, lentivirus, spumavirus (Coffin, J. M., Retroviridae: The viruses and their replication, In Fundamental Virology, Third Edition, B. N. Fields et al, Eds., Lippincott-Raven Publishers, Philadelphia, 1996).
- “Retroviruses” are viruses having an RNA genome, which is reverse-transcribed into DNA using a reverse transcriptase enzyme, the reverse-transcribed DNA is then incorporated into the host cell genome.
- “Gammaretrovirus” refers to a genus of the retroviridae family. Examples of gammaretroviruses include mouse stem cell virus, murine leukemia virus, feline leukemia virus, feline sarcoma virus, and avian reticuloendotheliosis viruses.
- Retroviral and lentiviral vector constructs and expression systems are also commercially available.
- Other viral vectors also can be used for polynucleotide delivery including DNA viral vectors, including, for example adenovirus-based vectors and adeno-associated virus (AAV)-based vectors; vectors derived from herpes simplex viruses (HSVs), including amplicon vectors, replication-defective HSV and attenuated HSV (Krisky et al., Gene Ther. 5:1517, 1998).
- HSVs herpes simplex viruses
- the viral vector may also comprise additional sequences between the two (or more) transcripts allowing for bicistronic or multi cistronic expression.
- additional sequences used in viral vectors include internal ribosome entry sites (IRES), furin cleavage sites, viral 2A peptide, or any combination thereof.
- a host cell may include any individual cell or cell culture which may receive a vector or the incorporation of nucleic acids or express proteins. The term also encompasses progeny of the host cell, whether genetically or phenotypically the same or different. Suitable host cells may depend on the vector and may include mammalian cells, animal cells, human cells, simian cells, insect cells, yeast cells, and bacterial cells. These cells may be induced to incorporate the vector or other material by use of a viral vector, transformation via calcium phosphate precipitation, DEAE-dextran, electroporation, microinjection, or other methods. See , for example, Sambrook etal., Molecular Cloning: A Laboratory Manual 2d ed. (Cold Spring Harbor Laboratory, 1989).
- a "host” refers to a cell or a subject infected with SARS-CoV-2.
- epitope includes any molecule, structure, amino acid sequence, or protein determinant that is recognized and specifically bound by a cognate binding molecule, such as an immunoglobulin, or other binding molecule, domain, or protein.
- Epitopic determinants generally contain chemically active surface groupings of molecules, such as amino acids or sugar side chains, and can have specific three-dimensional structural characteristics, as well as specific charge characteristics.
- the epitope can be comprised of consecutive amino acids (e.g ., a linear epitope), or can be comprised of amino acids from different parts or regions of the protein that are brought into proximity by protein folding (e.g., a discontinuous or conformational epitope), or non-contiguous amino acids that are in close proximity irrespective of protein folding.
- the present disclosure provides an isolated antibody, or an antigen-binding fragment thereof, that comprises a heavy chain variable domain (VH) comprising a CDRH1, a CDRH2, and a CDRH3, and a light chain variable domain (VL) comprising a CDRL1, a CDRL2, and a CDRL3, and is capable of binding to a surface glycoprotein of SARS-CoV-2.
- VH heavy chain variable domain
- VL light chain variable domain
- the antibody or antigen-binding fragment is capable of binding to a surface glycoprotein of SARS- CoV-2 expressed on a cell surface of a host cell and/or on a SARS-CoV-2 virion.
- an antibody or antigen-binding fragment of the present disclosure associates with or unites with a SARS-CoV-2 surface glycoprotein epitope or antigen comprising the epitope, while not significantly associating or uniting with any other molecules or components in a sample.
- an antibody or antigen-binding fragment of the present disclosure associates with or unites (e.g, binds) to a SARS-CoV-2 surface glycoprotein epitope, and can also associate with or unite with an epitope from another coronavirus (e.g, SARS-CoV-1) present in the sample, but not significantly associating or uniting with any other molecules or components in the sample.
- an antibody or antigen binding fragment of the present disclosure is cross-reactive for SARS-CoV-2 and one or more additional coronavirus.
- an antibody or antigen-binding fragment of the present disclosure specifically binds to a SARS-CoV-2 surface glycoprotein.
- “specifically binds” refers to an association or union of an antibody or antigen-binding fragment to an antigen with an affinity or K a (i.e., an equilibrium association constant of a particular binding interaction with units of 1/M) equal to or greater than 10 5 M -1 (which equals the ratio of the on-rate [K 0n ] to the off rate [K 0ff ] for this association reaction), while not significantly associating or uniting with any other molecules or components in a sample.
- K a i.e., an equilibrium association constant of a particular binding interaction with units of 1/M
- affinity may be defined as an equilibrium dissociation constant (K d ) of a particular binding interaction with units of M (e.g, 10 -5 M to 10 -13 M).
- Antibodies may be classified as “high-affinity” antibodies or as “low- affinity” antibodies.
- “High-affinity” antibodies refer to those antibodies having a K a of at least 10 7 M _1 , at least 10 8 M -1 , at least 10 9 M -1 , at least 10 10 M -1 , at least 10 11 M -1 , at least 10 12 M _1 , or at least 10 13 M -1 .
- “Low-affinity” antibodies refer to those antibodies having a K a of up to 10 7 M '1 , up to 10 6 M -1 , up to 10 5 M -1 .
- affinity may be defined as an equilibrium dissociation constant (K d ) of a particular binding interaction with units of M (e.g, 10 -5 M to 10 -13 M).
- assays for identifying antibodies of the present disclosure that bind a particular target, as well as determining binding domain or binding protein affinities, such as Western blot, ELISA (e.g, direct, indirect, or sandwich), analytical ultracentrifugation, spectroscopy, and surface plasmon resonance (Biacore®) analysis (see, e.g., Scatchard etal., Ann. N.Y. Acad. Sci. 57:660, 1949; Wilson, Science 295: 2103, 2002; Wolff etal., Cancer Res. 53: 2560, 1993; and U.S. Patent Nos. 5,283,173, 5,468,614, or the equivalent). Assays for assessing affinity or apparent affinity or relative affinity are also known.
- binding can be determined by recombinantly expressing a SARS-CoV-2 antigen in a host cell (e.g, by transfection) and immunostaining the (e.g, fixed, or fixed and permeabilized) host cell with antibody and analyzing binding by flow cytometery (e.g, using a ZE5 Cell Analyzer (BioRad®) and FlowJo software (TreeStar).
- flow cytometery e.g, using a ZE5 Cell Analyzer (BioRad®) and FlowJo software (TreeStar).
- positive binding can be defined by differential staining by antibody of SARS-CoV-2 -expressing cells versus control (e.g, mock) cells.
- an antibody or antigen-binding fragment of the present disclosure binds to SARS-CoV-2 S protein, as measured using biolayer interferometry. In certain embodiments, an antibody or antigen-binding fragment of the present disclosure binds to SARS-CoV-2 S protein with a KD of less than about 4.5x10 -9 M, less than about 5x 10 -9 M, less than about lx 10 -10 M, less than about 5x10 -10 M, less than about lx 10 -11 M, less than about 5x 10 -11 M, less than about 1x 10 -12 M, or less than about 5x 10 -12 M.
- an antibody or antigen-binding fragment of the present disclosure binds to SARS-CoV-2 S protein RBD with a KD of less than about 4.5x10 -9 M, less than about 5x10 -9 M, less than about lx10 -10 M, less than about 5x 10 -10 M, less than about 1x 10 -11 M, less than about 5x10 -11 M, less than about lx10 -12 M, or less than about 5x 10 -12 M.
- the antibody or antigen-binding fragment is capable of preventing and/or neutralizing a SARS-CoV-2 infection in an in vitro model of infection and/or in an in vivo animal model of infection (e.g, using a Syrian hamster model with intranasal delivery of SARS-CoV-2) and/or in a human.
- an antibody or antigen-binding fragment is capable of neutralizing a SARS-CoV-2 infection, or a virus pseudotyped with SARS-CoV-2 S protein, with an IC50, an IC80, and/or an IC90 as shown in Table 4.
- an antibody or antigen-binding fragment, or a composition comprising two or more antibodies or antigen-binding fragments, of the present disclosure is capable of neutralizing a SARS-CoV-2 infection, or a virus pseudotyped with SARS-CoV-2 S protein, with an IC50 of about 0.8 to about 0.9 ⁇ g/ml.
- an antibody or antigen-binding fragment, or a composition comprising two or more antibodies or antigen-binding fragments, of the present disclosure is capable of neutralizing a SARS-CoV-2 infection, or a virus pseudotyped with SARS-CoV-2 S protein, with an IC50 of about 0.5 to about 0.6 ⁇ g/ml.
- an antibody or antigen-binding fragment, or a composition comprising two or more antibodies or antigen-binding fragments, of the present disclosure is capable of neutralizing a SARS-CoV-2 infection, or a virus pseudotyped with SARS-CoV-2, with an IC50 of about 0.1 to about 0.2 ⁇ g/ml.
- the antibody or antigen-binding fragment (i) recognizes an epitope in the ACE2 receptor binding motif (RBM, SEQ ID NO.:5) of SARS-CoV- 2; (ii) is capable of blocking an interaction between SARS-CoV-2 and human ACE2 (i.e.
- antibody refers to an intact antibody comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, as well as any antigen-binding portion or fragment of an intact antibody that has or retains the ability to bind to the antigen target molecule recognized by the intact antibody, such as an scFv, Fab, or Fab'2 fragment.
- antibody herein is used in the broadest sense and includes polyclonal and monoclonal antibodies, including intact antibodies and functional (antigen-binding) antibody fragments thereof, including fragment antigen binding (Fab) fragments, F(ab')2 fragments, Fab' fragments, Fv fragments, recombinant IgG (rlgG) fragments, single chain antibody fragments, including single chain variable fragments (scFv), and single domain antibodies (e.g ., sdAb, sdFv, nanobody) fragments.
- variable binding regions refer to the variable binding region from an antibody light chain and an antibody heavy chain, respectively.
- a VL is a kappa (K) class (also “VK” herein).
- a VL is a lambda (l) class.
- the variable binding regions comprise discrete, well-defined sub-regions known as “complementarity determining regions” (CDRs) and “framework regions” (FRs).
- CDR complementarity determining region
- HVR hypervariable region
- a "variant" of a CDR refers to a functional variant of a CDR sequence having up to 1-3 amino acid substitutions (e.g ., conservative or nonconservative substitutions), deletions, or combinations thereof.
- Numbering of CDR and framework regions may be according to any known method or scheme, such as the Rabat, Chothia, EU, IMGT, and AHo numbering schemes (see, e.g., Rabat etal., "Sequences of Proteins of Immunological Interest, US Dept. Health and Human Services, Public Health Service National Institutes of Health, 1991, 5 th ed.; Chothia and Lesk, J. Mol. Biol. 196:901-911 (1987)); Lefranc etal., Dev. Comp. Immunol. 27:55, 2003; Honegger and Pluckthun, J. Mol. Bio. 309:651-610 (2001)).
- Rabat etal. "Sequences of Proteins of Immunological Interest, US Dept. Health and Human Services, Public Health Service National Institutes of Health, 1991, 5 th ed.; Chothia and Lesk, J. Mol. Biol. 196:901-911 (1987)
- Lefranc etal. Dev
- CDRs are according to the IMGT numbering method.
- CDRs are according to the antibody numbering method developed by the Chemical Computing Group (CCG); e.g ., using Molecular Operating Environment (MOE) software (www.chemcomp.com).
- CCG Chemical Computing Group
- MOE Molecular Operating Environment
- an antibody or an antigen-binding fragment comprises a heavy chain variable domain (VH) comprising a CDRH1, a CDRH2, and a CDRH3, and a light chain variable domain (VL) comprising a CDRLl, a CDRL2, and a CDRL3, wherein: (i) the CDRH1 comprises or consists of the amino acid sequence according to any one of SEQ ID NOs.: 23, 33, 43, 53, 63, 75, 85, 97, 107,
- the CDRH2 comprises or consists of the amino acid sequence according to any one of SEQ ID NOs.: 24, 34, 44, 54, 64, 76, 86, 98, 108, 121, 131, 141, 148, 151, 161, 171, 184, 200, 210, 220, 230, 242, 256, 266, 276, 286, 300, 314, 324, 334, 352, 360, 362, 364, 366,
- the CDRL2 comprises or consists of the amino acid sequence according to any one of SEQ ID NOs.: 28, 38, 48, 58, 68, 80, 90, 102, 112, 125, 135, 145, 153, 167, 182, 193, 204, 214, 224, 234, 246, 260, 270, 280, 290, 304, 318, 328, 338, 375, 385, 395, 405, 415, 425, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550
- the antibody or antigen-binding fragment is capable of preventing and/or neutralizing a SARS-CoV-2 infection in an in vitro model of infection and/or in an in vivo animal model of infection and/or in a human.
- the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences according to SEQ ID NOs.: (i) 23-25 and 27-29, respectively; (ii) 33-35 and 37-39, respectively; (iii) 43-45 and 47-49, respectively; (iv) 53-55 and 57-59, respectively; (v) 63-65 and 67-69, respectively; (vi) 75-77 and 79-81, respectively; (vii) 85-87 and 89-91, respectively; (viii) 97-99 and 101-103, respectively; (ix) 107-109 and 111-113, respectively; (x) 120-122 and 124-126, respectively; (xi) 130-132 and 134- 136, respectively; (xii) 23 or 147, any one of 24, 148 or 151, 25 or 149, any one of 27, 152, 155, 156, 158,
- the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences according to SEQ ID NOs.:631, 632 or 635 or 637 or 639 or 641 or 643 or 645 or 647 or 649 or 651 or 653 or 655 or 657 or 659 or 661 or 663 or 665 or 667 or 669 or 671 or 673 or 675 or 677 or 679 or 681 or 683 or 685, 633, and 697-699, respectively.
- the antibody or antigenbinding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences according to SEQ ID NOs.:693-695 and 697-699, respectively.
- the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences according to SEQ ID N0s.:400-402, and 404-406, respectively. In certain embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences according to SEQ ID NOs.:400, 401, 766, and 404-406, respectively. In certain embodiments, the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences according to SEQ ID N0s.:400-402, 404, 405, and 745, respectively.
- the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences according to SEQ ID NOs.:400, 401, 766, 404, 405, and 745, respectively.
- the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences according to SEQ ID N0s.:400-402, 404, 405, and 747, respectively.
- the antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences according to SEQ ID NOs.:400, 401, 766, 404, 405, and 747, respectively.
- an antibody or an antigen-binding fragment of the present disclosure comprises a CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and a CDRL3, wherein each CDR is independently selected from a corresponding CDR of SARS-CoV-2 S2X16-vl mAb, SARS-CoV-2 S2X16-v2 mAb, SARS-CoV-2 S2X16-v3 mAb, SARS-CoV-2 S2X16-v4 mAb, SARS-CoV-2 S2X16-v5 mAb, SARS-CoV-2 S2X16-v6 mAb, SARS-CoV-2 S2X16-v7 mAb, SARS-CoV-2 S2X16-v8 mA,b SARS- CoV-2 S2X28-vl mAb, SARS-CoV-2 S2X30-vl mAb, SARS-CoV-2 S2X30-vl mAb, S
- DNA in the germline variable (V), joining (J), and diversity (D) gene loci may be rearranged and insertions and/or deletions of nucleotides in the coding sequence may occur. Somatic mutations may be encoded by the resultant sequence, and can be identified by reference to a corresponding known germline sequence.
- somatic mutations that are not critical to a desired property of the antibody e.g ., binding to a SARS-CoV-2 antigen
- that confer an undesirable property upon the antibody e.g., an increased risk of immunogenicity in a subject administered the antibody
- Exemplary antibodies of the present disclosure include antibody S2E12 and engineered variants thereof.
- Engineered S2E12 variants include "Antibody 409_1 l_4_v2", “Antibody 409_1 l_4_v3", “Antibody 409_1 l_4_v4", “Antibody 409_1 l_4_v5", “Antibody 409_1 l_4_v6", “Antibody 409_1 l_4_v7", “Antibody 409_1 l_4_v8", “Antibody 409_1 l_4_v9", “Antibody 409_1 l_4_vl0”, “Antibody 409_1 l_4_vl 1", “Antibody 409_1 l_4_vl2”, “Antibody 409_1 l_4_vl3".
- an antibody or antigen-binding fragment comprises a CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and/or a CDRL3 selected from any of the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences (respectively) provided in Table 1.
- Table 1 also provides amino acid sequences that comprise S2E12 CDRH3 sequences and two amino acids (Ala-Ser) that are immediately N-terminal to CDRH3 in S2E12.
- an antibody or antigen-binding fragment comprises: a CDRH1, a CDRH2, and/or a CDRH3 of the VH amino acid sequence set forth in any one of SEQ ID NOs.:399, 748, 749, 750, 752, 754, 756, 758, 759, and 761; and a CDRL1, a CDRL2, and/or a CDRL3 of the VL amino acid sequence set forth in any one of SEQ ID NOs.:403, 738, 744, and 746 (i.e., according to any CDR numbering or determination method known in the art, such as IMGT, Rabat, Chothia, AHo, North, Contact, CCG, EU, or Martin (Enhanced Chothia)).
- the antibody or antigen-binding fragment comprises the CDRH1, the CDRH2, and/or the CDRH3 of the VH amino acid sequence set forth in SEQ ID NO.:399, and the CDRL1, the CDRL2, and/or the CDRL3 of the VL amino acid sequence set forth in SEQ ID NO.:738, wherein the CDRs are according to IMGT.
- the antibody or antigen-binding fragment comprises the CDRH1, the CDRH2, and the CDRH3 of the VH amino acid sequence set forth in SEQ ID NO.:399, and the CDRL1, the CDRL2, and the CDRL3 of the VL amino acid sequence set forth in SEQ ID NO.:738, wherein the CDRs are according to IMGT.
- the antibody or antigen-binding fragment comprises a VH having at least 85% identity (e.g., 85%, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96,
- VH amino acid sequence provided in Table 1 and/or a VL having at least 85% identity (e.g., 85%, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96,
- the antibody or antigen-binding fragment comprises a VH having at least 90% identity identity to a VH amino acid sequence provided in Table 1 and/or a VL having at least 90% identity to a VL amino acid sequence provided in Table 1.
- the antibody or antigen-binding fragment comprises a VH having at least 95% identity identity to a VH amino acid sequence provided in Table 1 and/or a VL having at least 95% identity to a VL amino acid sequence provided in Table 1.
- the antibody or antigen-binding fragment comprises a VH having at least 99% identity identity to a VH amino acid sequence provided in Table 1 and/or a VL having at least 99% identity to a VL amino acid sequence provided in Table 1.
- the antibody or antigen-binding fragment comprises a VH amino acid sequence selected from the VH amino acid sequences provided in Table 1 and a VL amino acid sequence selected from the VL amino acid sequence provided in Table 1.
- S2E12 antibodies comprise a kappa light chain, e.g, klm3, IGKC*01.
- an antibody, or an antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising complementarity determining region (CDR)H1, CDRH2, and CDRH3, and a light chain variable domain (VL) comprising CDRL1, CDRL2, and CDRL3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 comprise or consist of the amino acid sequences set forth in: (a) SEQ ID NOs.:400, 401, 766, 404, 405, and 406, respectively; (b) SEQ ID NOs.:400, 401, 769, 404, 405, and 406, respectively; (c) SEQ ID NOs.:400, 401, 770, 404, 405, and 406, respectively; (d) SEQ ID NOs.:400, 401, 771, 404, 405, and 406, respectively; (e) SEQ ID NOs.:400, 401, 772, 404, 405, and 406, respectively; (f)
- SEQ ID NOs.: 400, 401, 772, 404, 405, and 745 respectively; (1) SEQ ID NOs.: 400, 401, 773, 405, 405, and 745, respectively; (m) SEQ ID NOs.:400, 401, 766, 404, 405, and 747, respectively; (n) SEQ ID NOs.:400, 401, 769, 404, 405, and 747, respectively; (o) SEQ ID NOs.:400, 401, 770, 404, 405, and 747, respectively; (p) SEQ ID NOs.:400, 401,
- SEQ ID NOs.:400, 401, and 402 are amino acid sequences in VH
- SEQ ID NOs.:404, 405, and 406 are amino acid sequences in VL.
- an antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:525-527 and 529-531, respectively.
- the antibody or antigen-binding fragment comprises a VH having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or comprising or consisting of, the amino acid sequence set forth in SEQ ID NO.:524, and a VL having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or comprising or consisting of, the amino acid sequence set forth in SEQ ID NO.:528.
- an antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 585, 586, 587, 589, 590, and 591, respectively, or as set forth in SEQ ID NOs.:585, 625, 627, 589, 590, and 591, respectively.
- the antibody or antigen-binding fragment comprises a VH having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or comprising or consisting of, the amino acid sequence set forth in any one of SEQ ID NOs.:584, 624, 626, and 628, and a VL having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or comprising or consisting of, the amino acid sequence set forth in SEQ ID NO.:588.
- an antibody or antigen-binding fragment comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 229, 230, 231, 233, 234, and 235, respectively.
- the antibody or antigen-binding fragment comprises a VH having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or comprising or consisting of, the amino acid sequence set forth in any one of SEQ ID NOs.:228, 740, 741, 742, and 743, and a VL having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or comprising or consisting of, the amino acid sequence set forth in SEQ ID NO.:232.
- the antibody or antigen-binding fragment comprises a VH having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or comprising or consisting of, the amino acid sequence set forth in any one of SEQ ID NOs.:228, 740, 741, 742, and 743, and a VL having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or comprising or consisting of, the amino acid sequence set forth in SEQ ID NO.:238.
- an antibody or antigen-binding fragment comprises an amino acid modification (e.g ., a substitution mutation) to remove an undesired risk of oxidation, deamidation, and/or isomerization.
- an amino acid modification e.g ., a substitution mutation
- the variation is optionally limited to one or more framework regions and/or the variation comprises one or more substitution to a germline-encoded amino acid; and/or (ii) the VL comprises or consists of an amino acid sequence having at least 85% (e.g., having 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the amino acid sequence according to any one of SEQ ID NOs.: 26, 36, 46, 56, 66, 78, 88, 94, 100, 110, 123, 133, 143, 154,
- variation is optionally limited to one or more framework regions and/or the variation comprises one or more substitution to a germline-encoded amino acid.
- the VH has at least 85% (e.g, having 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%)identity to the amino acid sequence set forth in any one of SEQ ID NOs.:399, 748, 749, 750, 752, 754, 756, 758, 759, and 761, and the VL has at least 85% (e.g, having 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,
- the VH has at least 85% (e.g, having 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the amino acid sequence set forth in any one of SEQ ID NOs.:399, 748, 749, 750, 752, 754, 756, 758, 759, and 761, and the VL has at least 85% (e.g, having 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,
- the VH has at least 85% (e.g, having 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the amino acid sequence set forth in any one of SEQ ID NOs.:399, 748, 749, 750, 752, 754, 756, 758, 759, and 761, and the VL has at least 85% (e.g, having 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the amino acid sequence set forth in SEQ ID NO.:744.
- the VH has at least 85% (e.g, having 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%)identity to the amino acid sequence set forth in any one of SEQ ID NOs.:399, 748, 749, 750, 752, 754, 756, 758, 759, and 761, and the VL has at least 85% (e.g, having 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%)identity to the amino acid sequence set forth in SEQ ID NO.:746.
- the VH comprises or consists of the amino acid sequence set forth in SEQ ID NO.:399 and the VL comprises or consists of the amino acid sequence set forth in SEQ ID NO.:403.
- the VH comprises or consists of the amino acid sequence set forth in SEQ ID NO.:399 and the VL comprises or consists of the amino acid sequence set forth in SEQ ID NO.:738.
- the VH comprises or consists of the amino acid sequence set forth in SEQ ID NO.:399 and the VL comprises or consists of the amino acid sequence set forth in SEQ ID NO.:744.
- the VH comprises or consists of the amino acid sequence set forth in SEQ ID NO.:399 and the VL comprises or consists of the amino acid sequence set forth in SEQ ID NO.:746.
- a composition comprises a plurality of an antibody and/or an antigen-binding fragment of the present disclosure, wherein one or more antibody or antigen-binding fragment does not comprise a lysine residue at the C-terminal end of the heavy chain, CH1-CH3, or Fc polypeptide, and wherein one or more antibody or antigen-binding fragment comprises a lysine residue at the C-terminal end of the heavy chain, CH1-CH3, or Fc polypeptide.
- a heavy chain can comprise or consist of the amino acid sequence set forth in SEQ ID NO.:767 without the C-terminal lysine.
- a heavy chain or a CH1-CH3 can comprise of the amino acid sequence set forth in SEQ ID NO.:6 or SEQ ID ID NO.:7 without the C-terminal lysine.
- the antibody or antigen-binding fragment comprises: (i) a first VH and a first VL; and (ii) a second VH and a second VL, wherein the first VH and the second VH are different and each independently comprise an amino acid sequence having at least 85% (e.g, having 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) dentity to the amino acid sequence set forth in any one of SEQ ID NOs.: 22, 32, 42, 52, 62, 72, 74, 84, 96, 106, 119, 129, 139, 150, 163, 173, 175, 178, 186, 189, 191, 198, 208, 218, 228, 240, 298, 312, 322, 332, 350, 351, 353, 359, 361, 363, 365, 367, 368, 369,
- first VL and the second VL are different and each independently comprise an amino acid sequence having at least 85% (e.g ., having 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%)identity to the amino acid sequence set forth in any one of SEQ ID NOs.: 26, 36, 46, 56, 66, 78, 88, 94, 100, 110, 123, 133, 143, 154, 157, 168, 194, 196, 202, 212, 222, 232, 238, 244, 250, 252, 258, 268, 278, 288, 294, 296, 302, 308, 310, 316, 326, 336,
- first VH and the first VL together form a first antigen-binding site
- second VH and the second VL together form a second antigen-binding site
- the antibody or antigen-binding fragment comprises a Fc polypeptide, or a fragment thereof.
- the "Fc" fragment or Fc polypeptide comprises the carboxy -terminal portions (i.e., the CH2 and CH3 domains of IgG) of both antibody H chains that, in general, are held together by disulfides.
- Antibody “effector functions” refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody, and vary with the antibody isotype.
- antibody effector functions include: Clq binding and complement dependent cytotoxicity; Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B cell receptor); and B cell activation.
- modifications e.g ., amino acid substitutions
- Fc domain may be made to an Fc domain in order to modify (e.g., improve, reduce, or ablate) one or more functionality of an Fc-containing polypeptide (e.g, an antibody of the present disclosure).
- Such functions include, for example, Fc receptor (FcR) binding, antibody half-life modulation (e.g., by binding to FcRn), ADCC function, protein A binding, protein G binding, and complement binding.
- Amino acid modifications that modify (e.g., improve, reduce, or ablate) Fc functionalities include, for example, the T250Q/M428L, M252Y/S254T/T256E, H433K/N434F, M428L/N434S, E233P/L234V/L235A/G236 + A327G/A330S/P331S, E333A,
- FcR binding can be mediated by the interaction of the Fc moiety (of an antibody) with Fc receptors (FcRs), which are specialized cell surface receptors on cells including hematopoietic cells.
- Fc receptors belong to the immunoglobulin superfamily, and shown to mediate both the removal of antibody-coated pathogens by phagocytosis of immune complexes, and the lysis of erythrocytes and various other cellular targets (e.g. tumor cells) coated with the corresponding antibody, via antibody dependent cell mediated cytotoxicity (ADCC; Van de Winkel, J. G., and Anderson, C. L., J. Leukoc. Biol. 49 (1991) 511-524).
- ADCC antibody dependent cell mediated cytotoxicity
- FcyR In humans, three classes of FcyR have been characterized to-date, which are: (i) FcyRI (CD64), which binds monomeric IgG with high affinity and is expressed on macrophages, monocytes, neutrophils and eosinophils; (ii) FcyRII (CD32), which binds complexed IgG with medium to low affinity, is widely expressed, in particular on leukocytes, is believed to be a central player in antibody- mediated immunity, and which can be divided into FcyRIIA, FcyRIIB and FcyRIIC, which perform different functions in the immune system, but bind with similar low affinity to the IgG-Fc, and the ectodomains of these receptors are highly homologuous; and (iii) FcyRIII (CD 16), which binds IgG with medium to low affinity and has been found in two forms: FcyRIIIA, which has been found on NK cells, macrophages,
- FcyRIIA is found on many cells involved in killing (e.g. macrophages, monocytes, neutrophils) and seems able to activate the killing process.
- FcyRIIB seems to play a role in inhibitory processes and is found on B-cells, macrophages and on mast cells and eosinophils. Importantly, it has been shown that 75% of all FcyRIIB is found in the liver (Ganesan, L. P. et al, 2012: “FcyRIIb on liver sinusoidal endothelium clears small immune complexes,” Journal of Immunology 189: 4981-4988).
- FcyRIIB is abundantly expressed on Liver Sinusoidal Endothelium, called LSEC, and in Kupffer cells in the liver and LSEC are the major site of small immune complexes clearance (Ganesan, L. P. et al, 2012: FcyRIIb on liver sinusoidal endothelium clears small immune complexes. Journal of Immunology 189: 4981-4988).
- mutations that increase binding affinity of an Fc polypeptide or fragment thereof of the present disclosure to a (i.e., one or more) Fey receptor (e.g., as compared to a reference Fc polypeptide or fragment thereof or containing the same that does not comprise the mutation(s)). See, e.g., Delillo and Ravetch, Cell 161(5): 1035-1045 (2015) and Ahmed et al., J. Struc. Biol. 194(1):78 (2016), the Fc mutations and techniques of which are incorporated herein by reference.
- G236 A/S239D/I332E G236A/A330L/I332E (also referred to herein as "GAALIE”); or G236A/S239D/A330L/I332E.
- the Fc polypeptide or fragment thereof does not comprise S239D.
- the Fc polypeptide or fragment thereof comprises or is derived from a IgG Fc and a half-life-extending mutation comprises any one or more of: M428L; N434S; N434H; N434A; N434S; M252Y; S254T; T256E; T250Q; P257I Q31 II; D376V; T307A; E380A (EU numbering).
- a half-life-extending mutation comprises M428L/N434S (also referred to herein as "MLNS").
- a half-life-extending mutation comprises M252Y/S254T/T256E.
- an antibody or antigen-binding fragment includes an Fc polypeptide or fragment thereof that comprises the substitution mutations: M428L/N434S and G236A/A330L/I332E, and optionally does not comprise S239D.
- an antibody or antigen-binding fragment includes a Fc polypeptide or fragment thereof that comprises the substitution mutations: M428L/N434S and G236A/S239D/A330L/I332E.
- the antibody or antigen-binding fragment comprises a mutation that alters glycosylation, wherein the mutation that alters glycosylation comprises N297A, N297Q, or N297G, and/or the antibody or antigen-binding fragment is partially or fully aglycosylated and/or is partially or fully afucosylated.
- Host cell lines and methods of making partially or fully aglycosylated or partially or fully afucosylated antibodies and antigen-binding fragments are known (see, e.g., PCT Publication No. WO 2016/181357; Suzuki et al. Clin. Cancer Res. 73(6):1875-82 (2007); Huang et al. MAbs 6:1-12 (2018)).
- the antibody or antigen-binding fragment is capable of eliciting continued protection in vivo in a subject even once no detectable levels of the antibody or antigen-binding fragment can be found in the subject (i.e., when the antibody or antigen-binding fragment has been cleared from the subject following administration). Such protection is referred to herein as a vaccinal effect. Without wishing to be bound by theory, it is believed that dendritic cells can internalize complexes of antibody and antigen and thereafter induce or contribute to an endogenous immune response against antigen.
- an antibody or antigen-binding fragment comprises one or more modifications, such as, for example, mutations in the Fc comprising G236A, A330L, and I332E, that are capable of activating dendritic cells that may induce, e.g ., T cell immunity to the antigen.
- the antibody or antigen-binding fragment comprises a Fc polypeptide or a fragment thereof, including a CH2 (or a fragment thereof, a CH3 (or a fragment thereof), or a CH2 and a CH3, wherein the CH2, the CH3, or both can be of any isotype and may contain amino acid substitutions or other modifications as compared to a corresponding wild-type CH2 or CH3, respectively.
- a Fc polypeptide of the present disclosure comprises two CH2-CH3 polypeptides that associate to form a dimer.
- monoclonal antibodies useful in the present invention may be prepared by the hybridoma methodology first described by Kohler et al., Nature 256:495 (1975), or may be made using recombinant DNA methods in bacterial, eukaryotic animal, or plant cells (see, e.g, U.S. Pat. No. 4,816,567).
- Monoclonal antibodies may also be isolated from phage antibody libraries using the techniques described in Clackson et al., Nature, 352: 624-628 (1991) and Marks et al., J. Mol. Biol., 222:581-597 (1991), for example.
- Monoclonal antibodies may also be obtained using methods disclosed in PCT Publication No. WO 2004/076677A2.
- chimeric antibodies may comprise human and non-human residues.
- chimeric antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance. For further details, see Jones et al, Nature 321 :522-525 (1986); Riechmann et al, Nature 332:323-329 (1988); and Presta, Curr. Op. Struct.
- Chimeric antibodies also include primatized and humanized antibodies.
- a “humanized” antibody is one which is produced by a non-human cell or animal and comprises human sequences, e.g ., He domains.
- human antibody is an antibody containing only sequences that are present in an antibody that is produced by a human.
- human antibodies may comprise residues or modifications not found in a naturally occurring human antibody (e.g, an antibody that is isolated from a human), including those modifications and variant sequences described herein. These are typically made to further refine or enhance antibody performance.
- human antibodies are produced by transgenic animals. For example, see U.S. Pat. Nos. 5,770,429; 6,596,541 and 7,049,426.
- an antibody or antigen-binding fragment of the present disclosure is chimeric, humanized, or human.
- an antibody or antigen-binding fragment of the present disclosure is capable of binding to a SARS-CoV-2 surface glycoprotein with an EC50 of less than 500 ng/ml, less than 250 ng/ml, less than 100 ng/ml, less than 90 ng/ml, less than 80 ng/ml, less than 70 ng/ml, less than 60 ng/ml, less than 50 ng/ml, less than 40 ng/ml, less than 30 ng/ml, less than 25 ng/ml, less than 20 ng/ml, less than 16 ng/ml, less than 15 ng/ml, less than 14 ng/ml, less than 13 ng/ml, less than 12 ng/ml, less than 10 ng/ml, less than 9 ng/ml, less than 8 ng/ml, less than 7 ng/ml, less than 6 ng/ml, less than 5 ng/ml, less than 4 ng/ml
- antibody or antigen-binding fragment of the present disclosure is capable of binding to a SARS-CoV-2 surface glycoprotein RBD with an EC50 of less than 500 ng/ml, less than 250 ng/ml, less than 100 ng/ml, less than 90 ng/ml, less than 80 ng/ml, less than 70 ng/ml, less than 60 ng/ml, less than 50 ng/ml, less than 40 ng/ml, less than 30 ng/ml, less than 25 ng/ml, less than 20 ng/ml, less than 16 ng/ml, less than 15 ng/ml, less than 14 ng/ml, less than 13 ng/ml, less than 12 ng/ml, less than 10 ng/ml, less than 9 ng/ml, less than 8 ng/ml, less than 7 ng/ml, less than 6 ng/ml, less than 5 ng/ml, less than 4 ng/m
- antibody or antigen-binding fragment of the present disclosure is capable of binding to a SARS-CoV-2 RBD with a KD of less than 5 x 10 -8 M, less than 4 x 10 -8 M, less than 3 x 10 -8 M, less than 2 x 10 -8 M, less than 1 x 10 -8 M, less than 5 x 10 -9 M, less than 1 x 10 -9 M, less than 5 x 10 -10 M, less than 1 x 10 -10 M, less than 5 x 10 -11 M, less than 1 x 10 -11 M, less than 5 x 10 -12 M, or less than 1 x 10 -12 M, as determined using biolayer interferometry (BLI), optionally using an Octet instrument with antibody or antigen-binding fragment loaded on Protein A pins, optionally at 2.7 ⁇ g/ml, and SARS-CoV-2 RBD loaded for 5 minutes at 6 ⁇ g/ml, 1.5 ⁇ g/ml, or 0.4 ⁇ g/
- antibody or antigen-binding fragment of the present disclosure is capable of binding to a SARS-CoV-2 RBD with a KD of less than 6 x 10 -8 M, less than 5 x 10 -8 M, less than 4 x 10 -8 M, less than 3 x 10 -8 M, less than 2 x 10 -8 M, less than 1 x 10 -8 M, less than 5 x 10 -9 M, less than 4 x 10 -9 M, less than 3 x 10 -9 M, less than 2 x 10 -9 M, less than 1 x 10 -9 M, or less than 8 x 10 -10 M, as determined using surface plasmon resonance (SPR), optionally using a Biacore T200 instrument using a single-cycle kinetics approach.
- SPR surface plasmon resonance
- antibody or antigen-binding fragment of the present disclosure is capable of binding to a SARS-CoV-2 RBD and inhibiting an interaction between (i) the RBD and (ii) a human ACE2 and/or a human SIGLEC-1.
- antibody or antigen-binding fragment of the present disclosure is capable of neutralizing: (i) infection by a SARS-CoV-2 pseudovirus, optionally: (i)(a) with a neutralization IC50 of less than 100 ng/ml, less than 90 ng/ml, less than 80 ng/ml, less than 70 ng/ml, less than 60 ng/ml, less than 50 ng/ml, less than 40 ng/ml, less than 30 ng/ml, less than 25 ng/ml, less than 20 ng/ml, less than 15 ng/ml, less than 10 ng/ml, less than 9 ng/ml, less than 8 ng/ml, less than 7 ng/ml, less than 6 ng/ml, less than 5 ng/ml, less than 4 ng/ml, less than 3 ng/ml, less than 2 ng/ml, or less than 1 ng/ml, preferably less than 10 ng/ml,
- an antibody or antigen-binding fragment of the present disclosure is capable of neutralizing infection by a SARS-CoV-2 variant that comprises any one of the following mutations in the surface glycoprotein as compared to a SARS- CoV-2 surface glycoprotein comprising SEQ ID NO.:3: N501Y; S477N; N439K; L452R; E484K; K417N; T478K; S494P; A520S; N501T; A522S; Y453F; P384L.
- an antibody or antigen-binding fragment of the present disclosure is capable of activating a FcyRIIa, a FcyRIIIa, or both, wherein, optionally :(i) the FcyRIIa comprises a H131 allele; and/or (ii) the FcyRIIIa comprises a V158 allele; and/or (iii) activation is determined using a SARS-CoV-2 S-expressing target cell, such as a CHO cell, and a reporter cell expressing a NFAT-driven reporter, such as luciferase.
- an antibody or antigen-binding fragment of the present disclosure has an in vivo half-life in a non-human primate of between 20 and 30 days, or between 22 and 28 days, or between 23 and 27 days, or between 24 and 26 days, or of about 25 days.
- an antibody or antigen-binding fragment of the present disclosure is capable of neutralizing a SARS-CoV-2 infection and/or of neutralizing an infection of a target cell with an IC50 of about 20 to about 30 ng/ml.
- an antibody or antigen-binding fragment of the present disclosure is capable of neutralizing a SARS-CoV-2 infection and/or of neutralizing an infection of a target cell with an IC50 of about 10 to about 20 ng/ml.
- an antibody or antigen-binding fragment of the present disclosure is capable of neutralizing infection by SARS-CoV-2 and does not compete with a human ACE2 for binding to the SARS-CoV-2S protein, wherein, optionally, the neutralizing comprises neutralizing infection in an in vitro model of infection.
- a polynucleotide comprises (i) a polynucleotide having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% identity to, or that comprises or consists of, the nucleotide sequence set forth in SEQ ID NO.:407; and (ii) a polynucleotide having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% identity to, or that comprises or consists of, the nucleotide sequence set forth in SEQ ID NO.:408, 737, or 739.
- the polynucleotide can comprise deoxyribonucleic acid (DNA) or ribonucleic acid (RNA).
- the RNA comprises messenger RNA (mRNA).
- Vectors are also provided, wherein the vectors comprise or contain a polynucleotide as disclosed herein (e.g ., a polynucleotide that encodes an antibody or antigen-binding fragment that binds to SARS-CoV-2).
- a vector can comprise any one or more of the vectors disclosed herein.
- a vector is provided that comprises a DNA plasmid construct encoding the antibody or antigen-binding fragment, or a portion thereof (e.g., so-called "DMAb”; see, e.g, Muthumani et al, J Infect Dis. 214(3)369 -378 (2016); Muthumani etal., Hum Vaccin Immunother 9: 2253-2262 (2013));
- a DNA plasmid construct comprises a single open reading frame encoding a heavy chain and a light chain (or a VH and a VL) of the antibody or antigen-binding fragment, wherein the sequence encoding the heavy chain and the sequence encoding the light chain are optionally separated by polynucleotide encoding a protease cleavage site and/or by a polynucleotide encoding a self-cleaving peptide.
- the substituent components of the antibody or antigen-binding fragment are encoded by a polynucleotide comprised in a single plasmid. In other embodiments, the substituent components of the antibody or antigen-binding fragment are encoded by a polynucleotide comprised in two or more plasmids (e.g ., a first plasmid comprises a polynucleotide encoding a heavy chain, VH, or VH+CH, and a second plasmid comprises a polynucleotide encoding the cognate light chain, VL, or VL+CL).
- a first plasmid comprises a polynucleotide encoding a heavy chain, VH, or VH+CH
- a second plasmid comprises a polynucleotide encoding the cognate light chain, VL, or VL+CL.
- a single plasmid comprises a polynucleotide encoding a heavy chain and/or a light chain from two or more antibodies or antigenbinding fragments of the present disclosure.
- An exemplary expression vector is pVaxl, available from Invitrogen®.
- a DNA plasmid of the present disclosure can be delivered to a subject by, for example, electroporation (e.g., intramuscular electroporation), or with an appropriate formulation (e.g, hyaluronidase).
- the present disclosure also provides a host cell expressing an antibody or antigen-binding fragment according to the present disclosure; or comprising or containing a vector or polynucleotide according the present disclosure.
- the cells include but are not limited to, eukaryotic cells, e.g., yeast cells, animal cells, insect cells, plant cells; and prokaryotic cells, including E. coli.
- the cells are mammalian cells.
- the cells are a mammalian cell line such as CHO cells (e.g, DHFR- CHO cells (Urlaub et al, PNAS 77:4216 (1980)), human embryonic kidney cells (e.g, HEK293T cells), PER.C6 cells, Y0 cells, Sp2/0 cells.
- NS0 cells human liver cells, e.g. Hepa RG cells, myeloma cells or hybridoma cells.
- mammalian host cell lines include mouse sertoli cells (e.g, TM4 cells); monkey kidney CV1 line transformed by SV40 (COS-7); baby hamster kidney cells (BHK); African green monkey kidney cells (VERO-76); monkey kidney cells (CV1); human cervical carcinoma cells (HELA); human lung cells (W138); human liver cells (Hep G2); canine kidney cells (MDCK; buffalo rat liver cells (BRL 3 A); mouse mammary tumor (MMT 060562); TRI cells; MRC 5 cells; and FS4 cells.
- Mammalian host cell lines suitable for antibody production also include those described in, for example, Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (B. K. C. Lo, ed., Humana Press, Totowa, N.J.), pp. 255-268 (2003).
- a host cell is a prokaryotic cell, such as an E. coli.
- a prokaryotic cell such as an E. coli.
- the expression of peptides in prokaryotic cells such as E. coli is well established (see, e.g., Pluckthun, A. Bio/Technology 9:545-551 (1991).
- antibodies may be produced in bacteria, in particular when glycosylation and Fc effector function are not needed.
- For expression of antibody fragments and polypeptides in bacteria see, e.g., U.S. Pat. Nos. 5,648,237; 5,789,199; and 5,840,523.
- the cell may be transfected with a vector according to the present description with an expression vector.
- transfection refers to the introduction of nucleic acid molecules, such as DNA or RNA (e.g. mRNA) molecules, into cells, such as into eukaryotic cells.
- RNA e.g. mRNA
- transfection encompasses any method known to the skilled person for introducing nucleic acid molecules into cells, such as into eukaryotic cells, including into mammalian cells.
- Such methods encompass, for example, electroporation, lipofection, e.g, based on cationic lipids and/or liposomes, calcium phosphate precipitation, nanoparticle based transfection, virus based transfection, or transfection based on cationic polymers, such as DEAE-dextran or polyethylenimine, etc.
- the introduction is non-viral.
- host cells of the present disclosure may be transfected stably or transiently with a vector according to the present disclosure, e.g. for expressing an antibody, or an antigen-binding fragment thereof, according to the present disclosure.
- the cells may be stably transfected with the vector as described herein.
- cells may be transiently transfected with a vector according to the present disclosure encoding an antibody or antigen-binding fragment as disclosed herein.
- a polynucleotide may be heterologous to the host cell.
- the present disclosure also provides recombinant host cells that heterologously express an antibody or antigen-binding fragment of the present disclosure.
- the cell may be of a species that is different to the species from which the antibody was fully or partially obtained (e.g ., CHO cells expressing a human antibody or an engineered human antibody).
- the cell type of the host cell does not express the antibody or antigen-binding fragment in nature.
- the host cell may impart a post-translational modification (PTM; e.g., glysocylation or fucosylation) on the antibody or antigen-binding fragment that is not present in a native state of the antibody or antigen-binding fragment (or in a native state of a parent antibody from which the antibody or antigen binding fragment was engineered or derived).
- PTM post-translational modification
- Such a PTM may result in a functional difference (e.g, reduced immunogenicity).
- an antibody or antigen-binding fragment of the present disclosure that is produced by a host cell as disclosed herein may include one or more post-translational modification that is distinct from the antibody (or parent antibody) in its native state (e.g, a human antibody produced by a CHO cell can comprise a more post-translational modification that is distinct from the antibody when isolated from the human and/or produced by the native human B cell or plasma cell).
- Insect cells useful expressing a binding protein of the present disclosure include, for example, Spodoptera frugipera Sf9 cells, Trichoplusia ni BTI-TN5B1-4 cells, and Spodoptera frugipera SfSWTOl “MimicTM” cells. See, e.g., Palmberger et al., J. Biotechnol. 753(3-4): 160-166 (2011). Numerous baculoviral strains have been identified which may be used in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells.
- Eukaryotic microbes such as filamentous fungi or yeast are also suitable hosts for cloning or expressing protein-encoding vectors, and include fungi and yeast strains with "humanized” glycosylation pathways, resulting in the production of an antibody with a partially or fully human glycosylation pattern. See Gerngross, Nat.
- Plant cells can also be utilized as hosts for expressing a binding protein of the present disclosure.
- PLANTIBODIESTM technology described in, for example, U.S. Pat. Nos. 5,959,177; 6,040,498; 6,420,548;
- the host cell comprises a mammalian cell.
- the host cell is a CHO cell, a HEK293 cell, a PER.C6 cell, a Y0 cell, a Sp2/0 cell, aNSO cell, a human liver cell, a myeloma cell, or a hybridoma cell.
- the present disclosure provides methods for producing an antibody, or antigen-binding fragment, wherein the methods comprise culturing a host cell of the present disclosure under conditions and for a time sufficient to produce the antibody, or the antigen-binding fragment.
- Methods useful for isolating and purifying recombinantly produced antibodies may include obtaining supernatants from suitable host cell/vector systems that secrete the recombinant antibody into culture media and then concentrating the media using a commercially available filter. Following concentration, the concentrate may be applied to a single suitable purification matrix or to a series of suitable matrices, such as an affinity matrix or an ion exchange resin. One or more reverse phase HPLC steps may be employed to further purify a recombinant polypeptide. These purification methods may also be employed when isolating an immunogen from its natural environment.
- compositions that comprise any one or more of the presently disclosed antibodies, antigen-binding fragments, polynucleotides, vectors, or host cells, singly or in any combination, and can further comprise a pharmaceutically acceptable carrier, excipient, or diluent. Carriers, excipients, and diluents are discussed in further detail herein.
- a composition comprises two or more different antibodies or antigen-binding fragments according to the present disclosure.
- antibodies or antigen-binding fragments to be used in a combination each independently have one or more of the following characteristics: neutralize naturally occurring SARS-CoV-2 variants; do not compete with one another for Spike protein binding; bind distinct Spike protein epitopes; have a reduced formation of resistance to SARS-CoV-2; when in a combination, have a reduced formation of resistance to SARS-CoV-2; potently neutralize live SARS-CoV-2 virus; exhibit additive or synergistic effects on neutralization of live SARS-CoV-2 virus when used in combination; exhibit effector functions; are protective in relevant animal model(s) of infection; are capable of being produced in sufficient quantities for large-scale production.
- a composition comprises two or more different antibodies or antigen-binding fragments, which can be two or more presently disclosed antibodies or antigen-binding fragments.
- an antibody or antigen-binding fragment thereof can be comprised in a composition that further comprises an antibody or antigen-binding fragment that comprises: (i) CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:343-345 and 347-349, respectively; or (ii) CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 140-142 and 144-146, respectively; or (iii) VH and VL amino acid sequences as set forth in SEQ ID NOs.:342 and 346, respectively; or (iv) VH and VL amino acid sequences as set forth in SEQ ID NOs.: 139 and 143,
- a composition comprises a first antibody or antigen binding fragment, comprising a VH comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 32 and a VL comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 36; and a second antibody or antigen- binding fragment comprising a VH comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 139, and a VL comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 143.
- a composition comprises a first antibody or antigen-binding fragment comprising a heavy chain variable domain (VH) comprising a CDRH1, a CDRH2, and a CDRH3, and a light chain variable domain (VL) comprising a CDRL1, a CDRL2, and a CDRL3, wherein the CDRH1, CDRH2, and CDRH3 comprise or consist of the amino acid sequences set forth in SEQ ID NOs: 33-35, respectively, and the CDRL1, CDRL2, and CDRL3 comprise or consist of the amino acid sequences set forth in SEQ ID NOs: 37-39, respectively, and a second antibody or antigen-binding fragment comprising a heavy chain variable domain (VH) comprising a CDRH1, a CDRH2, and a CDRH3, and a light chain variable domain (VL) comprising a CDRL1, a CDRL2, and a CDRL3, wherein the CDRH1, CDRH2, and CDRH3 comprise or consist of the amino acid
- a composition comprises a first antibody or antigenbinding fragment, comprising a VH comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 139 or 342 and a VL comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 143 or 346; and a second antibody or antigen-binding fragment comprising a VH comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 399, 748, 749, 750, 752, 754, 756, 758, 759, or 761, and a VL comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 403, 744, or 746.
- a composition comprises a first antibody or antigen-binding fragment comprising a heavy chain variable domain (VH) comprising a CDRH1, a CDRH2, and a CDRH3, and a light chain variable domain (VL) comprising a CDRL1, a CDRL2, and a CDRL3, wherein the CDRH1, CDRH2, and CDRH3 comprise or consist of the amino acid sequences set forth in SEQ ID NOs: 140-142, respectively, or 343-345, respectively, and the CDRL1, CDRL2, and CDRL3 comprise or consist of the amino acid sequences set forth in SEQ ID NOs: 144-146, respectively, and a second antibody or antigen-binding fragment comprising a heavy chain variable domain (VH) comprising a CDRH1, a CDRH2, and a CDRH3, and a light chain variable domain (VL) comprising a CDRL1, a CDRL2, and a CDRL3, wherein the CDRH1, CDRH2, and CDR
- compositions that comprise (i) a first antibody or antigen-binding fragment that is capable of binding to a SARS-CoV-2 surface glycoprotein and inhibiting an interaction between the SARS-CoV-2 surface glycoprotein and a first cell surface receptor selected from ACE2, DC-SIGN, L-SIGN, and SIGLEC-1; and (ii) a second antibody or antigen-binding fragment that is capable of binding to a SARS-CoV-2 surface glycoprotein and inhibiting an interaction between the SARS-CoV-2 surface glycoprotein and a second cell surface receptor selected from ACE2, DC-SIGN, L-SIGN, and SIGLEC-1, wherein the first cell surface receptor and the second cell surface receptor are different.
- neutralization of infection can be achieved or improved by combingin antibodies or antigen-binding fragments, the binding of which to SARS-CoV-2 inhibits interactions between the SARS-CoV-2 and two or more cell surface receptors; e.g. , an attachment receptor and an entry receptor, two entry receptors, two attachment receptors, or the like.
- Methods of using such antibody combinations to treat or prevent a SARS-CoV-2 infection are also provided.
- a composition comprises a first vector comprising a first plasmid, and a second vector comprising a second plasmid, wherein the first plasmid comprises a polynucleotide encoding a heavy chain, VH, or VH+CH, and a second plasmid comprises a polynucleotide encoding the cognate light chain, VL, or VL+CL of the antibody or antigen-binding fragment thereof.
- a composition comprises a polynucleotide (e.g., mRNA) coupled to a suitable delivery vehicle or carrier.
- Exemplary vehicles or carriers for administration to a human subject include a lipid or lipid-derived delivery vehicle, such as a liposome, solid lipid nanoparticle, oily suspension, submicron lipid emulsion, lipid microbubble, inverse lipid micelle, cochlear liposome, lipid microtubule, lipid microcylinder, or lipid nanoparticle (LNP) or a nanoscale platform (see, e.g., Li et al. Wilery Interdiscip Rev. Nanomed Nanobiotechnol. 77(2):el530 (2019)).
- LNP lipid nanoparticle
- Principles, reagents, and techniques for designing appropriate mRNA and and formulating mRNA-LNP and delivering the same are described in, for example, Pardi et al.
- lipid nanoparticles e.g, ionizable cationic lipid/phosphatidylcholine/cholesterol/PEG-lipid; ionizable lipid:distearoyl PC:cholesterol:polyethylene glycol lipid
- subcutaneous, intramuscular, intradermal, intravenous, intraperitoneal, and intratracheal administration of the same, are incorporated herein by reference.
- Methods of diagnosis may include contacting an antibody, antibody fragment (e.g., antigen binding fragment) with a sample.
- Such samples may be isolated from a subject, for example an isolated tissue sample taken from, for example, nasal passages, sinus cavities, salivary glands, lung, liver, pancreas, kidney, ear, eye, placenta, alimentary tract, heart, ovaries, pituitary, adrenals, thyroid, brain, skin or blood.
- the methods of diagnosis may also include the detection of an antigen/antibody complex, in particular following the contacting of an antibody or antibody fragment with a sample.
- Such a detection step can be performed at the bench, i.e. without any contact to the human or animal body.
- detection methods are well-known to the person skilled in the art and include, e.g ., ELISA (enzyme-linked immunosorbent assay), including direct, indirect, and sandwich ELISA.
- Other detection methods include, but are not limited to, immunohistochemistry (IHC), flow cytometry (e.g, FACS), Western blot, immunocytochemistry (ICC), enzyme-linked immunospot (ELISPOT), and immunoprecipitation (IP).
- IHC immunohistochemistry
- FACS flow cytometry
- ICC immunocytochemistry
- ELISPOT enzyme-linked immunospot
- IP immunoprecipitation
- Antibodies and antigen-binding fragments used in detection methods can be, for example, fluorescently or otherwise detectably labeled (e.g., directly conjugated to a fluorophore or comprising a fluorophore- secondary conjugate).
- Treatment refers to medical management of a disease, disorder, or condition of a subject (e.g, a human or non-human mammal, such as a primate, horse, cat, dog, goat, mouse, or rat).
- an appropriate dose or treatment regimen comprising an antibody or composition of the present disclosure is administered in an amount sufficient to elicit a therapeutic or prophylactic benefit.
- therapeutic or prophylactic/preventive benefit includes a reduced or abrogated need for respiratory intervention, such as intubation and/or the use of a respirator device.
- therapeutic or prophylactic/preventive benefit includes reversing a late-stage disease pathology and/or reducing mortality.
- Embodiment 4 An antibody, or antigen-binding fragment thereof, comprising the CDRH1, the CDRH2, and the CDRH3 of the VH amino acid sequence set forth in SEQ ID NO.:399, and the CDRL1, the CDRL2 or a variant of the CDRL2 comprising one, two, or three amino acid substiutions, wherein each of the one, two, or three amino acid substitutions is optionally a conservative amino acid substitution, and the CDRL3 of the VL amino acid sequence set forth in SEQ ID NO.:738, wherein the CDRs are according to IMGT, and wherein the antibody or antigen-binding fragment is capable of binding to a surface glycoprotein of SARS-CoV-2 expressed on a cell surface of a host cell and/or on a virion.
- Embodiment 5 An antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable domain (VH) comprising complementarity determining region (CDR)H1, CDRH2, and CDRH3, and a light chain variable domain (VL) comprising CDRLl, CDRL2, and CDRL3, wherein CDRH1, CDRH2, CDRH3, CDRLl, CDRL2, and CDRL3 comprise the amino acid sequences set forth in: (a) SEQ ID NOs.:400, 401, 766, 404, 405, and 406, respectively; (b) SEQ ID NOs.:400, 401, 769, 404, 405, and 406, respectively; (c) SEQ ID NOs.:400, 401, 770, 404, 405, and 406, respectively; (d) SEQ ID NOs.:400, 401, 771, 404, 405, and 406, respectively; (e) SEQ ID NOs.:400, 401, 772, 404, 405, and 406, respectively; (f
- Embodiment 7 The antibody or antigen-binding fragment of any one of
- variation is optionally limited to one or more framework regions and/or the variation comprises one or more substitution to a germline-encoded amino acid;
- the VL comprises or consists of an amino acid sequence having at least
- variation is optionally limited to one or more framework regions and/or the variation comprises one or more substitution to a germline-encoded amino acid.
- Embodiment 14 The antibody or antigen-binding fragment of any one of Embodiments 1-13, wherein the VH comprises or consists of an amino acid sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO.:399 and the VL comprises or consists of an amino acid sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO.:403 or SEQ ID NO.:738.
- Embodiment 15 The antibody or antigen-binding fragment of any one of Embodiments 1-14, wherein the VH comprises or consists of an amino acid sequence having at least 95% identity to the amino acid sequence set forth in SEQ ID NO.:399 and the VL comprises or consists of an amino acid sequence having at least 95% identity to the amino acid sequence set forth in SEQ ID NO.:403 or SEQ ID NO.:738.
- Embodiment 18 The antibody or antigen-binding fragment of any one of
- Embodiments 1-12 wherein the VH and the VL have at least 85% identity (e.g 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) to the amino acid sequences set forth in:
- Embodiment 19 The antibody or antigen-binding fragment of any one of Embodiments 1-18, wherein the VH comprises or consists of any VH amino acid sequence set forth in Table 2, and wherein the VL comprises or consists of any VL amino acid sequence set forth in Table 2, wherein, optionally, the VH and the VL comprise or consist of the amino acid sequences according to SEQ ID NOs.: (i) 399 and 403 or 738, respectively; (ii) 32 and 36, respectively; (iii) 42 and 46, respectively; (iv) 52 and 56, respectively; (v) 62 and 66, respectively; (vi) 72 and 66, respectively; (vii)
- Embodiment 20 An antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the VH comprises or consists of the amino acid sequence set forth in SEQ ID NO:399 and the VL comprises or consists of the amino acid sequence set forth in SEQ ID NO:738, wherein the antibody or antigen-binding fragment is capable of binding to a surface glycoprotein of SARS-CoV-2 expressed on a cell surface of a host cell and/or on a virion.
- VH heavy chain variable domain
- VL light chain variable domain
- Embodiment 21 An antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the VH comprises or consists of the amino acid sequence set forth in SEQ ID NO:399 and the VL comprises or consists of the amino acid sequence set forth in SEQ ID NO:403, wherein the antibody or antigen-binding fragment is capable of binding to a surface glycoprotein of SARS-CoV-2 expressed on a cell surface of a host cell and/or on a virion.
- VH heavy chain variable domain
- VL light chain variable domain
- Embodiment 22 An antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the VH comprises or consists of the amino acid sequence set forth in any one of SEQ ID NOs:399, 748, 749, 750, 752, 754, 756, 758, 759, and 761, the VL comprises or consists of the amino acid sequence set forth in SEQ ID NO:403, wherein the antibody or antigen-binding fragment is capable of binding to a surface glycoprotein of SARS-CoV-2 expressed on a cell surface of a host cell and/or on a virion.
- VH heavy chain variable domain
- VL light chain variable domain
- Embodiment 23 An antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the VH comprises or consists of the amino acid sequence set forth in any one of SEQ ID NOs:399, 748, 749, 750, 752, 754, 756, 758, 759, and 761, the VL comprises or consists of the amino acid sequence set forth in SEQ ID NO:738, wherein the antibody or antigen-binding fragment is capable of binding to a surface glycoprotein of SARS-CoV-2 expressed on a cell surface of a host cell and/or on a virion.
- Embodiment 24 Embodiment 24.
- An antibody, or an antigen-binding fragment thereof comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the VH comprises or consists of the amino acid sequence set forth in any one of SEQ ID NOs:399, 748, 749, 750, 752, 754, 756, 758, 759, and 761, the VL comprises or consists of the amino acid sequence set forth in SEQ ID NO:744, wherein the antibody or antigen-binding fragment is capable of binding to a surface glycoprotein of SARS-CoV-2 expressed on a cell surface of a host cell and/or on a virion.
- VH heavy chain variable domain
- VL light chain variable domain
- Embodiment 25 An antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the VH comprises or consists of the amino acid sequence set forth in any one of SEQ ID NOs:399, 748, 749, 750, 752, 754, 756, 758, 759, and 761, the VL comprises or consists of the amino acid sequence set forth in SEQ ID NO:746, wherein the antibody or antigen-binding fragment is capable of binding to a surface glycoprotein of SARS-CoV-2 expressed on a cell surface of a host cell and/or on a virion.
- VH heavy chain variable domain
- VL light chain variable domain
- Embodiment 26 An antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the VH comprises or consists of the amino acid sequence set forth in SEQ ID NO:524 and the VL comprises or consists of the amino acid sequence set forth in SEQ ID NO:528, wherein the antibody or antigen-binding fragment is capable of binding to a surface glycoprotein of SARS-CoV-2 expressed on a cell surface of a host cell and/or on a virion.
- VH heavy chain variable domain
- VL light chain variable domain
- Embodiment 27 An antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the VH comprises or consists of the amino acid sequence set forth in any one of SEQ ID NOs.:584, 624, 626, and 628 and the VL comprises or consists of the amino acid sequence set forth in SEQ ID NO:588, wherein the antibody or antigen-binding fragment is capable of binding to a surface glycoprotein of SARS-CoV-2 expressed on a cell surface of a host cell and/or on a virion.
- VH heavy chain variable domain
- VL light chain variable domain
- Embodiment 29 An antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the VH comprises or consists of the amino acid sequence set forth in any one of SEQ ID NOs.:228, 740, 741, 742, and 743, and the VL comprises or consists of the amino acid sequence set forth in SEQ ID NO:238, wherein the antibody or antigen-binding fragment is capable of binding to a surface glycoprotein of SARS-CoV-2 expressed on a cell surface of a host cell and/or on a virion.
- VH heavy chain variable domain
- VL light chain variable domain
- Embodiment 30 An antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the VH comprises or consists of the amino acid sequence as set forth in SEQ ID NO: 32 and the VL comprises or consists of the amino acid sequence as set forth in SEQ ID NO: 36.
- Embodiment 31 An antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the VH comprises or consists of the amino acid sequence as set forth in SEQ ID NO: 32 and the VL comprises or consists of the amino acid sequence as set forth in SEQ ID NO: 36.
- Embodiment 31 An antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the VH comprises or consists of the amino acid sequence as set forth in SEQ ID NO: 32 and the VL comprises or
- An antibody, or an antigen-binding fragment thereof comprising a heavy chain variable domain (VH) comprising a CDRH1, a CDRH2, and a CDRH3, and a light chain variable domain (VL) comprising a CDRL1, a CDRL2, and a CDRL3, wherein the CDRH1, CDRH2, and CDRH3 comprise or consist of the amino acid sequences set forth in SEQ ID NOs: 33-35, respectively, and the CDRL1, CDRL2, and CDRL3 comprise or consist of the amino acid sequences set forth in SEQ ID NOs: 37-39, respectively.
- VH heavy chain variable domain
- VL light chain variable domain
- Embodiment 32 The antibody or antigen-binding fragment of any one of Embodiments 3-31, which is capable of neutralizing a SARS-CoV-2 infection in an in vitro model of infection and/or in an in vivo animal model of infection and/or in a human.
- Embodiment 33 The antibody or antigen-binding fragment of any one of Embodiments 1-32, which:
- (ii) is capable of blocking an interaction between SARS-CoV-2 (e.g, SARS- CoV-2 RBM) and human ACE2;
- SARS-CoV-2 e.g, SARS- CoV-2 RBM
- human ACE2 e.g, SARS-CoV-2 RBM
- (v) is cross-reactive against SARS-CoV-2 and SARS-CoV-1 coronavirus; (vii) recognizes an epitope in the SARS-CoV-2 surface glycoprotein that is not in the ACE2 RBM;
- (viii) is capable of binding to a SARS-CoV-2 S protein trimer in a prefusion conformation
- Embodiment 34 any combination of (i)-(viii).
- Embodiment 34 The antibody or antigen-binding fragment of any one of Embodiments 1-33, which is a IgG, IgA, IgM, IgE, or IgD isotype.
- Embodiment 35 The antibody or antigen-binding fragment of any one of Embodiments 1-34, which is an IgG isotype selected from IgGl, IgG2, IgG3, and IgG4.
- Embodiment 36 The antibody or antigen-binding fragment of any one of
- Embodiments 1-35 which is human, humanized, or chimeric.
- Embodiment 37 The antibody or antigen-binding fragment of any one of Embodiments 1-36, wherein the antibody, or the antigen-binding fragment, comprises a human antibody, a monoclonal antibody, a purified antibody, a single chain antibody, a Fab, a Fab’, a F(ab’)2, a Fv, a scFv, or a scFab.
- Embodiment 38 The antibody or antigen-binding fragment of Embodiment 37, wherein the scFv comprises more than one VH domain and more than one VL domain.
- Embodiment 39 The antibody or antigen-binding fragment of any one of
- Embodiments 1-38 wherein the antibody or antigen-binding fragment is a multi-specific antibody or antigen binding fragment.
- Embodiment 40 The antibody or antigen-binding fragment of Embodiment 39, wherein the antibody or antigen binding fragment is a bispecific antibody or antigen-binding fragment.
- Embodiment 41 The antibody or antigen-binding fragment of Embodiment
- first VH and the second VH are different and each independently comprise an amino acid sequence having at least 85% (e.g, 85%, 86%, 87%, 88%,
- first VL and the second VL are different and each independently comprise an amino acid sequence having at least 85% (e.g, 85%, 86%, 87%, 88%,
- Embodiment 51 The antibody or antigen-binding fragment of any one of Embodiments 47-50, wherein the mutation that enhances binding to a FcyR comprises S239D; I332E; A330L; G236A; or any combination thereof.
- Embodiment 52 The antibody or antigen-binding fragment of any one of Embodiments 47-51, wherein the mutation that enhances binding to a FcyR comprises: (i) S239D/I332E; (ii) S239D/A330L/I332E; (iii) G236A/S239D/I332E; or
- Embodiment 53 The antibody or antigen-binding fragment of any one of Embodiments 47-52, wherein the Fc polypeptide comprises a L234A mutation and a L235A mutation.
- Embodiment 54 The antibody or antigen-binding fragment of any one of Embodiments 1-53, which comprises a mutation that alters glycosylation, wherein the mutation that alters glycosylation comprises N297A, N297Q, or N297G, and/or which is aglycosylated and/or afucosylated.
- Embodiment 55 The antibody or antigen-binding fragment of any one of Embodiments 1-54, which is capable of binding to a SARS-CoV-2 surface glycoprotein with an EC50 of less than 500 ng/ml, less than 250 ng/ml, less than 100 ng/ml, less than 90 ng/ml, less than 80 ng/ml, less than 70 ng/ml, less than 60 ng/ml, less than 50 ng/ml, less than 40 ng/ml, less than 30 ng/ml, less than 25 ng/ml, less than 20 ng/ml, less than 16 ng/ml, less than 15 ng/ml, less than 14 ng/ml, less than 13 ng/ml, less than 12 ng/ml, less than 10 ng/ml, less than 9 ng/ml, less than 8 ng/ml, less than 7 ng/ml, less than 6 ng/ml, less than 5 ng/ml
- Embodiment 56 The antibody or antigen-binding fragment of any one of Embodiments 1-55, which is capable of binding to a SARS-CoV-2 surface glycoprotein RBD with an EC50 of less than 500 ng/ml, less than 250 ng/ml, less than 100 ng/ml, less than 90 ng/ml, less than 80 ng/ml, less than 70 ng/ml, less than 60 ng/ml, less than 50 ng/ml, less than 40 ng/ml, less than 30 ng/ml, less than 25 ng/ml, less than 20 ng/ml, less than 16 ng/ml, less than 15 ng/ml, less than 14 ng/ml, less than 13 ng/ml, less than 12 ng/ml, less than 10 ng/ml, less than 9 ng/ml, less than 8 ng/ml, less than 7 ng/ml, less than 6 ng/ml, less than 5 ng/
- Embodiment 57 The antibody or antigen-binding fragment of any one of Embodiments 1-56, which is capable of binding to a SARS-CoV-2 RBD with a KD of less than 5 x 10 -8 M, less than 4 x 10 -8 M, less than 3 x 10 -8 M, less than 2 x 10 -8 M, less than 1 x 10 -8 M, less than 5 x 10 -9 M, less than 1 x 10 -9 M, less than 5 x 10 -10 M, less than 1 x 10 -10 M, less than 5 x 10 -11 M, less than 1 x 10 -11 M, less than 5 x 10 -12 M, or less than 1 x 10 -12 M, as determined using biolayer interferometry (BLI), optionally using an Octet instrument with antibody or antigen-binding fragment loaded on Protein A pins, optionally at 2.7 ⁇ g/ml, and SARS-CoV-2 RBD loaded for 5 minutes at 6 ⁇ g/ml, 1.5 ⁇ g
- Embodiment 58 The antibody or antigen-binding fragment of any one of Embodiments 1-57, which is capable of binding to a SARS-CoV-2 RBD with a KD of less than 6 x 10 -8 M, less than 5 x 10 -8 M, less than 4 x 10 -8 M, less than 3 x 10 -8 M, less than 2 x 10 -8 M, less than 1 x 10 -8 M, less than 5 x 10 -9 M, less than 4 x 10 -9 M, less than 3 x 10 -9 M, less than 2 x 10 -9 M, less than 1 x 10 -9 M, or less than 8 x 10 -10 M, as determined using surface plasmon resonance (SPR), optionally using a Biacore T200 instrument using a single-cycle kinetics approach.
- SPR surface plasmon resonance
- Embodiment 59 The antibody or antigen-binding fragment of any one of claims 1-58, which is capable of binding to a SARS-CoV-2 RBD and inhibiting an interaction between (i) the RBD and (ii) a human ACE2 and/or a human SIGLEC-1.
- Embodiment 60 The antibody or antigen-binding fragment of any one of Embodiments 1-59, which is capable of neutralizing:
- the SARS-CoV-2 pseudovirus comprises a VSV pseudovirus and/or a MLV pseudovirus;
- the FcyRIIIa comprises a VI 58 allele; and/or (iii) activation is determined using a SARS-CoV-2 S-expressing target cell, such as a CHO cell, and a reporter cell expressing a NFAT-driven reporter, such as luciferase.
- a SARS-CoV-2 S-expressing target cell such as a CHO cell
- a reporter cell expressing a NFAT-driven reporter, such as luciferase.
- Embodiment 65 An isolated antibody comprising:
- Embodiment 66 The antibody or antigen-binding fragment of any one of Embodiments 1-65, which has an in vivo half-life in a non-human primate of between 20 and 30 days, or between 22 and 28 days, or between 23 and 27 days, or between 24 and 26 days, or of about 25 days.
- Embodiment 67 The antibody or antigen-binding fragment of any one of
- Embodiments 1-66 wherein the antibody or antigen-binding fragment is capable of neutralizing a SARS-CoV-2 infection and/or of neutralizing an infection of a target cell with an IC50 of about 20 to about 30 ng/ml.
- Embodiment 68 The antibody or antigen-binding fragment of any one of Embodiments 1-66, wherein the antibody or antigen-binding fragment is capable of neutralizing a SARS-CoV-2 infection and/or of neutralizing an infection of a target cell with an IC50 of about 10 to about 20 ng/ml.
- Embodiment 69 The antibody or antigen-binding fragment of any one of Embodiments 1-66, wherein the antibody or antigen-binding fragment is capable of neutralizing a SARS-CoV-2 infection and/or of neutralizing an infection of a target cell with an IC50 of about 5 to about 10 ng/ml.
- Embodiment 70 The antibody or antigen-binding fragment of any one of Embodiments 1-66, wherein the antibody or antigen-binding fragment is capable of neutralizing a SARS-CoV-2 infection and/or of neutralizing an infection of a target cell with an IC50 of about 1 to about 5 ng/ml.
- Embodiment 71 The antibody or antigen-binding fragment of any one of
- Embodiments 1-70 wherein the antibody or antigen-binding fragment is capable of neutralizing infection by SARS-CoV-2 and does not compete with a human ACE2 for binding to the SARS-CoV-2S protein, wherein, optionally, the neutralizing comprises neutralizing infection in an in vitro model of infection.
- Embodiment 72 An antibody, or an antigen-binding fragment thereof, that competes for binding to a SARS-CoV-2 surface glycoprotein with the antibody or antigen-binding fragment of any one of Embodiments 1-71.
- Embodiment 73 An isolated polynucleotide encoding the antibody or antigen-binding fragment of any one of Embodiments 1-72, or encoding a VH, a heavy chain, a VL, and/or a light chain of the antibody or the antigen-binding fragment.
- Embodiment 74 The polynucleotide of Embodimenf73, wherein the polynucleotide comprises deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), wherein the RNA optionally comprises messenger RNA (mRNA).
- DNA deoxyribonucleic acid
- RNA ribonucleic acid
- mRNA messenger RNA
- Embodiment 75 The polynucleotide of Embodiment73 or 74, which is codon-optimized for expression in a host cell.
- Embodiment 76 The polynucleotide of any one of Embodiments 73-75, comprising a polynucleotide having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% identity to, or comprises or consists of, the polynucleotide sequence according to any one or more of SEQ ID NOs.: 30, 31, 40, 41, 50, 51, 60, 61,
- a second antibody or antigen-binding fragment that is capable of binding to a SARS-CoV-2 surface glycoprotein and comprises
- VH comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences set forth in SEQ ID NOs.:140, 141 or 344, and 142, respectively, and
- a first antibody or antigen-binding fragment that is capable of binding to a SARS-CoV-2 surface glycoprotein and comprises
- a second antibody or antigen-binding fragment that is capable of binding to a SARS-CoV-2 surface glycoprotein and comprises
- Embodiment 92 A composition comprising the polynucleotide of any one of Embodiments 73-77 encapsulated in a carrier molecule, wherein the carrier molecule optionally comprises a lipid, a lipid-derived delivery vehicle, such as a liposome, a solid lipid nanoparticle, an oily suspension, a submicron lipid emulsion, a lipid microbubble, an inverse lipid micelle, a cochlear liposome, a lipid microtubule, a lipid microcylinder, lipid nanoparticle (LNP), or a nanoscale platform.
- a lipid-derived delivery vehicle such as a liposome, a solid lipid nanoparticle, an oily suspension, a submicron lipid emulsion, a lipid microbubble, an inverse lipid micelle, a cochlear liposome, a lipid microtubule, a lipid microcylinder, lipid nanoparticle (LNP), or a
- Embodiment 95 A method of treating a coronavirus infection, e.g. a SARS-CoV-2 infection, in a subject, the method comprising administering to the subject:
- a first antibody or antigen-binding fragment that is capable of binding to a SARS-CoV-2 surface glycoprotein and comprises
- a second antibody or antigen-binding fragment that is capable of binding to a SARS-CoV-2 surface glycoprotein and comprises
- a first antibody or antigen-binding fragment that is capable of binding to a SARS-CoV-2 surface glycoprotein and comprises
- a second antibody or antigen-binding fragment that is capable of binding to a SARS-CoV-2 surface glycoprotein and comprises
- Embodiment 97 A method of preventing or treating or neutralizing a coronavirus infection in a subject, the method comprising administering to a subject who has received a first antibody or antigen binding fragment comprising:
- Embodiment 99 A method of preventing or treating or neutralizing a coronavirus infection in a subject, the method comprising administering to a subject who has received a first antibody or antigen binding fragment comprising:
- Embodiment 100 A method of preventing or treating or neutralizing a coronavirus infection in a subject, the method comprising administering to a subject who has received a first antibody or antigen binding fragment comprising:
- Embodiment 101 The method of any one of Embodiments 95-100, wherein the first antibody or antigen-binding fragment and the second antibody or antigenbinding fragment each comprise an IgGl Fc polypeptide comprising a M428L mutation and a N434S mutation.
- Embodiment 102 The method of any one of Embodiments 95-101, wherein the first antibody or antigen-binding fragment and the second antibody or antigenbinding fragment each comprise an IgGl Fc polypeptide comprising a G236A mutation, a A330L mutation, and a I332E mutation.
- Embodiment 103 A method of treating a coronavirus (e.g. SARS-CoV-2) infection in a subject, the method comprising administering to the subject: (i) a first antibody or antigen-binding fragment that is capable of binding to a SARS-CoV-2 surface glycoprotein and inhibiting an interaction between the SARS- CoV-2 surface glycoprotein and a first cell surface receptor selected from ACE2, DC- SIGN, L-SIGN, and SIGLEC-1; and
- Binding of monoclonal antibodies isolated from patients who recovered from SARS-CoV-2 infection to the RBD of SARS-CoV-1 and SARS-CoV-2 Spike protein was assessed using enzyme-linked immunosorbent assays (ELISA).
- 96-well plates were coated with SARS-CoV Spike SI Subunit Protein (Sino Biological), SARS-CoV-2 RBD (produced in house; residues 331-550 of spike from BetaCoV/Wuhan-Hu-1 /2019, accession number MN908947), or SARS-CoV RBD (Sino Biological).
- Wells were washed and blocked with PBS+1%BSA for 1 hour at room temperature and were then incubated with serially diluted recombinant monoclonal antibodies for 1 hour at room temperature.
- Murine leukemia virus (MLV) pseudotyped with SARS-CoV-2 Spike protein (SARS-CoV-2pp) was used.
- VeroE6 cells were used as target cells and were seeded one day before addition of virus and antibodies.
- SARS-CoV-2pp was activated with trypsin TPCK at lOug/ml.
- Activated SARS-CoV-2pp was added to a dilution series of antibodies and incubated for 48 hours. Starting concentration for antibodies was 5ug/ml per antibody, 3 -fold dilution. Luminescence was measured after aspirating cell culture supernatant and adding Bio-Glo substrate (Promega). Results are shown in Figures 3A-3F.
- Antibody S2E12 shown in Figure 9E comprises the VH amino acid sequence of SEQ ID NO.:399 (CDRH1-H3 of SEQ ID NOs.AOO, 401, and 766, respectively) and the VL amino acid sequence of SEQ ID NO.:403 (CDRL1-CDRL3 of SEQ ID N0s.:404-406, respectively).
- Monoclonal antibodies isolated from patients who recovered from SARS-CoV-2 infection were expressed recombinantly and were tested in neutralization assays against live SARS-CoV-2 virus.
- Vero E6 cells cultured in DMEM supplemented with 10% FBS (VWR) and lx Penicillin/Streptomycin (Thermo Fisher Scientific) were seeded in white 96-well plates at 20,000 cells/well and attached overnight.
- Serial 1:4 dilutions of the monoclonal antibodies were incubated with 200 pfu of SARS-CoV-2 (isolate USA- WA1/2020, passage 3, passaged in Vero E6 cells) for 30 minutes at 37°C in a BSL-3 facility. Cell supernatant was removed and the virus-antibody mixture was added to the cells.
- S2E12 comprises the VH amino acid sequence set forth in SEQ ID NO.:399 (CDRH1-H3 as set forth in SEQ ID NOs.:400, 401, and 766, respectively), and the VL amino acid sequence set forth in SEQ ID NO.:403 (CDRL1-L3 as set forth in SEQ ID N0s.:404-406, respectively).
- Calculated IC50 (ng/ml) values are shown in Tables 9-12.
- Calculated EC50 and EC90 values are shown in Tables 13-16. Table 9.
- Recombinant IgGl antibodies are produced using the VH and VL sequences of monoclonal antibodies S2H58 and S2N22, or engineered variants thereof. The combinations are produced as indicated in Table 21. Each of the antibodies is produced by transient transfection and expression of a plasmid vector encoding the recombinant antibody in HD 293F cells (GenScript). Cells are harvested on day 4 and IgG expression is validated by Western blot and protein A titer analysis. Table 21.
- VSV SARS-CoV-2 pseudotyped virus
- Recombinant monoclonal antibodies were serially diluted and incubated with a constant amount of VSV-deltaG-luc pseudotyped with SARS-CoV-2 (strain BetaCoV/Wuhan-Hu- 1 /2019, accession number MN908947) for 1.5 hours at 37 °C.
- VeroE6 cells were then added in complete DMEM medium and plates were incubated for 24 hours at 37 °C.
- culture medium was aspirated and luciferase substrate Bio-Glo Luciferase assay system (Promega AG) warmed to room temperature was added. After 10 minutes incubation in the dark on a shaker, signals were measured in a luminometer using 1 second integration time. Results for certain monoclonal antibodies are shown in Figures 12A-12D.
- S2X246, S2X256, S2X269, and S2X278, along with four comparator antibodies, to SARS-CoV-1 RBD was also measured by Octet.
- Antibody was loaded on Protein A pins at 2.7 ⁇ g/ml.
- SARS-CoV-1 RBD was loaded for 5 minutes at 6 ⁇ g/ml.
- Dissociation was measured for 7 minutes. Results are shown in Figure 15. In each graph, the vertical dashed line indicates the start of the dissociation phase.
- SARS-CoV-2 Spike protein antibody binding was analyzed by antibody competition assays, cryo-EM data, and crystallography data. From this analysis, Spike RBD antigenic Sites la, lb, Ic, Id, II, and IV were identified. A map showing these sites and antibodies that bind within each site is shown in Figure 24.
- S2E12 neutralization data are shown in Figure 53 (SARS-CoV-2-Nluc) and Figure 54 (pseudotyped VSV). Notably, S2E12 showed comparable neutralizing activity on all target cells.
- Stable cell lines were incubated with different concentration of anti-SIGLECl mAb (clone 7-239) and infected with SARS-CoV-2-Nluc. Infection as a percentage of untreated cells remained near to exceeded 100% in 293T cells expressing DC-SIGN, L- SIGN, or ACE2, but dropped to below 50% (0.2 ⁇ g/ml anti-SIGLEC) to close to 0 (1 ⁇ g/ml or 5 ⁇ g/ml anti-SIGLEC) in 293T cells expressing SIGLEC-1.
- Single cell expression levels of selected potential SARS-CoV-2 (co)receptor candidates were determined in different lung cell types derived from the Human Lung Cell Atlas (nature.com/articles/s41586-020-2922-4).
- DC-SIGN, L-SIGN and SIGLEC- 1 are expressed in a variety of cell types in the lung at levels similar to or even higher than ACE2.
- Binding of antibodies targeting DC-/L-SIGN, DC-SIGN, SIGLEC1 or ACE2 on HEK293T cells stably over-expressing the respective attachment receptor was analyzed by flow cytometry and immunofluorescence analysis.
- HEK 293T cells over-expressing the respective attachment receptors were infected with VSV pseudotyped with SARS- COV-2 wildtype spike or spike bearing mutations of the Bl.1.7 lineage. Luminescence was analyzed one day post infection. Infection was increased in cells expressing the attachment receptors. Infection by VSV pseudotyped with either spike was similar for each test group. Cells expressing ACE2 gave the highest luminescence signal.
- ACE2 DC-SIGN (CD209), L-SIGN (CLEC4M), SIGLEC1 transcript counts were correlated with SARS-CoV-2 RNA counts in macrophages and in secretory cells. Correlation was based on counts (before log transformation), from Ren et al. Cell 2021.
- Neutralizing activity of S309 against the VSV pseudovirus was assessed in the engineered HEK293T cells. Data are shown in Figure 45; S309 fully neutralized infection via DC-SIGN and L-SIGN, and neutralized infection via ACE2 to a lesser extent.
- the HeLa and MRC5 cells remained refractory to infection even after expression of L-SIGN, DC-SIGN, or SIGLEC-1, and only become susceptible after expression of ACE2. These data indicate that L-SIGN, DC-SIGN, and SIGLEC-1 are not primary receptors for SARS-CoV-2.
- Figure 71 shows neutralization on Vero E6 cells using antibodies S309, S2E12, and S2X333.
- Figure 72 shows neutralization on Vero E6-TMPRSS2 cells using the same antibodies.
- Figures 75 and 76 show neutralization of infection by these antibodies on various cell types.
- Figures 77-80 show results from cell-cell fusion and fusion inhibition assays.
- Figures 81-84 show neutralization of infection by antibodies on stable HEK293T cell line overexpressing ACE2, SIGLEC1, DC-SIGN, or L-SIGN.
- S2E12-v2 shown in Figure 99 as "S2E12" having the VH amino acid sequence of SEQ ID NO:399 and the VL amino acid sequence of SEQ ID NO:738, and comprising M428L and N434S Fc mutations.
- S2E12-v2 MLNS had a mean T1/2 (across 3 animals) of 25.4 days.
- the full-length S gene of SARS-CoV-2 strain (2019-nCoV-S) isolate BetaCo V/W uhan-Hu- 1 /2019 (accession number MN908947) was codon optimized for human cell expression and cloned into the phCMVl expression vector (Genlantis).
- Expi-CHO cells were transiently transfected with phCMVl-SARS-CoV-2-S, phCMVl - MERS-CoV-S (Londonl/2012), SARS-spike_pcDNA.3 (strain SARS) or the empty phCMVl (Mock) using Expifectamine CHO Enhancer.
- anti-His sensors (BIOSENSOR ANTI PENT A-HIS (HIS IK)) were used to immobilize the SI subunit protein of SARS-CoV (Sino Biological Europe GmbH). Sensors were hydrated for 10 min with Kinetics Buffer (KB; 0.01% endotoxin-free BSA, 0.002 L Tween-20, 0.005% NaN3 in PBS). SARS-CoV SI subunit protein was then loaded for 8 min at a concentration of 10 ⁇ g/ml in KB.
- Kinetics Buffer KB; 0.01% endotoxin-free BSA, 0.002 L Tween-20, 0.005% NaN3 in PBS.
- pseudoparticle neutralization assays use a VSV- based luciferase reporter pseudotyping system (Kerafast). VSV pseudoparticles and antibody are mixed in DMEM and allowed to incubate for 30 minutes at 37C. The infection mixture is then allowed to incubate with Vero E6 cells for lh at 37C, followed by the addition of DMEM with Pen-Strep and 10% FBS (infection mixture is not removed). The cells are incubated at 37C for 18-24 hours. Luciferase is measured using an Ensight Plate Reader (Perkin Elmer) after the addition of Bio-Glo reagent (Promega).
- SARS-CoV-2 genomics sequences were downloaded from GISAID on March 29th 2020, using the “complete (>29,000 bp)” and “low coverage exclusion” filters.
- Bat and pangolin sequences were removed to yield human-only sequences.
- Sourced SARS-CoV genome sequences comprised all the major published strains, such as Urbani, Tor2, TW1, P2, Frankfurtl, among others.
- Pangolin sequences as shown by Tsan-Yuk Lam et al were sourced from GISAID.
- Bat sequences from the three clades of Sarbecoviruses as shown by Lu et al (Lancet 2020) were sourced from Genbank.
- Civet and racoon dog sequences were similarly sourced from Genbank.
- Lentiviruses were generated by co-transfection of Lenti-X 293T cells (Takara) with lentiviral expression plasmids encoding DC-SIGN (CD209), L-SIGN (CLEC4M), SIGLEC1, TMPRSS2 or ACE2 (all obtained from Genecopoeia) and the respective lentiviral helper plasmids. Forty-eight hours post transfection, lentivirus in the supernatant was harvested and concentrated by ultracentrifugation for 2 h at 20,000 rpm.
- Lenti-X 293T cells (Takara) were seeded in 10-cm dishes for 80% next day confluency. The next day, cells were transfected with a plasmid encoding for SARS-CoV-2 S-glycoprotein (YP 009724390.1) harboring a C-terminal 19 aa truncation using TransIT-Lenti (Mirus Bio) according to the manufacturer’s instructions. One day post-transfection, cells were infected with VSV(G* ⁇ G-luciferase) (Kerafast) at an MOI of 3 infectious units/cell.
- Viral inoculum was washed off after one hour and cells were incubated for another day at 37°C.
- the cell supernatant containing SARS-CoV-2 pseudotyped VSV was collected at day 2 post-transfection, centrifuged at 1000 x g for 5 minutes to remove cellular debris, aliquoted, and frozen at -80°C.
- Lenti-X 293T cells were transfected with plasmids encoding the following receptor candidates (all purchased from Genecopoeia): ACE2 (NM 021804), DC-SIGN (NM_021155), L-SIGN (BC110614), LGALS3 (NM_002306), SIGLEC1 (NM_023068), SIGLEC3 (XM_057602), SIGLEC9 (BC035365), SIGLEC10 (NM_033130), MGL (NM_182906), MINCLE (NM_014358), CD147 (NM_198589), ASGR1 (NM_001671.4), ASGR2 (NM_080913), NRP1 (NM_003873).
- CHO cells stably expressing SARS-CoV-2 S-glycoprotein were seeded in 96 well plates for microscopy (Thermo Fisher Scientific) at 12’ 500 cells/well and the following day, different concentrations of mAbs and nuclei marker Hoechst (final dilution 1 : 1000) were added to the cells and incubated for additional 24h hours. Fusion degree was established using the Cytation 5 Imager (BioTek) and an object detection protocol was used to detect nuclei as objects and measure their size.
- the nuclei of fused cells i.e., syncytia
- the area of the objects in fused cells divided by the total area of all the object multiplied by 100 provides the percentage of fused cells
- HEK 293T cells were seeded onto poly-D-Lysine-coated 96-well plates (Sigma- Aldrich) and fixed 24 h after seeding with 4% paraformaldehyde for 30 min, followed by two PBS (pH 7.4) washes and permeabilization with 0.25% Triton X-100 in PBS for 30 min.
- Cells were incubated with primary antibodies anti-DC-SIGN/L-SIGN (Biolegend, cat. 845002, 1:500 dilution), anti-DC-SIGN (Cell Signaling, cat. 13193 S, 1:500 dilution), anti-SIGLECl (Biolegend, cat.
- the SARS-CoV-2 strain used in this study BetaCov/Belgium/GHB-03021/2020 (EPI ISL 109407976
- a close relation with the prototypic Wuhan-Hu-1 2019-nCoV (GenBank accession 112 number MN908947.3) strain was confirmed by phylogenetic analysis. Infectious virus was isolated by serial passaging on HuH7 and Vero E6 cells; passage 6 virus was used for the study described here. The titer of the virus stock was determined by end-point dilution on Vero E6 cells by the Reed and Muench method.
- Vero E6 cells African green monkey kidney, ATCC CRL-1586 were cultured in minimal essential medium (Gibco) supplemented with 10% fetal bovine serum (Integra), 1% L- glutamine (Gibco) and 1% bicarbonate (Gibco). End-point titrations were performed with medium containing 2% fetal bovine serum instead of 10%.
- Immunocomplexes were generated by complexing S309 mAh (hamster IgG, either wt or N297A) with a biotinylated anti-idiotype fab fragment and Alexa-488- streptavidin, using a precise molar ratio (4:8:1, respectively). Pre-generated fluorescent IC were serially diluted incubated at 4°C for 3 hrs with freshly revitalized hamster splenocytes, obtained from a naive animal. Cellular binding was then evaluated by cytometry upon exclusion of dead cells and physical gating on monocyte population. Results are expressed as Alexa-488 mean florescent intensity of the entire monocyte population.
- Patent Application No. 63/153,784, filed February 25, 2021, and U.S. Patent Application No. 63/170, 368, filed April 2, 2021, are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments.
Abstract
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