Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/08—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from viruses
  • C07K16/10—RNA viruses
• • 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 [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/08—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from viruses
  • C07K16/10—RNA viruses
  • C07K16/102—Coronaviridae (F)
  • C07K16/104—Severe acute respiratory syndrome coronavirus 2 [SARS‐CoV‐2]
• • 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
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
  • C07K2317/22—Immunoglobulins specific features characterized by taxonomic origin from camelids, e.g. camel, llama or dromedary
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/52—Constant or Fc region; Isotype
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
  • C07K2317/565—Complementarity determining region [CDR]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
  • C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
  • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• • C—CHEMISTRY; METALLURGY
  • 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

• the polypeptide comprises an immunoglobulin heavy chain variable domain (VH).
• VH immunoglobulin heavy chain variable domain
• the polypeptide further comprises a paratope that is identical to the paratope of a single domain antibody comprising: a) SEQ ID NO: 4; or b) SEQ ID NO: 5.
• the invention provides a polypeptide that specifically binds SARS- CoV-2-Spike, wherein the polypeptide comprises an immunoglobulin heavy chain variable domain (VH) comprising a paratope that is identical to the paratope of an antibody comprising an amino acid sequence selected from: a) SEQ ID NO: 4; or b) SEQ ID NO: 5.
• VH immunoglobulin heavy chain variable domain
• all of the amino acid residues constituting the paratope are oriented less than about 5.0 angstroms from an epitope on a target antigen when the polypeptide is bound to the target antigen.
• SEQ ID NO: 2 The sequence identified as SEQ ID NO: 2 is shown below, which is a consensus VH sequence for SEQ ID Nos: 3-5 herein.
• Xi is V
• X2 is H
• X3 is L, or any combination of the foregoing.
• the amino acid substitutions are conservative substitutions.
• conservative amino acid substitution(s) or “conservative substitution(s)” refers to an amino acid substitution having a value of 0 or greater in BLOSUM62.
• the amino acid substitutions are highly conservative substitutions.
• the term “highly conservative amino acid substitution(s)” or “highly conservative substitution(s)” refers to an amino acid substitution having a value of at least 1 (e.g., at least 2) in BLOSUM62.
• a polypeptide disclosed herein comprises a VH that comprises the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 5. In some embodiments, a polypeptide disclosed herein comprises a VH that comprises the amino acid sequence of SEQ ID NO: 4. In some embodiments, a polypeptide disclosed herein comprises a VH that comprises the amino acid sequence of SEQ ID NO: 5.
• a polypeptide disclosed herein comprises the amino acid sequence of SEQ ID NO: 15 or SEQ ID NO: 16. In some embodiments, a polypeptide disclosed herein comprises the amino acid sequence of SEQ ID NO: 15. In some embodiments, a polypeptide disclosed herein comprises the amino acid sequence of SEQ ID NO: 16.
• a polypeptide disclosed herein is an immunoglobulin molecule, such as an antibody (e.g., a whole antibody, an intact antibody) or an antigen-binding fragment of an antibody.
• an antibody e.g., a whole antibody, an intact antibody
• an antigen-binding fragment of an antibody e.g., an antibody that is an immunoglobulin molecule capable of specific binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable region of the immunoglobulin molecule.
• the term “antibody” refers to a full-length antibody.
• a polypeptide disclosed herein is a single-domain antibody or an antigen-binding fragment thereof.
• the term “single-domain antibody (sdAb)” or “nanobody” refers to an immunoglobulin molecule consisting of a single monomeric variable antibody domain and capable of specific binding to a target.
• the single-domain antibody can be of any species, such as a murine antibody, a human antibody or a humanized single-domain antibody.
• the extent of the framework region and the CDRs of an antibody can be identified using one of several suitable methodologies that are well known in the art, for example, by the Kabat definition, the Chothia definition, the AbM definition, and/or the contact definition.
• Publicly and/or commercially available tools for identifying framework and/or CDR regions include, IgBlast (accessible at www.ncbi.nlm.nih.gov/igblast/), Scaligner (available from drugdesigntech at www.scaligner.com/), IMGT rules and/or tools (see, for example, www.imgt.org/IMGTScientificChart/Nomenclature/IMGT-FRCDRdefmition.html, also accessible at www.imgt.org/), Chothia Canonical Assignment (accessible at www.bioinf.org.uk/abs/chothia.html), Antigen receptor Numbering And Receptor Calssificatilon (ANARCI, accessible at opig.stats.ox.a
• the CAR comprises a transmembrane domain and an antigen-recognition moiety, wherein the antigen-recognition moiety binds SARS- CoV-2 (for example, an epitope within RBD, e.g., recognized by RBD Community 7).
• the polypeptide further comprises an antibody light chain constant domain sequence.
• the antibody light chain constant domain is selected from the group consisting of a K constant domain and a X constant domain.
• the antibody heavy chain constant region is an IgGl constant region, and the antibody light chain constant region is a K constant region.
• the polypeptide and the second polypeptide are linked to each other via a linker.
• the linker is a disulfide bond.
• the polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 3, 4 or 5; or b) the polypeptide comprises the amino acid sequence of SEQ ID NO: 5 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 3, 4 or 5.
• the polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 3. In some embodiments, the polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 4. In some embodiments, the polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 5. In some embodiments, the polypeptide comprises the amino acid sequence of SEQ ID NO: 5 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 3.
• the polypeptide comprises the amino acid sequence of SEQ ID NO: 16 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 15. In some embodiments, the polypeptide comprises the amino acid sequence of SEQ ID NO: 16 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 16.
• the antibody light chain constant region sequence is at least about 60% identical to the amino acid sequence of SEQ ID NO: 13 or SEQ ID NO: 14.
• the antibody light chain constant region sequence can be at least about: 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 13 or SEQ ID NO: 14.
• the antibody light chain constant region sequence is at least about 70% or at least about 80% identical to the amino acid sequence of SEQ ID NO: 13 or SEQ ID NO: 14.
• the polypeptide is conjugated to a heterologous moiety.
• conjugated refers to attached, via a covalent or noncovalent interaction. Conjugation can employ any of suitable linking agents. Non-limiting examples include peptide linkers, compound linkers, and chemical cross-linking agents.
• the heterologous moiety is a therapeutic agent, a diagnostic agent or a combination thereof.
• the heterologous moiety is polyethylene glycol (PEG), hexadecanoic acid, hydrogels, nanoparticles, multimerization domains and carrier peptides.
• the method is used for prophylactic therapy.
• the effective dosage is sufficient to prevent the subject of being infected by SARS-CoV-2.
• the effective dosage is sufficient to inhibit viral load in the subject.
• the reduction in viral load is by at least about 10%, e.g., by at least about: 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%.
• a polypeptide, composition, or pharmaceutical composition disclosed herein is administered to a subject in combination with one or more additional therapeutic agents (e.g., concurrently or sequentially with one or more additional therapeutic agents).
• a subject has been previously treated with one or more therapeutic agents prior to being administered a polypeptide, composition, or pharmaceutical composition disclosed herein.
• the method further comprises administering a therapeutically effective amount of one or more additional therapeutic agents to the subject at the same time as, or following administration of a polypeptide, composition, or pharmaceutical composition disclosed herein.
• the additional anti-SARS-CoV-2 monoclonal antibody targets the RBD of the S protein of SARS-CoV-2.
• the additional anti-SARS- CoV-2 monoclonal antibody is a neutralizing monoclonal antibody.
• Non-limiting examples of anti-SARS-CoV-2 monoclonal antibodies include bamlanivimab (LY-CoV555 or LY3819253), etesevimab (LY-C0VOI6 or LY3832479), casirivimab (REGN10933), and imdevimab (REGN10987). See, e.g., www.covidl9treatmentguidelines.nih.gov/therapies/anti-sars-cov-2- antibody-products/anti-sars-cov-2-monoclonal-antibodies.
• the invention provides a method of treating a SARS-CoV-2 infection in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, wherein as an active ingredient, any one of the polypeptides or fusion proteins described herein.
• the invention provides a method of reducing viral load of SARS- CoV-2 in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, wherein as an active ingredient, any one of the polypeptides or fusion proteins described herein.
• the conjunctive term “and/or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and/or,” a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and, therefore, satisfy the requirement of the term “and/or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and, therefore, satisfy the requirement of the term “and/or.”
• the molecule of interest is recombinantly expressed, purified, and quantified.
• An ELISA plate is coated with 1 pg/mL in PBS of commercial SARS-Cov-2 RBD overnight. The plate is then washed 3x with 200 pL of PBS-T on an automated plate washer and then blocked with 5% BSA in PBS for 1 hour at 37 °C to block non-specific binding. The plate is then washed 3x with 200 pL of PBS-T on an automated plate washer and the molecule of interest is titrated in a dilution series in the ELISA plate and incubated for 1 hour at 37 °C.
• the plate is then washed 3x with 200 pL of PBS-T on an automated plate washer and a secondary antibody (conjugated with HRP) specific to the target molecule is added a fixed dilution to the plate.
• the plate is incubated for 1 hour at 37 °C.
• the plate is then washed 3x with 200 pL of PBS-T on an automated plate washer and binding is probed with by adding TMB substrate to the wells of interest. After 5-10 minutes, the reaction is stopped with an acidic stop solution and the signal is quantified by measuring absorbance at 450 nm on a plate reader.
• a positive signal corresponds to an absorbance reading about background for a negative control (typically an antibody isotope control).
• a semi-quantitative understanding of the binding can be inferred by assessing strength of binding at greater dilutions of the target molecule.
• candidate molecules with greater affinity to the SARS-Cov-2 RBD should show greater signal at greater dilutions compared to weaker binders.
• the molecule of interest is recombinantly expressed, purified, and quantified.
• An ELISA plate is coated with 1 pg/mL in PBS of commercial SARS-Cov-2 RBD overnight. The plate is then washed 3x with 200 pL of PBS-T on an automated plate washer and then blocked with 5% BSA in PBS for 1 hour at 37 °C to block non-specific binding. The plate is then washed 3x with 200 pL of PBS-T on an automated plate washer and the molecule of interest is titrated in a dilution series in the ELISA plate. At the same time, a fixed concentration of commercial hACE2 (biotinylated) is co-incubated with the candidate molecule.
• the fixed concentration of hACE2 corresponds to the concentration at which 50% of maximal binding to SARS-Cov-2 RBD determined empirically in this assay format.
• the plate is incubated for 1 hour at 37 °C.
• the plate is then washed 3x with 200 pL of PBS-T on an automated plate washer and a secondary antibody (streptavidin conjugated with HRP) specific to the biotinylated hACE2 is added a fixed dilution to the plate.
• the plate is incubated for 1 hour at 37 °C.
• the plate is then washed 3x with 200 pL of PBS-T on an automated plate washer and binding is probed with by adding TMB substrate to the wells of interest.
• a positive signal corresponds to a decrease in absorbance for wells with the candidate molecule compared to wells without the candidate molecule above background for a negative control (typically an antibody isotope control).
• a semi -quantitative understanding of the target molecule’s ability to compete with hACE2 can be inferred by assessing total decrease of hACE2 binding at greater dilutions of the target molecule.
• candidate molecules with greater ability to compete with hACE2 for SARS-Cov-2 RBD should show greater signal at greater dilutions compared to molecules with weaker ability.
• the cells are then resuspended in a fixed volume of 0.2% BSA in PBS and subjected to flow cytometry.
• Total binding of the SARS-Cov-2 RBD is analyzed by median fluorescence intensity (MFI) of the FIT-C channel.
• MFI median fluorescence intensity
• a positive signal corresponds to a decrease in MFI for wells with the candidate molecule compared to wells without the candidate molecule above background for a negative control (typically an antibody isotope control).
• a semi- quantitative understanding of the ability to compete with SARS-Cov-2 RBD can be inferred by assessing total decrease of SARS-Cov-2 RBD MFI at greater dilutions of the target molecule.
• candidate molecules with greater ability to compete with the SARS-Cov-2 RBD for hACE2 should show greater signal at greater dilutions molecules with weaker ability.
• Binding kinetics and affinity were measured with Bio-layer interferometry (BLI) using a ForteBio Octet Red96e instrument. Antibodies were captured onto biosensors. Biosensors were then incubated with a serial dilution of SARS-CoV-2 RBD (Aero Biosystems) for association and dissociation.
• Pre-titrated amounts of rVSV-SARS-CoV-2 were incubated with serially diluted monoclonal antibodies at 37°C for 1 hour before addition to confluent Vero (ATCC CCL-81) monolayers in 96-well plates. Infection proceeded for 16-18 hours at 37°C in 5% CO2 before cells were fixed in 4% paraformaldehyde and stained with 10 pg/mL Hoechst. Cells were imaged using a Celllnsight CX5 imager and infection was quantified by automated enumeration of total cells and those expressing green fluorescent protein (GFP). Infection was normalized to the average number of cells infected with rVSV-SARS-CoV-2 incubated with human IgG isotype control.
• GFP green fluorescent protein
• Spike proteins were generated for epitope binning studies and structural biology using the HexaPro background (containing residues 14-1208 (Genbank: MN908947) of the ectodomain, six proline substitutions (F817P, A892P, A899P, A942P, K986P, V987P), as well as the D614G mutation established in all/most variants associated with spillover/spillback in Northern Europe, and replacement of cleavage site residues 682-685 (“RRAR” (SEQ ID NO: 18) to “GSAS” (SEQ ID NO: 19)).
• RRAR cleavage site residues 682-685
• the resulting spike variants were cloned into a phCMV mammalian expression vector containing an N-terminal Gaussia luciferase signal sequence (MGVKVLFALICIAVAEA (SEQ ID NO: 20)) and a C-terminal foldon trimerization domain, followed by an HRV-3C cleavage site and a Twin-Strep-Tag. Plasmids were transformed into Stellar competent cells and isolated using a Plasmid Plus Midi kit (Qiagen, Hilden, Germany). [00213] SARS-CoV-2 HexaPro spike was transiently transfected into Freestyle 293-F or ExpiCHO-S cells (Thermo Fisher Scientific, Inc., Waltham, MA).
• Both cell lines were maintained and transfected according to manufacturer’s protocols. Briefly, 293-F cells were grown to a density of 2.0xl0 6 cells/mL and diluted to l.OxlO 6 cell/mL on the day of transfection (day 0). Plasmid DNA and polyethyleneimine were mixed in Opti-MEM (Thermo Fisher Scientific, Inc., Waltham, MA), incubated for 25 minutes, and then added to the cells. Cell cultures were incubated at 37°C, 8% CO2, and 120 RPM, and harvested on day 5. For ExpiCHO cultures, manufacturer’s “High Titer” protocol was used.
• cells were grown to a density of IxlO 7 cells/mL and diluted to 6xl0 6 cells/mL on the day of transfection (day 0). Plasmid DNA and Expifectamine were mixed in Opti-PRO SFM (Thermo Fisher Scientific, Inc., Waltham, MA) according to manufacturer’s instructions, and added to the cells. On day 1, cells were fed with manufacturer-supplied feed and enhancer according to the suggested protocol, and cultures were then incubated at 32°C, 5% CO2 and 115 RPM. ExpiCHO cultures were harvested on day 7.
• Opti-PRO SFM Thermo Fisher Scientific, Inc., Waltham, MA
• Epitope binning was performed with a sandwich assay format on a Carterra LSA SPR instrument equipped with a CMDP sensor chip at 25°C and in a HBSTE-BSA running buffer (10 mM HEPES pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.05% Tween-20, supplemented with 0.5 mg/ml BSA).
• Surface preparation was performed with 25 mM MES (pH 5.5) with 0.05% Tween-20 as a running buffer.
• AB-1 was chosen to further investigate susceptibility of emerging mutations in COV- 2 RBD. Pseudovirus neutralization studies were performed with pseudovirus bearing point mutations found in multiple human and mink variants. Data are presented in FIG. 4. AB-1 was resistant to most mutations as indicated by ICso fold-change between -2.5 and 2.5.

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• 2021
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