WO2021238910A1 - Anticorps dirigés contre la protéine spike du coronavirus et leurs utilisations - Google Patents
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Classifications
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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
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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
- 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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- 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
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- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
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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
- C07K2317/70—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
- SARS-CoV-2 Like its cousin SARS-CoV, SARS-CoV-2 (or 2019 nCoV for novel coronavirus 2019) belongs to the betacoronavirus genus and likely originated in bats. Like other coronaviruses, SARS CoV-2 is believed to utilize a large surface protein called spike (S) protein for interaction with and entry into the target cell.
- S protein consists of an N-terminal S1 domain followed by membrane-proximal S2 domain, a transmembrane domain and an intracellular domain. S1 domain is responsible for interacting with the target cell through a receptor binding subdomain (RBD) while S2 domain mediates membrane fusion following receptor binding.
- RBD receptor binding subdomain
- S2 domain mediates membrane fusion following receptor binding.
- the viral RNA genome is then released into the cytoplasm and replicates itself. New virions can be assembled and burst out of the cell to start the whole cycle of infection again.
- Therapeutic strategies that may be contemplated include blocking cellular adhesion and entry, RNA synthesis and viral release as well as boosting host’s immune system. Since cellular binding is the very first step that triggers viral infection, in the case of coronavirus, it makes sense to target S protein in a manner that blocks its interaction with the cellular receptor thereby forestalling infection.
- human angiotensin converting enzyme II ACE2
- ACE2 angiotensin converting enzyme II
- the present disclosure provides antibodies and fragments thereof capable of binding to SARS-CoV-2 spike protein (Sprotein) , as well as their uses in therapeutic, diagnostic and analytical settings.
- Sprotein SARS-CoV-2 spike protein
- the present disclosure provides an antibody or fragment thereof, wherein the antibody or fragment thereof has specificity to the SARS-CoV-2 spike protein, and comprises a heavy chain variable region (VH) comprising heavy chain complementarity determining regions CDRH1, CDRH2, and CDRH3, and a light chain variable region (VL) comprising light chain complementarity determining regions CDRL1, CDRL2, and CDRL3, wherein the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, respectively, comprise the amino acid sequences of SEQ ID NO: 25, 26, 27, 52, 53, and 54; SEQ ID NO: 28, 29, 30, 55, 56, and 57; SEQ ID NO: 31, 32, 33, 58, 59, and 60; SEQ ID NO: 34, 35, 36, 61, 62, and 63; SEQ ID NO: 37, 38, 39, 64, 65, and 66; SEQ ID NO: 40, 41, 42, 67, 68, and 69; SEQ ID NO: 40, 43,
- the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, respectively comprise the amino acid sequences of SEQ ID NO: 25, 26, 27, 52, 53, and 54; SEQ ID NO: 28, 29, 30, 55, 56, and 57; SEQ ID NO: 34, 35, 36, 61, 62, and 63; SEQ ID NO: 37, 38, 39, 64, 65, and 66; or SEQ ID NO: 46, 47, 48, 76, 77, and 78.
- the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, respectively, comprise the amino acid sequences of SEQ ID NO: 25, 26, 27, 52, 53, and 54.
- the VH comprises the amino acid sequence of SEQ ID NO: 1 and the VL comprises the amino acid sequence of SEQ ID NO: 13.
- the antibody or fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 86 and a light chain comprising the amino acid sequence of SEQ ID NO: 88.
- the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, respectively, comprise the amino acid sequences of SEQ ID NO: 28, 29, 30, 55, 56, and 57.
- the VH comprises the amino acid sequence of SEQ ID NO: 2 and the VL comprises the amino acid sequence of SEQ ID NO: 14.
- the antibody or fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 90 and a light chain comprising the amino acid sequence of SEQ ID NO: 92.
- the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, respectively, comprise the amino acid sequences of SEQ ID NO: 34, 35, 36, 61, 62, and 63.
- the VH comprises the amino acid sequence of SEQ ID NO: 4 and the VL comprises the amino acid sequence of SEQ ID NO: 16.
- the antibody or fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 94 and a light chain comprising the amino acid sequence of SEQ ID NO: 96.
- the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, respectively, comprise the amino acid sequences of SEQ ID NO: 37, 38, 39, 64, 65, and 66.
- the VH comprises the amino acid sequence of SEQ ID NO: 5 and the VL comprises the amino acid sequence of SEQ ID NO: 17.
- the antibody or fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 98 and a light chain comprising the amino acid sequence of SEQ ID NO: 100.
- the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, respectively, comprise the amino acid sequences of SEQ ID NO: 46, 47, 48, 76, 77, and 78.
- the VH comprises the amino acid sequence of SEQ ID NO: 9 and the VL comprises the amino acid sequence of SEQ ID NO: 21.
- the antibody or fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 102 and a light chain comprising the amino acid sequence of SEQ ID NO: 104.
- an antibody or fragment thereof wherein the antibody or fragment thereof has specificity to the SARS-CoV-2 spike protein, and binds to at least two, three, four, five, or more amino acids within SEQ ID NO: 106 (CNGVEGFNCYFPLQSYGFQPTNGVGYQ) .
- an antibody or fragment thereof wherein the antibody or fragment thereof has specificity to the SARS-CoV-2 spike protein, and competes with an antibody or fragment thereof disclosed herein in binding to the SARS-CoV-2 spike protein, or binds to the same epitope as an antibody or fragment thereof disclosed herein.
- the antibody or fragment thereof does not bind to amino acid residues 438-479 of the binding loop of the SARS-CoV-2 spike protein (SEQ ID NO: 105) .
- the antibody or fragment thereof is a human antibody or fragment thereof. In some embodiments, the antibody or fragment thereof is of isotype IgG1, IgG2, IgG3, or IgG4.
- polynucleotides encoding the antibody or fragment thereof disclosed herein are also provided. Also provided is a cell comprising one or more polynucleotides encoding the antibody or fragment thereof disclosed herein. Still further disclosed is a composition comprising the antibody or fragment thereof disclosed herein and a pharmaceutically acceptable carrier.
- a method for detecting a SARS-CoV-2 virus or a variant thereof comprising contacting the antibody or fragment thereof of any one of claims 1-22 with a sample, wherein binding of the antibody or fragment thereof to the sample indicates that the sample contains a SARS-CoV-2 virus or a variant thereof.
- variants include B. 1.525, B. 1.526, B. 1.526.1, B. 1.617, B. 1.617.1, B. 1.617.2, B. 1.617.3, and P. 2. In some embodiments, this method is not for human diagnostic purpose.
- Yet another embodiment provides a method for treating or preventing a SARS-CoV-2 viral infection in a subject, comprising administering to the subject an effective amount of the antibody or fragment thereof disclosed herein or a polynucleotide disclosed herein. Also provided is a use of the antibody or fragment thereof disclosed herein or the polynucleotide disclosed herein for the manufacture of a medicament for treating or preventing a SARS-CoV-2 viral infection in a subject.
- the subject suffers from a COVID-19 symptom.
- the infection is by a SARS-CoV-2 virus or a variant thereof, such as B. 1.525, B. 1.526, B. 1.526.1, B. 1.617, B. 1.617.1, B. 1.617.2, B. 1.617.3, and P. 2.
- the polynucleotide administered is mRNA or DNA, which can be administered in, for instance, a plasmid, a viral vector, or a nanoparticle.
- FIG. 1 shows the ELISA binding results of four antibodies with strong affinity to the receptor binding domain (RBD) fragment from the SARS-CoV-2 spike protein (S-RBD) .
- FIG. 2 shows the ELISA binding results of six antibodies with strong affinity to the S-RBD in a reverse blocking test.
- FIG. 3 shows that the antibodies were able to block cell entry of a created A SARS-CoV-2 pseudovirus.
- FIG. 4 shows pseudovirus neutralization single point comparison.
- FIG. 5 shows sensor-grams of BIACORE experiments with immobilized antibodies.
- FIG. 6 shows sensor-grams of BIACORE experiments with antibodies fused to mouse Fc.
- FIG. 7 shows the results of epitope mapping for non-blocking antibody 34D1 and blocking antibodies 13H7 and 43H7.
- FIG. 8 illustrates the epitope region for blocking antibodies.
- FIG. 9 shows the results of plaque formation assay showing neutralization of SARS-CoV-2 by antibody 13H7.
- FIG. 10 shows the results of plaque formation assay showing neutralization of SARS-CoV-2 by antibody 43H7.
- FIG. 11 shows concentration-dependent neutralization of SARS-CoV-2 by 13H7 (left) and 43H7 (right) .
- FIG. 12 shows neutralization of SARS-CoV-2 in HACE2 mice by monoclonal antibodies 13H7 and 43H7 in a prevention model.
- A viral copy number in lungs on day 3 post infection.
- B body weight changes over 3 days following infection.
- C representative lung histopathology on day 3 post infection. Scale bar, 0.1 mm.
- the present disclosure relates to isolated antibodies, particularly human antibodies, which bind to the SARS-CoV-2 spike protein and that have desirable functional properties.
- the antibodies of the disclosure include certain CDR regions as disclosed herein.
- This disclosure provides isolated antibodies, methods of making such antibodies, immunoconjugates and bispecific molecules comprising such antibodies and pharmaceutical compositions containing the antibodies, immunoconjugates or bispecific molecules of the disclosure.
- This disclosure also relates to methods of using the antibodies, such as to detect the SARS-CoV-2 spike protein, as well as to methods of using the antibodies of the disclosure to treat or prevent viral infections.
- antibody as referred to herein includes whole antibodies and any antigen binding fragment (i.e., “antigen-binding portion” ) or single chains thereof.
- Whole antibodies are glycoproteins comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds.
- Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as V H ) and a heavy chain constant region.
- the heavy chain constant region is comprised of three domains, C H 1, C H 2, and C H 3.
- Each light chain is comprised of a light chain variable region (abbreviated herein as V L ) and a light chain constant region.
- the light chain constant region is comprised of one domain, C L .
- V H and V L regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs) , interspersed with regions that are more conserved, termed framework regions (FR) .
- CDRs complementarity determining regions
- FR framework regions
- Each V H and V L is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy terminus in the following order: FRl, CDRl, FR2, CDR2, FR3, CDR3, and FR4.
- the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
- the constant regions of the antibodies can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
- antigen-binding fragment or simply “fragment, ” as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., a SARS-CoV-2 spike protein) . It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.
- an antigen e.g., a SARS-CoV-2 spike protein
- binding fragments encompassed within the term “antigen binding portion” of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the V L , V H , C L and C H 1 domains; (ii) a F (ab') 2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fab'fragment, which is essentially a Fab with part of the hinge region; (iv) a Fd fragment consisting of the V H and C H 1 domains; (v) a F v fragment consisting of the V L and V H domains of a single arm of an antibody, (vi) a dAb fragment, which consists of a VH domain; (vii) an isolated complementarity determining region (CDR) ; and (viii) a nanobody, a heavy chain variable region containing a single variable domain and two constant domains.
- a Fab fragment a monovalent fragment consisting
- the two domains of the F v fragment, V L and V H are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the V L and V H regions pair to form monovalent molecules (known as single chain F v (scFv) .
- single chain F v single chain F v
- Such single chain antibodies are also intended to be encompassed within the term “antigen binding fragment” of an antibody.
- human antibody is intended to include antibodies having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region also is derived from human germline immunoglobulin sequences.
- the human antibodies of the disclosure can include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo) .
- the term “human antibody” is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
- isotype refers to the antibody class (e.g., IgM or IgG1) that is encoded by the heavy chain constant region genes.
- an antibody recognizing an antigen and “an antibody specific for an antigen” are used interchangeably herein with the term “an antibody which binds specifically to an antigen. ”
- an antibody that “specifically binds the SARS-CoV-2 spike protein” or “has specificity to the SARS-CoV-2 spike protein” is intended to refer to an antibody that binds to the SARS-CoV-2 spike protein but does not substantially bind to non-SARS-CoV-2 spike proteins.
- the antibody binds to a SARS-CoV-2 spike protein with “high affinity” , namely with a K D of 1 ⁇ 10 -7 M or less, more preferably 5 ⁇ 10 -8 M or less, more preferably 3 ⁇ 10 -8 M or less, more preferably 1 ⁇ 10 -8 M or less, more preferably 3 ⁇ 10 -9 M or less or even more preferably 1 ⁇ 10 -9 M or less.
- subject includes any human or nonhuman animal.
- nonhuman animal includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, cows, horses, chickens, amphibians, and reptiles, although mammals are preferred, such as non-human primates, sheep, dogs, cats, cows and horses.
- the present disclosure provides antibodies and fragments having specificity to the SARS-CoV-2 spike protein.
- the antibodies of the disclosure are characterized by particular functional features or properties of the antibodies.
- the amino acid sequence of the SARS-CoV-2 spike protein (Accession No: QHD43416, SEQ ID NO: 105) is shown in Table A.
- the receptor binding domain (RBD) fragment (amino acid 330-530, or SEQ ID NO: 107) of the spike protein was used to identify antibodies in the accompanying experimental examples.
- RBD receptor binding domain
- SEQ ID NO: 107 amino acid 330-530, or SEQ ID NO: 107 of the spike protein was used to identify antibodies in the accompanying experimental examples.
- Out of the 12 antibodies obtained at least six exhibited significant binding affinity to the spike protein, as well as significant activity in blocking the interaction between the spike protein and its human target, the angiotensin converting enzyme II (ACE2) protein, giving rise to their ability to block entry of the virus into human cells.
- ACE2 angiotensin converting enzyme II
- blocking antibodies including K23F01, K34B12, K34B01, L13H07, L43H07, and L34G10.
- the remaining antibodies also bind, with high affinity, to the spike protein as well, and can be referred to as “non-blocking antibodies. ” Although the non-blocking proteins may be less effective in blocking viral entry, they are nonetheless excellent tools for detecting the presence of the virus.
- Epitope mapping shows that the blocking antibodies bind to amino acid residues within SEQ ID NO: 106, which corresponds to amino acid residues 480-506 of the spike protein. This is interesting, as the “binding loop” between the spike protein and the ACE2 protein includes a longer portion (amino acid residues 438-506, SEQ ID NO: 108) . In other words, the blocking antibodies identified in the present disclosure do not seem to interact with amino acid residues 438-479 of the spike protein.
- SARS-CoV-2 spike protein epitopope, SEQ ID NO: 106 of the blocking antibodies is underlined, which is a portion of the binding loop (bold and italic)
- an antibody or fragment thereof having specificity to the SARS-CoV-2 spike protein.
- the antibody or fragment thereof binds to at least one or two amino acids within SEQ ID NO: 106 (CNGVEGFNCYFPLQSYGFQPTNGVGYQ) .
- the antibody or fragment thereof binds to at least three, four, five, six, seven, eight, nine or ten amino acids within SEQ ID NO: 106.
- an antibody or fragment thereof wherein the antibody or fragment thereof has specificity to the SARS-CoV-2 spike protein, and competes with an antibody or fragment thereof of the present disclosure in binding to the SARS-CoV-2 spike protein, or binds to the same epitope as the antibody or fragment thereof.
- the antibody or fragment thereof is a blocking antibody or fragment thereof.
- the antibody or fragment thereof is a non-blocking antibody or fragment thereof.
- the antibody or fragment thereof does not bind to amino acid residues 438-479 of the binding loop of the SARS-CoV-2 spike protein (SEQ ID NO: 105) . In some embodiments, the antibody or fragment thereof inhibits binding between the spike protein and the human ACE2 protein.
- the present disclosure presents an antibody or fragment thereof, wherein the antibody or fragment thereof has specificity to the SARS-CoV-2 spike protein, and wherein the antibody or fragment thereof comprises a heavy chain variable region (VH) comprising heavy chain complementarity determining regions CDRH1, CDRH2, and CDRH3, and a light chain variable region (VL) comprising light chain complementarity determining regions CDRL1, CDRL2, and CDRL3.
- VH heavy chain variable region
- VL light chain variable region
- CDRL1, CDRL2, and CDRL3 are as described herein.
- the CDRH1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 25, 28, 31, 34, 37, 40, and 46.
- the CDRH2 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 26, 29, 32, 35, 38, 41, 43, and 47.
- the CDRH3 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 27, 30, 33, 36, 39, 42, 44, 45, 48, 49, 50, and 51.
- the CDRL1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 52, 55, 58, 61, 64, 67, 70, 73, 76, 79, and 82.
- the CDRL2 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 53, 56, 59, 62, 65, 68, 71, 74, 77, and 80.
- the CDRL3 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 54, 57, 60, 63, 66, 69, 72, 75, 78, 81, 83, and 84.
- the CDRH1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 25, 28, 34, 37, and 46.
- the CDRH2 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 26, 29, 35, 38, and 47.
- the CDRH3 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 27, 30, 36, 39, and 48.
- the CDRL1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 52, 55, 61, 64, and 76.
- the CDRL2 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 53, 56, 62, 65, and 77.
- the CDRL3 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 54, 57, 63, 66, and 78.
- an antibody or fragment thereof wherein the antibody or fragment thereof has specificity to the SARS-CoV-2 spike protein, and comprises a heavy chain variable region (VH) comprising heavy chain complementarity determining regions CDRH1, CDRH2, and CDRH3, and a light chain variable region (VL) comprising light chain complementarity determining regions CDRL1, CDRL2, and CDRL3, wherein the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, respectively, comprise the amino acid sequences of SEQ ID NO: 25, 26, 27, 52, 53, and 54; SEQ ID NO: 28, 29, 30, 55, 56, and 57; SEQ ID NO: 31, 32, 33, 58, 59, and 60; SEQ ID NO: 34, 35, 36, 61, 62, and 63; SEQ ID NO: 37, 38, 39, 64, 65, and 66; SEQ ID NO: 40, 41, 42, 67, 68, and 69; SEQ ID NO: 40, 43, 44
- an antibody or fragment thereof wherein the antibody or fragment thereof has specificity to the SARS-CoV-2 spike protein, and comprises a heavy chain variable region (VH) comprising heavy chain complementarity determining regions CDRH1, CDRH2, and CDRH3, and a light chain variable region (VL) comprising light chain complementarity determining regions CDRL1, CDRL2, and CDRL3, wherein the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, respectively, comprise the amino acid sequences SEQ ID NO: 25, 26, 27, 52, 53, and 54; SEQ ID NO: 28, 29, 30, 55, 56, and 57; SEQ ID NO: 34, 35, 36, 61, 62, and 63; SEQ ID NO: 37, 38, 39, 64, 65, and 66; or SEQ ID NO: 46, 47, 48, 76, 77, and 78.
- VH heavy chain variable region
- VL light chain variable region
- an antibody or fragment thereof wherein the antibody or fragment thereof has specificity to the SARS-CoV-2 spike protein, and comprises a heavy chain variable region (VH) comprising heavy chain complementarity determining regions CDRH1, CDRH2, and CDRH3, and a light chain variable region (VL) comprising light chain complementarity determining regions CDRL1, CDRL2, and CDRL3, wherein the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, respectively, comprise the amino acid sequences of SEQ ID NO: 25, 26, 27, 52, 53, and 54.
- the VH comprises the amino acid sequence of SEQ ID NO: 1
- the VL comprises the amino acid sequence of SEQ ID NO: 13.
- the antibody has a heavy chain comprising the amino acid sequence of SEQ ID NO: 86 and a light chain comprising the amino acid sequence of SEQ ID NO: 88.
- an antibody or fragment thereof wherein the antibody or fragment thereof has specificity to the SARS-CoV-2 spike protein, and comprises a heavy chain variable region (VH) comprising heavy chain complementarity determining regions CDRH1, CDRH2, and CDRH3, and a light chain variable region (VL) comprising light chain complementarity determining regions CDRL1, CDRL2, and CDRL3, wherein the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, respectively, comprise the amino acid sequences of SEQ ID NO: 28, 29, 30, 55, 56, and 57.
- the VH comprises the amino acid sequence of SEQ ID NO: 2
- the VL comprises the amino acid sequence of SEQ ID NO: 14.
- the antibody has a heavy chain comprising the amino acid sequence of SEQ ID NO: 90 and a light chain comprising the amino acid sequence of SEQ ID NO: 92.
- an antibody or fragment thereof wherein the antibody or fragment thereof has specificity to the SARS-CoV-2 spike protein, and comprises a heavy chain variable region (VH) comprising heavy chain complementarity determining regions CDRH1, CDRH2, and CDRH3, and a light chain variable region (VL) comprising light chain complementarity determining regions CDRL1, CDRL2, and CDRL3, wherein the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, respectively, comprise the amino acid sequences of SEQ ID NO: 34, 35, 36, 61, 62, and 63.
- the VH comprises the amino acid sequence of SEQ ID NO: 4
- the VL comprises the amino acid sequence of SEQ ID NO: 16.
- the antibody has a heavy chain comprising the amino acid sequence of SEQ ID NO: 94 and a light chain comprising the amino acid sequence of SEQ ID NO: 96.
- an antibody or fragment thereof wherein the antibody or fragment thereof has specificity to the SARS-CoV-2 spike protein, and comprises a heavy chain variable region (VH) comprising heavy chain complementarity determining regions CDRH1, CDRH2, and CDRH3, and a light chain variable region (VL) comprising light chain complementarity determining regions CDRL1, CDRL2, and CDRL3, wherein the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, respectively, comprise the amino acid sequences of SEQ ID NO: 37, 38, 39, 64, 65, and 66.
- the VH comprises the amino acid sequence of SEQ ID NO: 5
- the VL comprises the amino acid sequence of SEQ ID NO: 17.
- the antibody has a heavy chain comprising the amino acid sequence of SEQ ID NO: 98 and a light chain comprising the amino acid sequence of SEQ ID NO: 100.
- an antibody or fragment thereof wherein the antibody or fragment thereof has specificity to the SARS-CoV-2 spike protein, and comprises a heavy chain variable region (VH) comprising heavy chain complementarity determining regions CDRH1, CDRH2, and CDRH3, and a light chain variable region (VL) comprising light chain complementarity determining regions CDRL1, CDRL2, and CDRL3, wherein the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, respectively, comprise the amino acid sequences of SEQ ID NO: 46, 47, 48, 76, 77, and 78.
- the VH comprises the amino acid sequence of SEQ ID NO: 9
- the VL comprises the amino acid sequence of SEQ ID NO: 21.
- the antibody has a heavy chain comprising the amino acid sequence of SEQ ID NO: 102 and a light chain comprising the amino acid sequence of SEQ ID NO: 104.
- the antibody can be, for example, a human antibody.
- the V H and/or V L amino acid sequences can have at least 85%, 90%, 95%, 96%, 97%, 98%, or 99%sequence identify to the sequences set forth above.
- An antibody having V H and V L regions having high (i.e., 80%or greater) homology to the V H and V L regions of the sequences set forth above, can be obtained by mutagenesis (e.g., site-directed or PCR-mediated mutagenesis) of nucleic acids of V H and/or V L amino acid sequences, followed by testing of the encoded altered antibody for retained function (i.e., the functions set forth above) using the functional assays described herein.
- mutagenesis e.g., site-directed or PCR-mediated mutagenesis
- the antibody or fragment thereof is of an isotype of IgG, IgM, IgA, IgE or IgD.
- the isotype is IgG1, IgG2, IgG3 or IgG4.
- the antibody or fragment is of isotype IgG2.
- the IgG2 antibody is contemplated to be able to increase mucosal immunity for protection against the virus at the site of entry.
- the IgG2 antibody is formulated for suitable administration via intravenous injection, subcutaneous injection, intramuscular injection, or intranasal administration.
- the antibody or fragment is of isotype IgG4.
- the IgG4 antibody is contemplated to useful in mitigating ADE (antibody dependent enhancement) effects.
- ADE occurs when the antibodies generated during an immune response recognize and bind to a pathogen, but they are unable to prevent infection. Instead, these antibodies act as a “Trojan horse, ” allowing the pathogen to get into cells and exacerbate the immune response.
- the IgG4 antibody of the present disclosure can reduce ADE and thus enhance treatment of the infection.
- the CDR regions recited in this disclosure can also be changed to each of its biological variants.
- a biological variant of CDR sequence is derived from the original sequence by one, two or three amino acid addition, deletion and/or substitutions. In some embodiments, the substitution is conservative amino acid substitution.
- a “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain.
- Families of amino acid residues having similar side chains have been defined in the art, including basic side chains (e.g., lysine, arginine, histidine) , acidic side chains (e.g., aspartic acid, glutamic acid) , uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine) , nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan) , beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine
- a nonessential amino acid residue in an immunoglobulin polypeptide is preferably replaced with another amino acid residue from the same side chain family.
- a string of amino acids can be replaced with a structurally similar string that differs in order and/or composition of side chain family members.
- Non-limiting examples of conservative amino acid substitutions are provided in the tables below, where a similarity score of 0 or higher indicates conservative substitution between the two amino acids.
- the present disclosure provides bifunctional or bispecific molecules comprising an anti-spike protein antibody/fragment linked to at least one other functional molecule, e.g., another peptide or protein (e.g., another antibody or ligand for a receptor) to generate a bifunctional or bispecific molecule that binds to at least two different binding sites or target molecules.
- bispecific molecule includes molecules that have three or more specificities.
- the bispecific molecule comprises a first binding specificity for the SARS-CoV-2 spike protein and a second binding specificity for a triggering molecule that recruits cytotoxic effector cells that can kill the SARS-CoV-2 virus.
- suitable triggering molecules are CD64, CD89, CD16, and CD3. See, e.g., Kufer et al., Trends in Biotech. 22 (5) : 238-44, 2004.
- the second function/specificity can be for an anti-enhancement factor (EF) , e.g., a molecule that binds to a surface protein involved in cytotoxic activity and thereby increases the immune response against the target virus or an infected cell.
- EF anti-enhancement factor
- the anti-enhancement factor can bind a cytotoxic T cell (e.g. via CD2, CD3, CDS, CD28, CD4, CD40, or ICAM-1) , other immune regulatory molecules (e.g.
- PD-1 via PD-1, PD-L1, CTLA-4, CD122, 4-1BB, TIM3, OX-40, OX40L, CD40L, LIGHT, ICOS, ICOSL, GITR, GITRL, TIGIT, CD27, VISTA, B7H3, B7H4, HEVM, BTLA, KIR, CD47 or CD73) or other immune cell, resulting in an increased immune response against the virus or an infected cell.
- Bifunctional/bispecific molecules also encompass bi-epitopic ones, which have a first specificity to one portion of a target antigen and a second specificity to another portion of the same antigen.
- the other portion may or may not overlap with the first portion.
- the binding to other portion may not, on its own, has the intended blocking activity, but enhances the activity of the first specificity.
- the enhancement without being bound by any particular theory, may be due to tighter binding or stabilized conformation.
- both bindings can independently exhibit the desired activities.
- Bifunctional molecules that include not just antibody or antigen binding fragment are also provided.
- an antibody or antigen-binding fragment specific to the spike protein such as those described here, can be combined with an immune cytokine or ligand optionally through a peptide linker.
- the linked immune cytokines or ligands include, but not limited to, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-13, IL-15, GM-CSF, TNF- ⁇ , CD40L, OX40L, CD27L, CD30L, 4-1BBL, LIGHT and GITRL.
- Bispecific molecules can come in many different formats and sizes. At one end of the size spectrum, a bispecific molecule retains the traditional antibody format, except that, instead of having two binding arms of identical specificity, it has two binding arms each having a different specificity. At the other extreme are bispecific molecules consisting of two single-chain antibody fragments (scFv's) linked by a peptide chain, a so-called Bs (scFv) 2 construct. Intermediate-sized bispecific molecules include two different F (ab) fragments linked by a peptidyl linker. Bispecific molecules of these and other formats can be prepared by genetic engineering, somatic hybridization, or chemical methods.
- the treatment methods can further include administration of an effective amount of another agent.
- the anti-spike protein antibody or fragment is co-administered with an effective amount of the other agent.
- the second agent is also an anti-spike antibody of fragment thereof. In some embodiments, the second agent is co-administered with the antibody or fragment thereof simultaneously or sequentially.
- the second agent is effective in reducing or inhibiting cytokine release storm.
- the second agent is a corticosteroid.
- Non-limiting examples include methylprednisolone (in particular in patients with a rheumatic disease) , dexamethasone (in particular in patients with FHLH) .
- the second agent is a cytoablative therapy.
- cytoablative therapy includes cyclophosphamide (in particular in patients with JIA and MAS) , etoposide (in particular in patients with FHLH) , rituximab (in particular in Epstein-Barr virus (EBV) -associated HLH) , antithymocyte globulin (in particular for patients at bone marrow transplant phase of FHLH therapy) , alemtuzumab (in particular in patients with FHLH or SLE-associated MAS) .
- cyclophosphamide in particular in patients with JIA and MAS
- etoposide in particular in patients with FHLH
- rituximab in particular in Epstein-Barr virus (EBV) -associated HLH
- antithymocyte globulin in particular for patients at bone marrow transplant phase of FHLH therapy
- alemtuzumab in particular in patients with FHLH or
- the second agent is a cytokine inhibitor, such inhibitors targeting INF ⁇ , IL-1 ⁇ , IL-18, IL-33, IL-6, and/or TNF.
- the second agent targets the underlying disease or condition, such as SARS-CoV-2 infection.
- underlying disease or condition such as SARS-CoV-2 infection.
- Non-limiting examples include lopinavir, ritonavir, oseltamivir (Tamiflu) , favipiravir, fingolimod, methylprednisolone, bevacizumab, chloroquine phosphate, chloroquine, hydroxychloroquine sulfate and remdesivir.
- the present disclosure provides a pharmaceutical composition
- a pharmaceutical composition comprising an antibody of the present disclosure formulated together with a pharmaceutically acceptable earlier. It may optionally contain one or more additional pharmaceutically active ingredients, such as another antibody or a drug.
- the pharmaceutical compositions of the disclosure also can be administered in a combination therapy with, for example, an anti-viral agent, or a vaccine.
- the pharmaceutical composition can comprise any number of excipients.
- Excipients that can be used include carriers, surface active agents, thickening or emulsifying agents, solid binders, dispersion or suspension aids, solubilizers, colorants, flavoring agents, coatings, disintegrating agents, lubricants, sweeteners, preservatives, isotonic agents, and combinations thereof.
- the selection and use of suitable excipients is taught in Gennaro, ed., Remington: The Science and Practice of Pharmacy, 20th Ed. (Lippincott Williams &Wilkins 2003) , the disclosure of which is incorporated herein by reference.
- a pharmaceutical composition is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion) .
- the active compound can be coated in a material to protect it from the action of acids and other natural conditions that may inactivate it.
- parenteral administration means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal injection and infusion.
- an antibody of the disclosure can be administered via a non-parenteral route, such as a topical, epidermal or mucosal route of administration, e.g., intranasally, orally, vaginally, rectally, sublingually or topically.
- compositions can be in the form of sterile aqueous solutions or dispersions. They can also be formulated in a microemulsion, liposome, or other ordered structure suitable to high drug concentration.
- the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration and will generally be that amount of the composition which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.01%to about ninety-nine percent of active ingredient, preferably from about 0.1%to about 70%, most preferably from about 1%to about 30%of active ingredient in combination with a pharmaceutically acceptable carrier.
- Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response) .
- a single bolus can be administered, several divided doses can be administered over time or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
- parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
- Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
- antibody can be administered as a sustained release formulation, in which case less frequent administration is required.
- the dosage ranges from about 0.0001 to 500 mg/kg, and more usually 1 to 200 mg/kg, or 10 to 100 mg/kg, of the host body weight.
- dosages can be 0.3 mg/kg body weight, 1 mg/kg body weight, 3 mg/kg body weight, 5mg/kg body weight or 10 mg/kg body weight or within the range of 1-10 mg/kg.
- dosages can be 1-150 mg/kg, 10-120 mg/kg, 20-100 mg/kg, 30-90 mg/kg, 40-80 mg/kg.
- An exemplary treatment regime entails administration once per week, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3 months or once every 3 to 6 months.
- Preferred dosage regimens for an antibody of the disclosure include 1-500 mg/kg body weight via intravenous administration, with the antibody being given using one of the following dosing schedules: (i) every four weeks for six dosages, then every three months; (ii) every three weeks; (iii) 100 mg/kg body weight once followed by 50 mg/kg body weight every three weeks.
- dosage is adjusted to achieve a plasma antibody concentration of about 1-1000 ⁇ g/mL and in some methods about 25-300 ⁇ g/mL.
- a “therapeutically effective dosage” of an antibody of the disclosure preferably results in a decrease in severity of disease symptoms, an increase infrequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
- a “therapeutically effective dosage” preferably inhibits tumor growth by at least about 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80%relative to untreated subjects.
- a therapeutically effective amount of a therapeutic compound can decrease tumor size, or otherwise ameliorate symptoms in a subject, which is typically a human or can be another mammal.
- the antibodies, antibody compositions and methods of the present disclosure have numerous in vitro and in vivo utilities involving, for example, detection of a SARS-CoV-2 spike protein or preventing or treating SARS-CoV-2 viral infection, or inhibiting viral replication.
- the antibodies of the present disclosure are human antibodies.
- these molecules can be administered to cells in culture, in vitro or ex vivo, or to human subjects, e.g., in vivo, to enhance immunity in a variety of situations.
- the disclosure provides a method of modifying an immune response in a subject comprising administering to the subject the antibody, or antigen-binding portion thereof, of the disclosure such that the immune response in the subject is modified.
- the response is enhanced, stimulated or up-regulated.
- a polynucleotide that encodes the antibody or fragment can be administered.
- the polynucleotide for instance, can be DNA and is carried in a vector, such as a plasmid vector or viral vector. It can also be an mRNA molecule. Whether DNA or RNA, the polynucleotide can be further packaged into a nanoparticle (e.g., viral particle, liposome particle) or vesicle for delivery.
- Preferred subjects include human patients infected with the SARS-CoV-2 virus or a variant thereof, or is at risk of developing SARS-CoV-2 (or a variant) infection.
- Example variants are provided in Table B.
- the antibody or fragment thereof is of an isotype of IgG, IgM, IgA, IgE or IgD.
- the isotype is IgG1, IgG2, IgG3 or IgG4.
- the antibody or fragment is of isotype IgG2.
- the IgG2 antibody is contemplated to be able to increase mucosal immunity for protection against the virus at the site of entry.
- the IgG2 antibody is administered via intravenous injection, subcutaneous injection, intramuscular injection, or preferably intranasal administration.
- the antibody or fragment is of isotype IgG4.
- the IgG4 antibody is contemplated to useful in mitigating ADE (antibody dependent enhancement) effects.
- the IgG4 antibody of the present disclosure is administered to a patient that suffers from ADE.
- the disclosure further provides methods for detecting the presence of a SARS-CoV-2 virus or a variant thereof in a sample, or measuring the amount of the SARS-CoV-2 virus or a variant thereof, comprising contacting the sample, and a control sample, with an antibody or an antigen binding thereof of the present disclosure, under conditions that allow for formation of a complex between the antibody or portion thereof and the SARS-CoV-2 spike protein. The formation of a complex is then detected, wherein a difference complex formation between the sample compared to the control sample is indicative the presence of a SARS- CoV-2 virus in the sample.
- the antibodies of the disclosure can be used to purify SARS-CoV-2 spike proteins.
- the amplified pool of phages were subjected to the next round of panning. There were altogether four rounds of panning with the antigen concentration reduced from 30 ⁇ g/ml to 15 ⁇ g/ml starting from the second panning to increase the stringency. Bound phages were also counter-screened against blank plates as vehicle control.
- the positive monoclones from the output phages of the final round were sequenced to assess the diversity of the output. They were also incubated with the RBD antigen in a single point binding ELISA assay to confirm binding. The confirmed clones were consolidated and grouped based on sequence.
- the Fab sequences were cloned into expression vectors and transiently transfected into HEK 293F cells. Full length human IgG1 monoclonal antibodies were then purified from supernatant of HEK293F culture by Protein A affinity column. The integrity, quantity and purity of the purified mAbs were quality checked by reducing and non-reducing SDS-PAGE and SEC-HPLC, respectively.
- the human ACE2-Fc protein was coated on the plate and incubated with His-tagged human S protein RBD fragment.
- Different concentrations of the RBD-binding IgG1 up to 10 ⁇ g/ml were added to test their ability to compete with ACE2 binding by using HRP-conjugated anti-His to detect plate-bound RBD protein.
- a decrease in signal compared to no antibody added indicates that the IgG1 could block RBD from interacting with ACE2.
- IC50 and blocking efficacy was then determined for blocking antibodies.
- This example used ELISA tests to demonstrate the ability of the antibodies for their ability in blocking S protein RBD domain from interacting with the cellular receptor ACE2.
- ELISA was conducted to test the ability of the 12 antibodies to block binding between SARS-CoV-2 S protein RBD200 (in the form of his-tagged 200 amino acids RBD domain, antigen) with the cellular receptor human ACE2 (in the form of ACE2-Fc fusion protein) .
- the ACE2-Fc protein was coated on plates at a final concentration of 1 ⁇ g/ml.
- RBD200-his was then added in the presence of increasing concentrations of the antibodies (from 100 to 0 ⁇ g/ml in three-fold dilutions) . After incubation and a number of washes, ACE2-bound RBD200-his was detected by HRP-conjugated anti-His antibody. As shown in FIG. 1, out of the 12 antibodies tested, four (13H7, 43H7, 23F1, 34G10) exhibited significant activity in blocking RBD200 binding to ACE2.
- the blocking testing was then conducted in reverse, i.e., by coating RBD200-his protein on the plates followed by incubation with ACE2-Fc in the presence of a series of diluted RBD200-binding antibodies (or human IgG as negative control) and detecting bound ACE2-Fc by HRP-conjugated anti-Fc.
- a series of diluted RBD200-binding antibodies or human IgG as negative control
- HRP-conjugated anti-Fc HRP-conjugated anti-Fc.
- 6 out of the 12 antibodies were able to block RBD200 interaction with ACE2 in a concentration-dependent manner. This format appeared to provide a better signal window and the results were consistent with those from the pseudovirus neutralization experiment.
- the IC50 calculated from this set of experiment was then used as the IC50 for the antibodies.
- This example tested the candidate antibodies’ inhibition of pseudovirus entry into cells.
- a SARS-CoV-2 pseudovirus was created by replacing the lentiviral surface G protein in a lentivirus with the spike protein of SARS-CoV-2 (with a further insertion of a luciferase gene) .
- the virus was packaged in Lenti-293T cells and the viral titer was determined.
- the antibodies at various dilutions were mixed with the pseudovirus for 1 h and infected ACE2-expressing mammalian cells (HeLa/ACE2 maintained in puromycin culture, Genscript) with the pseudovirus mixture in triplicates. After 48 hr of culturing, expression of the luciferase was detected by BioGlo luminescence (Promega) which would indicate successful entry of the pseudovirus. Half maximal inhibition (of luminescence) concentration (IC50) was determined after curve fitting.
- Biacore experiments have been performed with immobilized antibodies and antibodies fused to mouse Fc to confirm the binding affinity of the antibodies.
- the analyte (diluted RBD-his) was injected over the flow cells at concentrations of 40, 20, 10, 5, 2.5, and 1.25 nM at a flow rate of 30 ⁇ l/min for 180 s as association phase, followed by injecting running buffer for 180 s as dissociation phase.
- the surfaces were then regenerated with H 3 PO 4 .
- amino acid sequences and their coding sequences of these five antibodies are listed in Table 4 below.
- the extracellular portion of the S protein (S1) was expressed as a fusion protein with mouse Fc (40591-V05H1, Sino Biological) and served as the immobilizing ligand while the antibodies were the analyte in the liquid phase.
- Series S sensor chip CM5 was used as the solid phase and the assay was performed at 25 °C.
- Anti-mouse antibody was immobilized using HBS-EP+ as running buffer.
- FCs 1, 2, 3, 4 The sensor chip surface of FCs 1, 2, 3, 4 was activated by freshly mixed 50 mM N-hydroxysuccinimide (NHS) and 200 mM 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) for 420 s (10 ⁇ L/min) . Afterwards, anti-mouse antibody diluted in 10 mM NaOAC (pH 5.0) was injected into FCs 2, 3, 4 to achieve conjugation of 5776 ⁇ 5893 Response Unit. FC1 was left blank to serve as a reference surface. After the amine coupling reaction, the remaining active coupling sites on chip surface were blocked with 420 s injection of 1 M ethanolamine hydrochloride. S1 protein was injected over the surface of FC2 as capture for 45 s at a flow rate of 10 ⁇ L/min.
- NHS N-hydroxysuccinimide
- EDC 1-ethyl-3- (3-dimethylaminopropyl) car
- the analyte (diluted antibodies) was injected over the flow cells at concentrations of 0.1875, 0.375, 0.75, 1.5, 3, 6 and 12 nM at a flow rate of 30 ⁇ l/min for 180 s as association phase, followed by injecting running buffer for 360 s as dissociation phase.
- the concentration series was 0.625, 1.25, 2.5, 5, 10, 20 and 40 nM for mAb 34B12 instead.
- the surfaces were then regenerated with H 3 PO 4 .
- Data were collected at a rate of 1 Hz.
- FC 1 and blank injection were used as double reference for Response Units subtraction.
- the binding kinetic data were fit to a simple 1: 1 interaction model using the global data analysis option available within BiaEvaluation 3.1 software.
- the kinetic parameters are shown in Table 5, and sensor-grams are shown inf FIG. 6.
- This example examined the epitope of the antibodies.
- a library of overlapping peptides covering the entire antigen was constructed to identify the epitopes in the target antigen.
- the target antigen was a 201 amino acid long RBD region of the spike protein (S-RBD residues 330-530) .
- Fifteen-mer peptides were designed with each peptide overlapping with its adjacent peptide by 12 amino acids. Thus, altogether 63 15-mer peptides corresponding to amino acids 330-344, 333-347, 336-350, ..., 513-527 and 516-530 were synthesized to >90%purity. Cysteines were replaced by serines. All peptides were biotinylated at the N-terminus.
- mapping experiment was carried out by ELISA. Briefly, ELISA plates were pre-coated with streptavidin and each well coated with 0.1 ml of the individual peptide at 2 ⁇ g/ml in PBS in duplicates. The plate was incubated with 0.1 ml of the target antibody at 2 ⁇ g/ml before binding was detected by an HRP-labeled goat anti-human IgG and substrates.
- FIG. 7 presents a graph showing ELISA binding of blocking antibodies 13H7 (L13H07) and 43H7 (L43H07) and non-blocking antibody 34D1 (L34D01) to the peptide panel.
- Results clearly indicate that while only peptide #6 (amino acids 345-359) bound to the non-blocking antibody 34D1, peptides 51-54 could bind to blocking antibodies 13H7 and 43H7 in a significant manner. This corresponds to amino acids residues 480-506 of the S protein, which outlines the epitope region for blocking antibodies 13H7 and 43H7, as well as for 23F1, 34B12 and 34G10 (data not shown) .
- This region is CNGVEGFNCYFPLQSYGFQPTNGVGYQ (SEQ ID NO: 106) .
- This region is part of an extended loop that spans across the RBD-ACE2 interface (see FIG. 8, outlined with dotted lines) . More importantly, this region makes extensive contacts with the N-terminal helix of the protease domain in ACE2 (Lan J et al. Nature. 2020 Mar 30 (online ahead of print) . Structure of the SARS-CoV-2 Spike Receptor-Binding Domain Bound to the ACE2 Receptor; Yan R et al. Science. 2020 Mar 27; 367 (6485) : 1444-1448.
- SARS-CoV-2 virus wild type was isolated and kept at Wuhan Institute of Virology. Infectivity studies were conducted under BSL-3 conditions.
- Vero E6 cells used for the assay were cultured in DMEM supplemented with 10%FCS, 100 U/ml penicillin and 100 mcg/ml streptomycin at 37 °C and 5%CO 2 . Vero E6 cells were inoculated at a density of 1.5 ⁇ 10 5 in 24-well plates overnight.
- Antibodies 13H7 (2.43 mg/mL) and 43H7 (4.75 mg/mL) were tested several times. They were half-log serially diluted in 2%FBS+DMEM and mixed with an equal volume of virus stock and incubated at 37 °C for 1 h. The mixture was added to Vero E6 cell culture in duplicates (medium removed) at 200 mcL/well and further incubated at 37 °C for 1 h, with periodic brief mild shaking for 3 times. After PBS washing, 0.9%carboxyl methylcellulose in 2%FBS+DMEM was added (0.5 mL/well) and incubated for 3 d at 37 °C/5%CO 2 .
- a decrease in plaque number indicates the degree of viral neutralization by the antibodies. Results show that both antibodies reduced plaque formation in a concentration dependent manner (FIG. 9 and 10) .
- the IC50 for SARS-CoV-2 neutralization of infection was 0.1934 ⁇ g/mL and 1.177 ⁇ g/mL for 13H7 and 43H7, respectively (FIG. 11) .
- Human ACE2 is a receptor for the virus and has been genetically engineered into the mice to render them susceptible to SARS-CoV-2 infection making these transgenic mice a suitable and accepted model for evaluating drug or vaccine efficacy.
- Avertin 250 mg/kg
- PFU SARS-CoV-2 wild type, IVCAS 6.7512
- mice were weighed every day following infection. On day 3 post infection, mice were sacrificed and lung tissues were obtained for (a) 4%paraformaldehyde fixation and (b) tissue homogenation in DMEM for viral RNA quantitation. Fixed lung tissues were prepared and sectioned for hematoxylin and eosin staining and photographed. Lung homogenates were lysed to extract viral RNA by QIAamp viral RNA mini kit. Viral RNA was quantitated by RT-PCR.
- Lung histopathology indicated no significant abnormalities in both antibody-treated groups aside from patchy areas of alveolar wall thickening, minor inflammatory cell infiltrate (black arrow) and minor irregular epithelial lining (red arrow) .
- black arrow minor inflammatory cell infiltrate
- red arrow minor irregular epithelial lining
- large areas of alveolar thickening could be observed in PBS-treated mice.
- black arrow There were clearly inflammatory cells that infiltrated in the alveolar wall (black arrow) that sometimes formed aggregates (yellow arrow) with macrophages in the alveolar space (red arrow) , and even hemorrhage (green arrow) , all features of inflammation and significant pathological changes.
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Abstract
L'invention concerne des anticorps et des fragments de ceux-ci ayant une spécificité de liaison à la protéine spike du SARS-CoV-2. Les anticorps et fragments peuvent être utilisés pour prévenir ou traiter une infection par le virus SARS-CoV-2 ou pour détecter la présence du virus dans un échantillon.
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