WO2021045836A1 - Anti-sars-cov-2-spike glycoprotein antibodies and antigen-binding fragments - Google Patents
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Classifications
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- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
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- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
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Definitions
- the present invention relates to antibodies and antigen-binding fragments that bind specifically to coronavirus spike proteins and methods for treating or preventing coronavirus infections with said antibodies and fragments.
- BACKGROUND OF THE INVENTION [0003] Newly identified viruses, such as coronaviruses, can be difficult to treat because they are not sufficiently characterized. The emergence of these newly identified viruses highlights the need for the development of novel antiviral strategies. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly-emergent coronavirus which causes a severe acute respiratory disease, COVID-19.
- SARS-CoV-2 was first identified from an outbreak in Wuhan, China and as of March 20, 2020, the World Health Organization has reported 209,839 confirmed cases in 168 countries, areas, or territories, resulting in 8,778 deaths. Clinical features of COVID-19 include fever, dry cough, and fatigue, and the disease can cause respiratory failure resulting in death. [0004] Thus far, there has been no vaccine or therapeutic agent to prevent or treat SARS-CoV- 2 infection. In view of the continuing threat to human health, there is an urgent need for preventive and therapeutic antiviral therapies for SARS-CoV-2 control.
- this virus uses its spike glycoprotein for interaction with the cellular receptor ACE2 and the serine protease TMPRSS2 for entry into a target cell, this spike protein represents an attractive target for antibody therapeutics.
- fully human antibodies that specifically bind to the SARS-Coactivated virus
- CoV-2-Spike protein SARS-CoV-2-S
- SARS-CoV-2-S SARS-CoV-2-S
- the present disclosure addresses this need, in part, by providing human anti-SARS-CoV-2-S antibodies, such as those of Table 1, and combinations thereof including, for example, combinations with other therapeutics (e.g., anti-inflammatory agents, antimalarial agents, antiviral agents, or other antibodies or antigen-binding fragments), and methods of use thereof for treating viral infections.
- therapeutics e.g., anti-inflammatory agents, antimalarial agents, antiviral agents, or other antibodies or antigen-binding fragments
- the present disclosure provides neutralizing human antigen-binding proteins that specifically bind to SARS-CoV-2-S, for example, antibodies or antigen-binding fragments thereof.
- the present disclosure provides an isolated recombinant antibody or antigen-binding fragment thereof that specifically binds to a coronavirus spike protein (CoV-S), wherein the antibody has one or more of the following characteristics: (a) binds to CoV-S with an EC50 of less than about 10 -9 M; (b) demonstrates an increase in survival in a coronavirus- infected animal after administration to said coronavirus-infected animal, as compared to a comparable coronavirus-infected animal without said administration; and/or (c) comprises three heavy chain complementarity determining regions (CDRs) (CDR-H1, CDR-H2, and CDR-H3) contained within a heavy chain variable region (HCVR) comprising an amino acid sequence having at least about 90% sequence identity to an HCVR of
- CDRs heavy chain complementar
- the antibody or antigen-binding fragment comprises: (a) an immunoglobulin heavy chain variable region comprising the CDR-H1, CDR-H2, and CDR-H3 of an antibody of Table 1; and/or (b) an immunoglobulin light chain variable region comprising the CDR-L1, CDR-L2, and CDR-L3 of an antibody of Table 1.
- the antibody or antigen-binding fragment comprises: (a) a heavy chain immunoglobulin variable region comprising an amino acid sequence having at least 90%
- the antibody or antigen-binding fragment comprises the CDR- H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of a single antibody of Table 1.
- the antibody or antigen-binding fragment comprises an immunoglobulin that comprises the HCVR and the LCVR of a single antibody of Table 1.
- the present disclosure provides an antigen-binding protein that competes with any one of the antibodies or antigen-binding fragments discussed above or herein for binding to CoV-S.
- the present disclosure provides an antigen-binding protein that binds to the same epitope as, or to an overlapping epitope on, CoV-S as any one of the antibodies or antigen-binding fragments discussed above or herein.
- the antibody or antigen-binding fragment may be multispecific.
- the antibody or antigen-binding fragment may comprise one or more of the following properties: a) inhibits growth of coronavirus; b) binds to the surface of a coronavirus; c) limits spread of coronavirus infection of cells in vitro; and d) protects mice engineered to express the human ACE2 or TMPRSS2 protein from death and/or weight loss caused by coronavirus infection.
- CoV-S is SARS-CoV-2-S.
- the present disclosure provides a complex comprising an antibody or antigen-binding fragment as discussed above or herein bound to a CoV-S polypeptide.
- the CoV-S is SARS-CoV-2-S.
- the present disclosure provides a method for making an antibody or antigen-binding fragment as discussed above or herein, comprising: (a) introducing into a host cell one or more polynucleotides encoding said antibody or antigen-binding fragment; (b) culturing the host cell under conditions favorable to expression of the one or more polynucleotides; and (c) optionally, isolating the antibody or antigen-binding fragment from the host cell and/or a medium in which the host cell is grown.
- the host cell is a Chinese hamster ovary cell.
- the present disclosure provides an antibody or antigen-binding fragment that is a product of the method discussed above.
- the present disclosure provides a polypeptide comprising: (a) CDR-H1, CDR-H2, and CDR-H3 of an HCVR domain of an antibody or antigen-binding fragment that comprises an HCVR amino acid sequence set forth in Table 1; or (b) CDR-L1, CDR-L2, and CDR-L3 of an LCVR domain of an immunoglobulin chain that comprises an LCVR amino acid sequence set forth in Table 1.
- the present disclosure provides a polynucleotide encoding the polypeptide discussed above.
- the present disclosure provides a vector comprising the polynucleotide discussed above.
- the present disclosure provides a host cell comprising the antibody or antigen-binding fragment or polypeptide or polynucleotide or vector as discussed above or herein.
- the present disclosure provides a composition or kit comprising the antibody or antigen-binding fragment discussed above or herein in association with a further therapeutic agent.
- the present disclosure provides a pharmaceutical composition comprising the antigen-binding protein, antibody or antigen-binding fragment discussed above or herein and a pharmaceutically acceptable carrier and, optionally, a further therapeutic agent.
- the further therapeutic agent is an anti-viral drug or a vaccine.
- the further therapeutic agent is selected from the group consisting of: an anti- inflammatory agent, an antimalarial agent, an antibody or antigen-binding fragment thereof that specifically binds TMPRSS2, and an antibody or antigen-binding fragment thereof that specifically binds to CoV-S.
- the antimalarial agent is chloroquine or hydroxychloroquine.
- the anti-inflammatory agent is an antibody, such as sarilumab, tocilizumab, or gimsilumab.
- the further therapeutic agent is a second antibody or antigen-binding fragment comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences of Table 1.
- the present disclosure provides a vessel or injection device comprising the antigen-binding protein, antibody or antigen-binding fragment, or composition as discussed above or herein.
- the present disclosure provides a method for treating or preventing infection with a coronavirus, in a subject in need thereof, comprising administering a therapeutically effective amount of an antigen-binding protein, antibody or antigen-binding fragment as discussed above or herein.
- the coronavirus is selected from the group consisting of SARS-CoV-2, SARS-CoV, and MERS-CoV.
- the subject is administered one or more further therapeutic agents.
- the one or more further therapeutic agents is an anti-viral drug or a vaccine.
- the one or more further therapeutic agents is selected from the group consisting of: an anti- inflammatory agent, an antimalarial agent, an antibody or antigen-binding fragment thereof that specifically binds TMPRSS2, and an antibody or antigen-binding fragment thereof that specifically binds to CoV-S.
- the antimalarial agent is chloroquine or hydroxychloroquine.
- the anti-inflammatory agent is an antibody, such as for example, sarilumab, tocilizumab, or gimsilumab.
- the further therapeutic agent is a second antibody or antigen-binding fragment comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences of Table 1.
- Other antibodies that can be used alone or in combination with one another or with one or more of the antibodies disclosed herein for use in the context of the methods of the present disclosure include, e.g., LY-CoV555 (Eli Lilly); 47D11 (Wang et al Nature Communications Article No.2251); B38, H4, B5 and/or H2 (Wu et al., 10.1126/science.abc2241 (2020); STI-1499 (Sorrento Therapeutics); VIR-7831 and VIR-7832 (Vir Biotherapeutics).
- the present disclosure provides a method for administering an antibody or antigen-binding fragment discussed above or herein into the body of a subject comprising injecting the antibody or antigen-binding fragment into the body of the subject.
- the antibody or antigen-binding fragment is injected into the body of the subject subcutaneously, intravenously or intramuscularly.
- the antibody or antigen- binding binding fragment comprises a VH3-66 or Vk1-33 variable domain sequence.
- the present disclosure provides an isolated antibody or antigen-binding fragment thereof that binds a SARS-CoV-2 spike protein comprising the amino acid sequence set forth in SEQ ID NO: 832, wherein said isolated antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence set forth in SEQ ID NO: 202, and three light chain complementarity determining regions (CDRs) (LCDR1, LCDR2 and LCDR3) contained within a light chain variable region (LCVR) comprising the amino acid sequence set forth in SEQ ID NO: 210.
- CDRs heavy chain complementarity determining regions
- LCVR light chain complementarity determining regions
- the HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 204
- the HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 206
- the HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 208
- the LCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 212
- the LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 55
- the LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 214.
- the isolated antibody or antigen-binding fragment thereof comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 202.
- the isolated antibody or antigen-binding fragment thereof comprises an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 210. In some embodiments, the isolated antibody or antigen-binding fragment thereof comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 202 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 210.
- the present disclosure provides an isolated antibody that binds a SARS- CoV-2 spike protein comprising the amino acid sequence set forth in SEQ ID NO: 832, wherein said isolated antibody comprises an immunoglobulin constant region, three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence set forth in SEQ ID NO: 202, and three light chain complementarity determining regions (CDRs) (LCDR1, LCDR2 and LCDR3) contained within a light chain variable region (LCVR) comprising the amino acid sequence set forth in SEQ ID NO: 210.
- CDRs heavy chain complementarity determining regions
- LCVR light chain complementarity determining regions
- the HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 204
- the HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 206
- the HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 208
- the LCDR1 comprises
- the isolated antibody comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 202 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 210.
- the isolated antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 216 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 218.
- the immunoglobulin constant region is an IgG1 constant region.
- the isolated antibody is a recombinant antibody. In some cases, the isolated antibody is multispecific.
- the present disclosure provides a pharmaceutical composition comprising an isolated antibody as discussed above or herein, and a pharmaceutically acceptable carrier or diluent.
- the pharmaceutical composition further comprises a second therapeutic agent.
- the second therapeutic agent is selected from the group consisting of: a second antibody, or an antigen-binding fragment thereof, that binds a SARS- CoV-2 spike protein comprising the amino acid sequence set forth in SEQ ID NO: 832, an anti- inflammatory agent, an antimalarial agent, and an antibody or antigen-binding fragment thereof that binds TMPRSS2.
- the second therapeutic agent is a second antibody, or an antigen- binding fragment thereof, that binds a SARS-CoV-2 spike protein comprising the amino acid sequence set forth in SEQ ID NO: 832.
- the second antibody or antigen-binding fragment thereof comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 640, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 646.
- the second antibody or antigen-binding fragment thereof comprises: HCDR1, comprising the amino acid sequence set forth in SEQ ID NO: 642; HCDR2, comprising the amino acid sequence set forth in SEQ ID NO: 499; HCDR3, comprising the amino acid sequence set forth in SEQ ID NO: 644; LCDR1, comprising the amino acid sequence set forth in SEQ ID NO: 648; LCDR2, comprising the amino acid sequence set forth in SEQ ID NO: 650; and LCDR3, comprising the amino acid sequence set forth in SEQ ID NO: 652.
- the second antibody or antigen-binding fragment thereof comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 640 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 646. In some cases, the second antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 654 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 656.
- the present disclosure provides an isolated antibody or antigen-binding fragment thereof that binds a SARS-CoV-2 spike protein comprising the amino acid sequence set forth in SEQ ID NO: 832, wherein said isolated antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence set forth in SEQ ID NO: 640, and three light chain complementarity determining regions (CDRs) (LCDR1, LCDR2 and LCDR3) contained within a light chain variable region (LCVR) comprising the amino acid sequence set forth in SEQ ID NO: 646.
- CDRs heavy chain complementarity determining regions
- LCVR light chain complementarity determining regions
- the HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 642
- the HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 499
- the HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 644
- the LCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 648
- the LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 650
- the LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 652.
- the isolated antibody or antigen-binding fragment thereof comprises an HCVR that comprises an amino acid sequence set forth in SEQ ID NO: 640.
- the isolated antibody or antigen-binding fragment thereof comprises an LCVR that comprises an amino acid sequence set forth in SEQ ID NO: 646. In some embodiments, the isolated antibody or antigen-binding fragment thereof comprises an HCVR that comprises an amino acid sequence set forth in SEQ ID NO: 640 and an LCVR that comprises an amino acid sequence set forth in SEQ ID NO: 646.
- the present disclosure provides an isolated antibody that binds a SARS- CoV-2 spike protein comprising the amino acid sequence set forth in SEQ ID NO: 832, wherein said isolated antibody comprises an immunoglobulin constant region, three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence set forth in SEQ ID NO: 832, wherein said isolated antibody comprises an immunoglobulin constant region, three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence set forth in SEQ ID NO: 832, wherein said isolated antibody comprises an immunoglobulin constant region, three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence set forth in SEQ ID NO: 832, wherein said isolated antibody comprises
- the HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 642
- the HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 499
- the HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 644
- the LCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 648
- the LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 650
- the LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 652.
- the isolated antibody comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 640 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 646.
- the isolated antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 654 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 656.
- the immunoglobulin constant region is an IgG1 constant region.
- the isolated antibody is a recombinant antibody.
- the isolated antibody is multispecific.
- the present disclosure provides a pharmaceutical composition
- a pharmaceutical composition comprising an isolated antibody, as discussed above or herein, and a pharmaceutically acceptable carrier or diluent.
- the pharmaceutical composition further comprising a second therapeutic agent.
- the second therapeutic agent is selected from the group consisting of: a second antibody, or an antigen-binding fragment thereof, that binds a SARS- CoV-2 spike protein comprising the amino acid sequence set forth in SEQ ID NO: 832, an anti- inflammatory agent, an antimalarial agent, and an antibody or antigen-binding fragment thereof that binds TMPRSS2.
- the second therapeutic agent is a second antibody, or an antigen- binding fragment thereof, that binds a SARS-CoV-2 spike protein comprising the amino acid sequence set forth in SEQ ID NO: 832.
- the second antibody or antigen-binding fragment thereof comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 202, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within an LCVR comprising the
- the second antibody or antigen-binding fragment thereof comprises: HCDR1, comprising the amino acid sequence set forth in SEQ ID NO: 204; HCDR2, comprising the amino acid sequence set forth in SEQ ID NO: 206; HCDR3, comprising the amino acid sequence set forth in SEQ ID NO: 208 LCDR1, comprising the amino acid sequence set forth in SEQ ID NO: 212; LCDR2, comprising the amino acid sequence set forth in SEQ ID NO: 55; and LCDR3, comprising the amino acid sequence set forth in SEQ ID NO: 214.
- the second antibody or antigen-binding fragment thereof comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 202 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 210. In some cases, the second antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 216 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 218. [00044] In various embodiments, any of the features or components of embodiments discussed above or herein may be combined, and such combinations are encompassed within the scope of the present disclosure.
- Figure 1 shows ELISA blocking data for selected anti-SARS-CoV-2-S antibodies against SARS-CoV-2 spike protein, preventing the spike protein from binding to its receptor ACE2.
- Figure 2 shows ELISA blocking data for selected anti-SARS-CoV-2-S antibodies against SARS-CoV-2 spike protein, preventing the spike protein from binding to its receptor ACE2.
- Figure 3 shows ELISA blocking data for selected anti-SARS-CoV-2-S antibodies against SARS-CoV-2 spike protein, preventing the spike protein from binding to its receptor ACE2.
- Figure 4 shows ELISA blocking data for selected anti-SARS-CoV-2-S antibodies against SARS-CoV-2 spike protein, preventing the spike protein from binding to its receptor ACE2.
- Figure 5 shows ELISA blocking data for selected anti-SARS-CoV-2-S antibodies against SARS-CoV-2 spike protein, preventing the spike protein from binding to its receptor ACE2.
- Figure 6 shows ELISA blocking data for selected anti-SARS-CoV-2-S antibodies against SARS-CoV-2 spike protein, preventing the spike protein from binding to its receptor ACE2.
- Figure 7 shows ELISA blocking data for selected anti-SARS-CoV-2-S antibodies against SARS-CoV-2 spike protein, preventing the spike protein from binding to its receptor ACE2.
- Figure 8 shows ELISA blocking data for selected anti-SARS-CoV-2-S antibodies against SARS-CoV-2 spike protein, preventing the spike protein from binding to its receptor ACE2.
- Figure 10A and Figure 10B display neutralization potency.
- Figure 10A displays the neutralization potency of anti-SARS-CoV-2 Spike mAbs.
- Serial dilutions of anti-Spike mAbs, IgG1 isotype control, and recombinant dimeric ACE2 (hACE2.hFc) were added with pVSV- SARS-CoV-2-S-mNeon to Vero cells and mNeon expression was measured 24 hours post- infection as a read-out for virus infectivity.
- Figure 10B displays neutralization potency of individual anti-Spike mAbs and combinations of mAbs against SARS-CoV-2-S virus in VeroE6 cells.
- Figure 11 displays epitope bin analysis from a matrix of pre-mix binding assays for different anti-SARS-CoV-2 mAbs. Epitope binning was performed against nine anti-SARS- CoV-2 mAb as described. There were three phases (I, II, and III) for each graph. In phase I anti-
- FIG. 12 displays a 3D surface model for the structure of the Spike protein RBD domain showing the ACE2 interface and HDX-MS epitope mapping results. RBD residues protected by anti-SARS-CoV2-Spike antibodies are indicated with shading that represent the extent of protection as determined by HDX-MS experiments.
- FIG. 13A and Figure 13B display a complex of mAb10933 and mAb10987 with the SARS-CoV-2 RBD.
- Figure 13A displays a 3.9 ⁇ cryoEM map of mAb10933 + RBD + mAb10987 complex, shaded according to the chains in the refined model of Figure 13B.
- RBD, mAb10933 heavy and light chains, and mAb10987 heavy and light chain are identified.
- Figure 14 displays cryoEM data statistics. Data collection and refinement statistics are reported for the mAb10987 + mAb10933 + SARS-CoV-2 RBD complex structure shown in Figure 13A and Figure 13B.
- coronavirus refers to any virus of the coronavirus family, including but not limited to SARS-CoV-2, MERS-CoV, and SARS-CoV.
- SARS-CoV-2 refers to any virus of the coronavirus family, including but not limited to SARS-CoV-2, MERS-CoV, and SARS-CoV.
- SARS-CoV-2 refers to any virus of the coronavirus family, including but not limited to SARS-CoV-2, MERS-CoV, and SARS-CoV.
- SARS-CoV-2 refers to any virus of the coronavirus family, including but not limited to SARS-CoV-2, MERS-CoV, and SARS-CoV.
- SARS-CoV-2 refers to any virus of the coronavirus family, including but not limited to SARS-CoV-2, MERS-CoV, and SARS-CoV.
- SARS-CoV-2 refers to any virus of the coronavirus family
- SARS-CoV-2 has also been known as 2019-nCoV and Wuhan coronavirus. It binds via the viral spike protein to human host cell receptor angiotensin-converting enzyme 2 (ACE2). The spike protein also binds to and is cleaved by TMPRSS2, which activates the spike protein for membrane fusion of the virus.
- ACE2 human host cell receptor angiotensin-converting enzyme 2
- CoV-S also called “S” or “S protein” refers to the spike protein of a coronavirus, and can refer to specific S proteins such as SARS-CoV-2-S, MERS-CoV S, and SARS-CoV S.
- SARS-CoV-2-Spike protein is a 1273 amino acid type I membrane glycoprotein which assembles into trimers that constitute the spikes or peplomers on the surface of the enveloped coronavirus particle.
- the protein has two essential functions, host receptor binding and membrane fusion, which are attributed to the N-terminal (S1) and C-terminal (S2) halves of the S protein.
- CoV-S binds to its cognate receptor via a receptor binding domain (RBD) present in the S1 subunit.
- RBD receptor binding domain
- the amino acid sequence of full-length SARS-CoV-2 spike protein is exemplified by the amino acid sequence provided in SEQ ID NO: 832.
- the term “CoV-S” includes protein variants of CoV spike protein isolated from different CoV isolates as well as recombinant CoV spike protein or a fragment thereof. The term also encompasses CoV spike protein or a fragment thereof coupled to, for example, a histidine tag, mouse or human Fc, or a signal sequence such as ROR1.
- coronavirus infection refers to infection with a coronavirus such as SARS-CoV-2, MERS-CoV, or SARS-CoV.
- the term includes coronavirus respiratory tract infections, often in the lower respiratory tract. Symptoms can include high fever, dry cough, shortness of breath, pneumonia, gastro-intestinal symptoms such as diarrhea, organ failure (kidney failure and renal dysfunction), septic shock, and death in severe cases.
- Viruses [00064] The present invention includes methods for treating or preventing a viral infection in a subject.
- virus includes any virus whose infection in the body of a subject is treatable or preventable by administration of an anti-CoV-S antibody or antigen-binding fragment thereof (e.g., wherein infectivity of the virus is at least partially dependent on CoV-S).
- an anti-CoV-S antibody or antigen-binding fragment thereof e.g., wherein infectivity of the virus is at least partially dependent on CoV-S.
- a “virus” is any virus that expresses spike protein (e.g., CoV-S).
- the term “virus” also includes a CoV-S-dependent respiratory virus which is a virus that infects the respiratory tissue of a subject (e.g., upper and/or lower respiratory tract, trachea, bronchi, lungs) and is treatable or preventable by administration of an anti-CoV-S antibody or antigen- binding fragment thereof.
- virus includes coronavirus, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), SARS-CoV (severe acute respiratory syndrome coronavirus), and MERS-CoV (Middle East respiratory syndrome (MERS) coronavirus).
- Coronaviruses can include the genera of alphacoronaviruses, betacoronaviruses, gammacoronaviruses, and deltacoronaviruses.
- the antibodies or antigen-binding fragments provided herein can bind to and/or neutralize an alphacoronavirus, a betacoronavirus, a gammacoronavirus, and/or a deltacoronavirus. In certain embodiments, this binding and/or neutralization can be specific for a particular genus of coronavirus or for a particular subgroup of a genus.
- “Viral infection” refers to the invasion and multiplication of a virus in the body of a subject.
- Coronavirus virions are spherical with diameters of approximately 125 nm. The most prominent feature of coronaviruses is the club-shape spike projections emanating from the surface of the virion. These spikes are a defining feature of the virion and give them the appearance of a solar corona, prompting the name, coronaviruses. Within the envelope of the virion is the nucleocapsid. Coronaviruses have helically symmetrical nucleocapsids, which is uncommon among positive-sense RNA viruses, but far more common for negative-sense RNA viruses. SARS-CoV-2, MERS-CoV, and SARS-CoV belong to the coronavirus family.
- the initial attachment of the virion to the host cell is initiated by interactions between the S protein and its receptor.
- the sites of receptor binding domains (RBD) within the S1 region of a coronavirus S protein vary depending on the virus, with some having the RBD at the C-terminus of S1.
- the S-protein/receptor interaction is the primary determinant for a coronavirus to infect a host species and also governs the tissue tropism of the virus.
- Many coronaviruses utilize peptidases as their cellular receptor. Following receptor binding, the virus must next gain access to the host cell cytosol. This is generally accomplished by acid-dependent proteolytic cleavage of S protein by a cathepsin, TMPRRS2 or another protease, followed by fusion of the viral and cellular membranes.
- the present invention provides antigen-binding proteins, such as antibodies and antigen-binding fragments thereof, that specifically bind to CoV spike protein or an antigenic fragment thereof.
- antigen-binding proteins such as antibodies and antigen-binding fragments thereof, that specifically bind to CoV spike protein or an antigenic fragment thereof.
- antibody refers to immunoglobulin molecules comprising four polypeptide chains, two heavy chains (HCs) and two light chains (LCs) inter-connected by disulfide bonds (i.e., "full antibody molecules"), as well as multimers thereof (e.g. IgM).
- Exemplary antibodies include, for example, those listed in Table 1.
- Each heavy chain comprises a heavy chain variable region (“HCVR” or “V H ”) and a heavy chain constant region (comprised of domains C H 1, C H 2 and C H 3).
- Each light chain is comprised of a light chain variable region (“LCVR or “VL”) and a light chain constant region (CL).
- the VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
- CDR complementarity determining regions
- FR framework regions
- Each V H and VL comprises three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
- Heavy chain CDRs can also be referred to as HCDRs or CDR-Hs, and numbered as described above (e.g., HCDR1, HCDR2, and HCDR3 or CDR-H1, CDR-H2, and CDR-H3).
- light chain CDRs can be referred to as LCDRs or CDR-Ls, and numbered LCDR1, LCDR2, and LCDR3, or CDR-L1, CDR-L2, and CDR-L3.
- the FRs of the antibody (or antigen binding fragment thereof) are identical to the human germline sequences, or are naturally or artificially modified.
- Exemplary human germline sequences include, but are not limited to, VH3-66 and Vk1-33.
- anti-CoV-S antibodies or antigen- binding fragments thereof comprising HCDR and LCDR sequences of Table 1 within a VH3-66 or Vk1-33 variable heavy chain or light chain region.
- the present disclosure further provides anti-CoV-S antibodies or antigen-binding fragments thereof (e.g., anti-SARS-CoV-2-S antibodies or antigen- binding fragments thereof) comprising HCDR and LCDR sequences of Table 1 within a combination of a light chain selected from IgKV4-1, IgKV 1-5, IgKV1-9, IgKV1-12, IgKV3-15, IgKV1-16, IgKV1-17, IgKV3-20, IgLV3-21, IgKV2-24, IgKV1-33, IgKV1-39, IgLV1-40, IgLV1-44, IgLV1-51, IgLV3-1, IgKV1-6, IgLV2-8, IgKV3-11, IgLV2-11, IgLV2-14, IgLV2-23, or IgLV6-57, and a heavy chain selected from IgHV1-69, IgHV3-64, IgHV4-59, IgHV3-53,
- the present disclosure further provides anti-CoV-S antibodies or antigen-binding fragments thereof (e.g., anti-SARS-CoV-2-S antibodies or antigen-binding fragments thereof) comprising HCVR and LCVR sequences of Table 1 within a combination of a light chain selected from IgKV4-1, IgKV 1-5, IgKV1-9, IgKV1-12, IgKV3-15, IgKV1-16, IgKV1-17, IgKV3-20, IgLV3-21, IgKV2-24, IgKV1-33, IgKV1-39, IgLV1-40, IgLV1-44, IgLV1-51, IgLV3-1, IgKV1-6, IgLV2-8, IgKV3- 11, IgLV2-11, IgLV2-14, IgLV2-23, or IgLV6-57, and a heavy chain selected from IgHV1-69, IgHV3-64, IgHV4-59, IgHV3-53, IgH
- variable domains of both the heavy and light immunoglobulin chains comprise three hypervariable regions, also called complementarity determining regions (CDRs), located within relatively conserved framework regions (FR).
- CDRs complementarity determining regions
- FR framework regions
- both light and heavy chains variable domains comprise FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.
- the assignment of amino acids to each domain is in accordance with the definitions of Sequences of Proteins of Immunological Interest, Kabat, et al.; National Institutes of Health, Bethesda, Md.; 5 th ed.; NIH Publ. No.91-3242 (1991); Kabat (1978) Adv. Prot.
- the present invention includes monoclonal anti-CoV-S antigen-binding proteins, e.g., antibodies and antigen-binding fragments thereof, as well as monoclonal compositions comprising a plurality of isolated monoclonal antigen-binding proteins.
- monoclonal antibody refers to a population of substantially homogeneous antibodies, i.e., the antibody molecules comprising the population are identical in amino acid sequence except for possible naturally occurring mutations that may be present in minor amounts.
- a "plurality" of such monoclonal antibodies and fragments in a composition refers to a concentration of identical (i.e., as discussed above, in amino acid sequence except for possible naturally occurring
- an anti-CoV-S antigen-binding protein e.g., antibody or antigen-binding fragment comprises a heavy chain constant domain, e.g., of the type IgA (e.g., IgA1 or IgA2), IgD, IgE, IgG (e.g., IgG1, IgG2, IgG3 and IgG4) or IgM.
- an antigen-binding protein e.g., antibody or antigen-binding fragment comprises a light chain constant domain, e.g., of the type kappa or lambda.
- the term "human” antigen-binding protein, such as an antibody, as used herein, includes antibodies having variable and constant regions derived from human germline immunoglobulin sequences whether in a human cell or grafted into a non-human cell, e.g., a mouse cell. See e.g., US8502018, US6596541 or US5789215.
- the human mAbs of the invention may 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), for example in the CDRs and, in particular, CDR3.
- human antibody as used herein, is not intended to include mAbs in which CDR sequences derived from the germline of another mammalian species (e.g., mouse) have been grafted onto human FR sequences.
- the term includes antibodies recombinantly produced in a non-human mammal or in cells of a non-human mammal.
- the term is not intended to include antibodies isolated from or generated in a human subject. See below.
- the present invention includes anti-CoV-S chimeric antigen-binding proteins, e.g., antibodies and antigen-binding fragments thereof, and methods of use thereof.
- a "chimeric antibody” is an antibody having the variable domain from a first antibody and the constant domain from a second antibody, where the first and second antibodies are from different species. (US4816567; and Morrison et al., (1984) Proc. Natl. Acad. Sci. USA 81: 6851-6855).
- the present invention includes anti-CoV-S hybrid antigen-binding proteins, e.g., antibodies and antigen-binding fragments thereof, and methods of use thereof.
- hybrid antibody is an antibody having the variable domain from a first antibody and the constant domain from a second antibody, wherein the first and second antibodies are from different animals, or wherein the variable domain, but not the constant region, is from a first animal.
- a variable domain can be taken from an antibody isolated from a human
- hybrid antibodies are described in Example 1, which refers to antibody heavy chain variable region and light chain variable region derived PCR products that were cloned into expression vectors containing a heavy constant region and a light constant region, respectively.
- Hybrid antibodies are synthetic and non-natrually occurring because the variable and constant regions they contain are not isolated from a single natural source.
- the term “recombinant” antigen-binding proteins, such as antibodies or antigen-binding fragments thereof refers to such molecules created, expressed, isolated or obtained by technologies or methods known in the art as recombinant DNA technology which include, e.g., DNA splicing and transgenic expression.
- the term includes antibodies expressed in a non- human mammal (including transgenic non-human mammals, e.g., transgenic mice), or a cell (e.g., CHO cells) expression system, or a non-human cell expression system, or isolated from a recombinant combinatorial human antibody library.
- a recombinant antibody shares a sequence with an antibody isolated from an organism (e.g., a mouse or a human), but has been expressed via recombinant DNA technology.
- Such antibodies may have post-translational modifications (e.g., glycosylation) that differ from the antibody as isolated from the organism.
- Recombinant anti-CoV-S antigen-binding proteins e.g., antibodies and antigen-binding fragments, disclosed herein may also be produced in an E. coli/T7 expression system.
- nucleic acids encoding the anti-CoV-S antibody immunoglobulin molecules of the invention e.g., as found in Table 1 may be inserted into a pET-based plasmid and expressed in the E. coli/T7 system.
- the present invention includes methods for expressing an antibody or antigen-binding fragment thereof or immunoglobulin chain thereof in a host cell (e.g., bacterial host cell such as E.
- a bacterial host cell such as an E. coli, includes a polynucleotide encoding the T7 RNA polymerase gene operably linked to a lac promoter and expression of the polymerase and the chain is induced by incubation of the host cell with IPTG (isopropyl-beta-D- thiogalactopyranoside). See US4952496 and US5693489 or Studier & Moffatt, Use of
- Transformation can be by any known method for introducing polynucleotides (e.g., DNA or RNA, including mRNA) into a host cell.
- polynucleotides e.g., DNA or RNA, including mRNA
- nucleic acid molecules may be introduced into mammalian cells by viral vectors such as lentivirus or adeno-associated virus. Methods of transforming cells are well known in the art. See, for example, U.S. Pat.
- an antibody or antigen-binding fragment thereof of the present disclosure can be introduced to a subject in nucleic acid form (e.g, DNA or RNA, including mRNA), such that the subject’s own cells produce the antibody.
- nucleic acid form e.g, DNA or RNA, including mRNA
- the present disclosure further provides modifications to nucleotide sequences encoding the anti-CoV-S antibodies described herein that result in increased antibody expression, increased antibody stability, increased nucleic acid (e.g., mRNA) stability, or improved affinity or specificity of the antibodies for the CoV spike protein.
- the present invention includes recombinant methods for making an anti-CoV-S antigen-binding protein, such as an antibody or antigen-binding fragment thereof of the present invention, or an immunoglobulin chain thereof, comprising (i) introducing one or more polynucleotides (e.g., including the nucleotide sequence of any one or more of the sequences of Table 2) encoding light and/or heavy immunoglobulin chains, or CDRs, of the antigen-binding protein, e.g., of Table 1, for example, wherein the polynucleotide is in a vector; and/or integrated into a host cell chromosome and/or is operably linked to a promoter; (ii) culturing the host cell (e.g., CHO or Pichia or Pichia pastoris) under condition favorable to expression of the polynucleotide and, (iii) optionally, isolating the antigen-binding protein, (e.g.,
- insertion with a vector such as adeno-associated virus (AAV), e.g., after cleavage of the chromosome using a gene editing system (e.g., CRISPR (for example, CRISPR-Cas9), TALEN, megaTAL, zinc finger, or Argonaute).
- AAV adeno-associated virus
- Targeted insertions can take place, for example, at host cell loci such as an albumin or immunoglopbulin genomic locus.
- insertion can be at a random locus, e.g., using a vector such as lentivirus.
- an antigen-binding protein e.g., antibody or antigen-binding fragment
- an immunoglobulin chain e.g., an antibody that comprises two heavy immunoglobulin chains and two light immunoglobulin chains
- co-expression of the chains in a single host cell leads to association of the chains, e.g., in the cell or on the cell surface or outside the cell if such chains are secreted, so as to form the antigen-binding protein (e.g., antibody or antigen-binding fragment).
- the methods include those wherein only a heavy immunoglobulin chain or only a light immunoglobulin chain (e.g., any of those discussed herein including mature fragments and/or variable domains thereof) is expressed.
- the present invention also includes anti-CoV-S antigen-binding proteins, such as antibodies and antigen-binding fragments thereof, comprising a heavy chain immunoglobulin (or variable domain thereof or comprising the CDRs thereof) encoded by a polynucleotide comprising a nucleotide sequence set forth in Table 2 and a light chain immunoglobulin (or variable domain thereof or comprising the CDRs thereof) encoded by a nucleotide sequence set forth in Table 2 which are the product of such production methods, and, optionally, the purification methods set forth herein.
- anti-CoV-S antigen-binding proteins such as antibodies and antigen-binding fragments thereof, comprising a heavy chain immunoglobulin (or variable domain thereof or comprising the CDRs thereof) encoded by a polynucleotide comprising a nucleotide sequence set forth in Table 2 and a light chain immunoglobulin (or variable domain thereof or comprising the CDRs thereof) encoded by a nucleot
- the product of the method is an anti-CoV-S antigen-binding protein which is an antibody or fragment comprising an HCVR comprising an amino acid sequence set forth in Table 1 and an LCVR comprising an amino acid sequence set forth in Table 1, wherein the HCVR and LCVR sequences are selected from a single antibody listed in Table 1.
- the product of the method is an anti-CoV-S antigen-binding protein which is an antibody or fragment comprising HCDR1, HCDR2, and HCDR3 comprising amino acid sequences set forth in Table 1 and LCDR1, LCDR2, and LCDR3 comprising amino acid sequences set forth in Table 1, wherein the six CDR sequences are selected from a single antibody listed in Table 1.
- the product of the method is an anti-CoV-S antigen-binding protein which is an antibody or fragment
- Eukaryotic and prokaryotic host cells including mammalian cells, may be used as hosts for expression of an anti-CoV-S antigen-binding protein.
- host cells are well known in the art and many are available from the American Type Culture Collection (ATCC).
- These host cells include, inter alia, Chinese hamster ovary (CHO) cells, NS0, SP2 cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), A549 cells, 3T3 cells, HEK-293 cells and a number of other cell lines.
- Mammalian host cells include human, mouse, rat, dog, monkey, pig, goat, bovine, horse and hamster cells.
- Other cell lines that may be used are insect cell lines (e.g., Spodoptera frugiperda or Trichoplusia ni), amphibian cells, bacterial cells, plant cells and fungal cells.
- Fungal cells include yeast and filamentous fungus cells including, for example, Pichia pastoris, Pichia finlandica, Pichia trehalophila, Pichia koclamae, Pichia membranaefaciens, Pichia minuta (Ogataea minuta, Pichia lindneri), Pichia opuntiae, Pichia thermotolerans, Pichia salictaria, Pichia guercuum, Pichia pijperi, Pichia stiptis, Pichia methanolica, Pichia sp., Saccharomyces cerevisiae, Saccharomyces sp., Hansenula polymorpha, Kluyveromyces sp., Kluyveromyces lactis, Candida albicans, Aspergillus nidulans, Aspergillus niger, Aspergillus oryzae, Trichoderma reesei, Chrysosporium
- the present invention includes an isolated host cell (e.g., a CHO cell) comprising an antigen-binding protein, such as those of Table 1; or a polynucleotide encoding such a polypeptide thereof.
- an antigen-binding protein e.g., mAbs
- mAbs a binding affinity to an antigen
- an antigen such as a CoV-S protein (e.g., SARS-CoV-2-S)
- KD e.g., SARS-CoV-2-S
- the present invention includes antigen-binding proteins that specifically bind to a CoV-S protein.
- antigen-binding portion or “antigen-binding fragment” of an antibody or antigen-binding protein, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex.
- antigen-binding portion or “antigen-binding fragment” of an antibody or antigen-binding protein, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex.
- antigen-binding portion or “antigen-binding fragment” of an antibody or antigen-binding protein, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex.
- fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide.
- CDR complementarity determining region
- engineered molecules such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR- grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., as defined in WO08/020079 or WO09/138519) (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression "antigen-binding fragment," as used herein.
- SMIPs small modular immunopharmaceuticals
- the antigen-binding fragment comprises three or more CDRs of an antibody of Table 1 (e.g., CDR-H1, CDR-H2 and CDR-H3; or CDR-L1, CDR-L2 and CDR-L3).
- An antigen-binding fragment of an antibody will, in an embodiment of the invention, comprise at least one variable domain.
- the variable domain may be of any size or amino acid composition and will generally comprise at least one CDR, which is adjacent to or in frame with one or more framework sequences.
- the VH and VL domains may be situated relative to one another in any suitable arrangement.
- variable region may be dimeric and contain VH - VH, VH - VL or V L - V L dimers.
- the antigen-binding fragment of an antibody may contain a monomeric VH or VL domain.
- an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain.
- Non-limiting, exemplary configurations of variable and constant domains that may be found within an antigen- binding fragment of an antibody of the present invention include: (i) VH-CH1; (ii) VH-CH2; (iii) V H -C H 3; (iv) V H -C H 1-C H 2; (v) V H -C H 1-C H 2-C H 3; (vi) V H -C H 2-C H 3; (vii) V H -C L ; (viii) V L -C H 1; (ix) V L -C H 2; (x) V L -C H 3; (xi) V L -C H 1-C H 2; (xii) V L -C H 1-C H 2-C H 3; (xiii) V L -C H 2-C H 3; and (xiv) VL-CL.
- variable and constant domains may be either directly linked to one another or may be linked by a full or partial hinge or linker region.
- a hinge region may consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids, which result in a flexible or semi-flexible linkage between adjacent variable and/or constant domains in a single polypeptide
- an antigen-binding fragment of an antibody of the present invention may comprise a homo-dimer or hetero-dimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with one another and/or with one or more monomeric VH or VL domain (e.g., by disulfide bond(s)).
- Antigen-binding proteins e.g., antibodies and antigen-binding fragments
- antibody or antibody fragments of the invention may be conjugated to a moiety such a ligand or a therapeutic moiety (“immunoconjugate”), such as an anti-viral drug, a second anti-influenza antibody, or any other therapeutic moiety useful for treating a viral infection, e.g., influenza viral infection. See below.
- the present invention also provides a complex comprising an anti-CoV-S antigen- binding protein, e.g., antibody or antigen-binding fragment, discussed herein complexed with CoV-S polypeptide or an antigenic fragment thereof and/or with a secondary antibody or antigen-binding fragment thereof (e.g., detectably labeled secondary antibody) that binds specifically to the anti-CoV-S antibody or fragment.
- an anti-CoV-S antigen- binding protein e.g., antibody or antigen-binding fragment
- the antibody or fragment is in vitro (e.g., is immobilized to a solid substrate) or is in the body of a subject.
- the CoV-S is in vitro (e.g., is immobilized to a solid substrate) or is on the surface of a virus or is in the body of a subject.
- Immobilized anti-CoV-S antibodies and antigen-binding fragments thereof which are covalently linked to an insoluble matrix material (e.g., glass or polysaccharide such as agarose or sepharose, e.g., a bead or other particle thereof) are also part of the present invention; optionally, wherein the immobilized antibody is complexed with CoV-S or antigenic fragment thereof or a secondary antibody or fragment thereof.
- isolated antigen-binding proteins antibodies or antigen-binding fragments thereof, polypeptides, polynucleotides and vectors, are at least partially free of other biological molecules from the cells or cell culture from which they are produced.
- biological molecules include nucleic acids, proteins, other antibodies or antigen-binding fragments, lipids, carbohydrates, or other material such as cellular debris and growth medium.
- An isolated antibody or antigen- binding fragment may further be at least partially free of expression system components such as biological molecules from a host cell or of the growth medium thereof.
- expression system components such as biological molecules from a host cell or of the growth medium thereof.
- epitope refers to an antigenic determinant (e.g., a CoV-S polypeptide) that interacts with a specific antigen-binding site of an antigen-binding protein, e.g., a variable region of an antibody molecule, known as a paratope.
- a specific antigen-binding site of an antigen-binding protein e.g., a variable region of an antibody molecule, known as a paratope.
- a single antigen may have more than one epitope.
- different antibodies may bind to different areas on an antigen and may have different biological effects.
- epitopes also refers to a site on an antigen to which B and/or T cells respond. It also refers to a region of an antigen that is bound by an antibody.
- Epitopes may be defined as structural or functional. Functional epitopes are generally a subset of the structural epitopes and have those residues that directly contribute to the affinity of the interaction. Epitopes may be linear or conformational, that is, composed of non-linear amino acids.
- epitopes may include determinants that are chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and, in certain embodiments, may have specific three-dimensional structural characteristics, and/or specific charge characteristics.
- Methods for determining the epitope of an antigen-binding protein include alanine scanning mutational analysis, peptide blot analysis (Reineke (2004) Methods Mol. Biol.248: 443-63), peptide cleavage analysis, crystallographic studies and NMR analysis.
- methods such as epitope excision, epitope extraction and chemical modification of antigens can be employed (Tomer (2000) Prot. Sci.9: 487-496).
- Another method that can be used to identify the amino acids within a polypeptide with which an antigen-binding protein e.g., antibody or fragment or polypeptide
- an antigen-binding protein e.g., antibody or fragment or polypeptide
- the hydrogen/deuterium exchange method involves deuterium-labeling the protein of interest, followed by binding the antigen-binding protein, e.g., antibody or fragment or polypeptide, to the deuterium-labeled protein.
- the CoV-S protein/ antigen-binding protein complex is transferred to water and exchangeable protons within amino acids that are protected by the antibody complex undergo deuterium-to-hydrogen back-exchange at a slower rate than exchangeable protons within amino acids that are not part of the interface.
- amino acids that form part of the protein/ antigen-binding protein interface may retain deuterium and
- the target protein After dissociation of the antigen-binding protein (e.g., antibody or fragment or polypeptide), the target protein is subjected to protease cleavage and mass spectrometry analysis, thereby revealing the deuterium-labeled residues which correspond to the specific amino acids with which the antigen-binding protein interacts. See, e.g., Ehring (1999) Analytical Biochemistry 267: 252-259; Engen and Smith (2001) Anal. Chem.73: 256A-265A.
- the term “competes” as used herein refers to an antigen-binding protein (e.g., antibody or antigen-binding fragment thereof) that binds to an antigen (e.g., CoV-S) and inhibits or blocks the binding of another antigen-binding protein (e.g., antibody or antigen-binding fragment thereof) to the antigen.
- an antigen e.g., CoV-S
- another antigen-binding protein e.g., antibody or antigen-binding fragment thereof
- the term also includes competition between two antigen-binding proteins e.g., antibodies, in both orientations, i.e., a first antibody that binds and blocks binding of second antibody and vice versa.
- the first antigen-binding protein (e.g., antibody) and second antigen-binding protein (e.g., antibody) may bind to the same epitope.
- the first and second antigen-binding proteins (e.g., antibodies) may bind to different, but, for example, overlapping epitopes, wherein binding of one inhibits or blocks the binding of the second antibody, e.g., via steric hindrance.
- Competition between antigen-binding proteins (e.g., antibodies) may be measured by methods known in the art, for example, by a real- time, label-free bio-layer interferometry assay.
- Epitope mapping (e.g., via alanine scanning or hydrogen-deuterium exchange (HDX)) can be used to determine whether two or more antibodies are non-competing (e.g., on a spike protein receptor binding domain (RBD) monomer), competing for the same epitope, or competing but with diverse micro-epitopes (e.g., identified through HDX).
- HDX hydrogen-deuterium exchange
- competition between a first and second anti- CoV-S antigen-binding protein is determined by measuring the ability of an immobilized first anti-CoV-S antigen-binding protein (e.g., antibody) (not initially complexed with CoV-S protein) to bind to soluble CoV-S protein complexed with a second anti-CoV-S antigen-binding protein (e.g., antibody).
- the degree of competition can be expressed as a percentage of the reduction in binding. Such competition can be measured using a real time, label-free bio-
- Binding competition between anti-CoV-S antigen-binding proteins can be determined using a real time, label-free bio-layer interferometry assay on an Octet RED384 biosensor (Pall ForteBio Corp.).
- the anti-CoV-S mAb can be first captured onto anti-hFc antibody coated Octet biosensor tips (Pall ForteBio Corp., # 18-5060) by submerging the tips into a solution of anti-CoV-S mAb (subsequently referred to as “mAb1”).
- mAb1 anti-CoV-S mAb
- the antibody captured biosensor tips can then be saturated with a known blocking isotype control mAb (subsequently referred to as “blocking mAb”) by dipping into a solution of blocking mAb.
- the biosensor tips can then be subsequently dipped into a co-complexed solution of CoV-S polypeptide and a second anti-CoV-S mAb (subsequently referred to as “mAb2”), that had been pre-incubated for a period of time and binding of mAb1 to the CoV-S polypeptide can be determined.
- the biosensor tips can be washed in buffer in between every step of the experiment. The real-time binding response can be monitored during the course of the experiment and the binding response at the end of every step can be recorded.
- the competition assay is conducted at 25 o C and pH about 7, e.g., 7.4, e.g., in the presence of buffer, salt, surfactant and a non-specific protein (e.g., bovine serum albumin).
- a non-specific protein e.g., bovine serum albumin.
- an antibody or antigen-binding fragment of the invention which is modified in some way retains the ability to specifically bind to CoV-S, e.g., retains at least 10% of its CoV-S binding activity (when compared to the parental antibody) when that activity is expressed on a molar basis.
- an antibody or antigen-binding fragment of the invention retains at least 20%, 50%, 70%, 80%, 90%, 95% or 100% or more of the CoV-S binding affinity as the parental antibody. It is also intended that an antibody or antigen-binding fragment of the invention can include conservative or non-conservative amino acid substitutions (referred to as “conservative variants” or “function conserved variants” of the antibody) that do not substantially alter its biologic activity.
- a “variant” of a polypeptide refers to a polypeptide, such as an immunoglobulin chain (e.g., mAb8021 VH, VL, HC, or LC, mAb8028 VH, VL, HC, or LC, or mAb8029 VH, VL, HC, or LC), refers to a polypeptide, such as an immunoglobulin chain (e.g., mAb8021 VH, VL, HC, or LC, mAb8028 VH, VL, HC, or LC, or mAb8029 VH, VL, HC, or LC), refers to a polypeptide, such as an immunoglobulin chain (e.g., mAb8021 VH, VL, HC, or LC, mAb8028 VH, VL, HC, or LC, or mAb8029 VH, VL, HC, or LC), refers to a polypeptide,
- polypeptide comprising an amino acid sequence that is at least about 70-99.9% (e.g., 70, 72, 74, 75, 76, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5, 99.9%) identical or similar to a referenced amino acid sequence that is set forth herein (e.g., SEQ ID NO: 2, 10, 18, 20, 22, 30, 38, 40, 42, 50, 58, or 60); when the comparison is performed by a BLAST algorithm wherein the parameters of the algorithm are selected to give the largest match between the respective sequences over the entire length of the respective reference sequences (e.g., expect threshold: 10; word size: 3; max matches in a query range: 0; BLOSUM 62 matrix; gap costs: existence 11, extension 1; conditional compositional score matrix adjustment).
- a referenced amino acid sequence that is set forth
- a “variant” of a polynucleotide refers to a polynucleotide comprising a nucleotide sequence that is at least about 70-99.9% (e.g., at least about 70, 72, 74, 75, 76, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5, or 99.9%) identical to a referenced nucleotide sequence that is set forth herein (e.g., SEQ ID NO: 1, 9, 17, 19, 21, 29, 37, 39, 41, 49, 57, or 59); when the comparison is performed by a BLAST algorithm wherein the parameters of the algorithm are selected to give the largest match between the respective sequences over the entire length of the respective reference sequences (e.g., expect threshold: 10; word size: 28; max matches in a query range: 0
- Anti-CoV-S antigen-binding proteins e.g., antibodies and antigen-binding fragments thereof of the present invention, in an embodiment of the invention, include a heavy chain immunoglobulin variable region having at least 70% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater) amino acid sequence identity to the HCVR amino acid sequences set forth in Table 1; and/or a light chain immunoglobulin variable region having at least 70% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater) amino acid sequence identity to the LCVR amino acid sequences set forth in Table 1.
- a heavy chain immunoglobulin variable region having at least 70% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%,
- a variant anti-CoV-S antigen-binding protein may include a polypeptide comprising an amino acid sequence that is set forth herein except for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) mutations such as, for example, missense mutations (e.g., conservative substitutions), non-sense mutations, deletions, or insertions.
- the present invention includes antigen-binding proteins which include an immunoglobulin light chain variant comprising an LCVR amino acid sequence set forth in Table 1 but having one or more of such mutations and/or an immunoglobulin heavy chain variant comprising an HCVR amino acid sequence set forth in Table 1 but having one or more of such mutations.
- a variant anti-CoV-S antigen-binding protein includes an immunoglobulin light chain variant comprising CDR-L1, CDR-L2 and CDR-L3 wherein one or more (e.g., 1 or 2 or 3) of such CDRs has one or more of such mutations (e.g., conservative substitutions) and/or an immunoglobulin heavy chain variant comprising CDR-H1, CDR-H2 and CDR-H3 wherein one or more (e.g., 1 or 2 or 3) of such CDRs has one or more of such mutations (e.g., conservative substitutions).
- Substitutions can be in a CDR, framework, or constant region.
- the invention further provides variant anti-CoV-S antigen-binding proteins, e.g., antibodies or antigen-binding fragments thereof, comprising one or more variant CDRs (e.g., any one or more of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and/or CDR-H3) that are set forth herein with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% sequence identity or similarity to, e.g., the heavy chain and light chain CDRs of Table 1.
- variant CDRs e.g., any one or more of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and/or CDR-H3
- Embodiments of the present invention also include variant antigen-binding proteins, e.g., anti-CoV-S antibodies and antigen-binding fragments thereof, that comprise immunoglobulin VHs and VLs; or HCs and LCs, which comprise an amino acid sequence having 70% or more (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater) overall amino acid sequence identity or similarity to the amino acid sequences of the corresponding VHs, VLs, HCs or LCs specifically set forth herein, but wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 of such immunoglobulins are not variants and comprise CDR amino acid sequence set forth in Table 1.
- variant antigen-binding proteins e.g., anti-CoV-S antibodies and antigen-binding fragments thereof, that comprise immunoglobulin V
- variant antigen-binding proteins are not, themselves, variants.
- Conservatively modified variant anti-CoV-S antibodies and antigen-binding fragments thereof are also part of the present invention.
- a “conservatively modified variant” or a “conservative substitution” refers to a variant wherein there is one or more substitutions of amino acids in a polypeptide with other amino acids having similar characteristics (e.g. charge, side-chain size, hydrophobicity/hydrophilicity, backbone conformation and rigidity, etc.). Such changes can frequently be made without significantly disrupting the biological activity of the antibody or fragment.
- Those of skill in this art recognize that, in general, single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, e.g., Watson et al. (1987) Molecular Biology of the Gene, The
- substitutions of structurally or functionally similar amino acids are less likely to significantly disrupt biological activity.
- groups of amino acids that have side chains with similar chemical properties include 1) aliphatic side chains: glycine, alanine, valine, leucine and isoleucine; 2) aliphatic-hydroxyl side chains: serine and threonine; 3) amide-containing side chains: asparagine and glutamine; 4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; 5) basic side chains: lysine, arginine, and histidine; 6) acidic side chains: aspartate and glutamate, and 7) sulfur-containing side chains: cysteine and methionine.
- Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine-glutamine.
- a conservative replacement is any change having a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256: 144345.
- Function-conservative variants of the anti-CoV-S antibodies and antigen-binding fragments thereof are also part of the present invention.
- variants of the anti-CoV-S antibodies and antigen-binding fragments thereof may be “function- conservative variants”. Such function-conservative variants may, in some cases, also be characterized as conservatively modified variants.
- “Function-conservative variants,” as used herein, refers to variants of the anti-CoV-S antibodies or antigen-binding fragments thereof in which one or more amino acid residues have been changed without significantly altering one or more functional properties of the antibody or fragment.
- a function-conservative variant anti-CoV-S antibody or antigen-binding fragment thereof of the present invention comprises a variant amino acid sequence and exhibits one or more of the following functional properties: ⁇ Inhibits growth of coronavirus (e.g., SARS-CoV-2, SARS-CoV, and/or MERS-CoV) in ACE2- and/or TMPRSS2-expressing cells (e.g., Calu-3 cells); ⁇ Does not significantly bind to MDCK/Tet-on cells which do not express ACE2 and/or TMPRSS2; ⁇ Limits spread of coronavirus infection (e.g., by SARS-CoV-2, SARS-CoV, and/or MERS-CoV) of cells, e.g., Calu-3, in vitro; and/or ⁇ Protects a mouse engineered to express the human TMPRSS2 and/or ACE2 protein from death caused by coronavirus infection (e.g., SARS-Co
- coronavirus
- MERS-CoV MERS-CoV
- the mice are infected with an otherwise lethal dose of the virus, optionally when combined with a second therapeutic agent.
- ⁇ Protects a mouse engineered to express the human TMPRSS2 and/or ACE2 protein from weight loss caused by coronavirus infection (e.g., SARS-CoV-2, SARS-CoV, or MERS-CoV), for example, wherein the mice are infected with a dose of the virus that would otherwise cause weighht loss, optionally when combined with a second therapeutic agent.
- coronavirus infection e.g., SARS-CoV-2, SARS-CoV, or MERS-CoV
- a “neutralizing” or “antagonist” anti-CoV-S antigen-binding protein refers to a molecule that inhibits an activity of CoV-S to any detectable degree, e.g., inhibits the ability of CoV-S to bind to a receptor such as ACE2, to be cleaved by a protease such as TMPRSS2, or to mediate viral entry into a host cell or viral reproduction in a host cell.
- Table 1 refers to antigen-binding proteins, such as antibodies and antigen-binding fragments thereof, that comprise the heavy chain or VH (or a variant thereof) and light chain or VL (or a variant thereof) as set forth below; or that comprise a VH that comprises the CDRs thereof (CDR-H1 (or a variant thereof), CDR-H2 (or a variant thereof) and CDR-H3 (or a variant thereof)) and a VL that comprises the CDRs thereof (CDR-L1 (or a variant thereof), CDR-L2 (or a variant thereof) and CDR-L3 (or a variant thereof)), e.g., wherein the immunoglobulin chains, variable regions and/or CDRs comprise the specific amino acid sequences described below.
- the antibodies described herein also include embodiments wherein the VH is fused to a wild-type IgG4 (e.g., wherein residue 108 is S) or to IgG4 variants (e.g., wherein residue 108 is P).
- Antibodies and antigen-binding fragments of the present invention comprise immunoglobulin chains including the amino acid sequences set forth herein as well as cellular and in vitro post-translational modifications to the antibody.
- the present invention includes antibodies and antigen-binding fragments thereof that specifically bind to CoV-S comprising heavy and/or light chain amino acid sequences set forth herein (e.g., CDR-H1, CDR- H2, CDR-H3, CDR-L1, CDR-L2 and/or CDR-L3) as well as antibodies and fragments wherein one or more amino acid residues is glycosylated, one or more Asn residues is deamidated, one or more residues (e.g., Met, Trp and/or His) is oxidized, the N-terminal Gln is pyroglutamate (pyroE) and/or the C-terminal Lysine is missing.
- CDR-H1, CDR- H2, CDR-H3, CDR-L1, CDR-L2 and/or CDR-L3 as well as antibodies and fragments wherein one or more amino acid residues is glycosylated, one or more Asn residues is deamidated, one or more residues (e.g., Met
- the present invention provides methods for administering an anti-CoV-S antigen- binding protein of the present invention, e.g., those of Table 1, comprising introducing the antigen-binding protein into the body of a subject (e.g., a human).
- the method comprises piercing the body of the subject with a needle of a syringe and injecting the antigen- binding protein into the body of the subject, e.g., into the vein, artery, tumor, muscular tissue or subcutis of the subject.
- the present invention provides a vessel (e.g., a plastic or glass vial, e.g., with a cap or a chromatography column, hollow bore needle or a syringe cylinder) comprising an anti-CoV- S antigen-binding protein of the present invention, e.g., those of Table 1.
- a vessel e.g., a plastic or glass vial, e.g., with a cap or a chromatography column, hollow bore needle or a syringe cylinder
- an anti-CoV- S antigen-binding protein of the present invention e.g., those of Table 1.
- the present invention also provides an injection device comprising one or more antigen-binding proteins (e.g., antibody or antigen-binding fragment) that bind specifically to CoV-S, e.g., those of Table 1, or a pharmaceutical composition thereof.
- the injection device may be packaged into a kit.
- An injection device is a device that introduces a substance into the body of a subject via a parenteral route, e.g., intramuscular, subcutaneous or intravenous.
- an injection device may be a syringe (e.g., pre-filled with the pharmaceutical composition, such as an auto-injector) which, for example, includes a cylinder or barrel for holding fluid to be injected (e.g., comprising the antibody or fragment or a pharmaceutical composition thereof), a needle for piecing skin and/or blood vessels for injection of the fluid; and a plunger for pushing the fluid out of the cylinder and through the needle bore.
- an injection device that comprises an antigen-binding protein, e.g., an antibody or antigen-binding fragment thereof, from a combination of the present invention, or
- a pharmaceutical composition thereof is an intravenous (IV) injection device.
- IV intravenous
- a device can include the antigen-binding protein or a pharmaceutical composition thereof in a cannula or trocar/needle which may be attached to a tube which may be attached to a bag or reservoir for holding fluid (e.g., saline) introduced into the body of the subject through the cannula or trocar/needle.
- the antibody or fragment or a pharmaceutical composition thereof may, in an embodiment of the invention, be introduced into the device once the trocar and cannula are inserted into the vein of a subject and the trocar is removed from the inserted cannula.
- the IV device may, for example, be inserted into a peripheral vein (e.g., in the hand or arm); the superior vena cava or inferior vena cava, or within the right atrium of the heart (e.g., a central IV); or into a subclavian, internal jugular, or a femoral vein and, for example, advanced toward the heart until it reaches the superior vena cava or right atrium (e.g., a central venous line).
- an injection device is an autoinjector; a jet injector or an external infusion pump.
- a jet injector uses a high-pressure narrow jet of liquid which penetrate the epidermis to introduce the antibody or fragment or a pharmaceutical composition thereof to a subject’s body.
- External infusion pumps are medical devices that deliver the antibody or fragment or a pharmaceutical composition thereof into a subject’s body in controlled amounts. External infusion pumps may be powered electrically or mechanically.
- Different pumps operate in different ways, for example, a syringe pump holds fluid in the reservoir of a syringe, and a moveable piston controls fluid delivery, an elastomeric pump holds fluid in a stretchable balloon reservoir, and pressure from the elastic walls of the balloon drives fluid delivery.
- a set of rollers pinches down on a length of flexible tubing, pushing fluid forward.
- a multi-channel pump fluids can be delivered from multiple reservoirs at multiple rates.
- Preparation of Human Antibodies Methods for generating human antibodies in transgenic mice are known in the art. Any such known methods can be used in the context of the present invention to make human antibodies that specifically bind to CoV-S.
- An immunogen comprising any one of the following can be used to generate antibodies to CoV-S.
- the antibodies of the invention are obtained from mice immunized with a full length, native CoV-S, or with a live attenuated or inactivated virus, or with DNA encoding the protein or fragment thereof.
- the CoV-S protein or a fragment thereof may be produced using standard
- the immunogen is a recombinantly produced CoV-S protein or fragment thereof.
- the immunogen may be a CoV-S polypeptide vaccine.
- one or more booster injections may be administered.
- the immunogen may be a recombinant CoV-S polypeptide expressed in E. coli or in any other eukaryotic or mammalian cells such as Chinese hamster ovary (CHO) cells.
- VELOCIMMUNE® technology see, for example, US 6,596,541, Regeneron Pharmaceuticals, VELOCIMMUNE®
- any other known method for generating monoclonal antibodies high affinity chimeric antibodies to CoV-S can be initially isolated having a human variable region and a mouse constant region.
- the VELOCIMMUNE® technology involves generation of a transgenic mouse having a genome comprising human heavy and light chain variable regions operably linked to endogenous mouse constant region loci such that the mouse produces an antibody comprising a human variable region and a mouse constant region in response to antigenic stimulation.
- the DNA encoding the variable regions of the heavy and light chains of the antibody are isolated and operably linked to DNA encoding the human heavy and light chain constant regions.
- the DNA is then expressed in a cell capable of expressing the fully human antibody.
- lymphatic cells such as B-cells
- the lymphatic cells may be fused with a myeloma cell line to prepare immortal hybridoma cell lines, and such hybridoma cell lines are screened and selected to identify hybridoma cell lines that produce antibodies specific to the antigen of interest.
- DNA encoding the variable regions of the heavy chain and light chain may be isolated and linked to desirable isotypic constant regions of the heavy chain and light chain.
- Such an antibody protein may be produced in a cell, such as a CHO cell.
- DNA encoding the antigen-specific chimeric antibodies or the variable domains of the light and heavy chains may be isolated directly from antigen-specific lymphocytes.
- high affinity chimeric antibodies are isolated having a human variable region and a mouse constant region. As in the experimental section below, the antibodies are characterized and selected for desirable characteristics, including affinity, selectivity, epitope, etc. The mouse constant regions are replaced with a desired human constant region to generate
- anti-CoV-S antigen- binding proteins e.g., antibodies or antigen-binding fragments
- an Fc domain comprising one or more mutations, which, for example, enhance or diminish antibody binding to the FcRn receptor, e.g., at acidic pH as compared to neutral pH.
- the present invention includes anti-CoV-S antibodies comprising a mutation in the C H 2 or a C H 3 region of the Fc domain, wherein the mutation(s) increases the affinity of the Fc domain to FcRn in an acidic environment (e.g., in an endosome where pH ranges from about 5.5 to about 6.0).
- mutations may result in an increase in serum half-life of the antibody when administered to an animal.
- Non-limiting examples of such Fc modifications include, e.g., a modification at position 250 (e.g., E or Q); 250 and 428 (e.g., L or F); 252 (e.g., L/Y/F/W or T), 254 (e.g., S or T), and 256 (e.g., S/R/Q/E/D or T); or a modification at position 428 and/or 433 (e.g., H/L/R/S/P/Q or K) and/or 434 (e.g., A, W, H, F or Y [N434A, N434W, N434H, N434F or N434Y]); or a modification at position 250 and/or 428; or a modification at position 307 or 308 (e.g., 308F, V308F), and 434.
- a modification at position 250 e.g., E or Q
- 250 and 428 e.g., L or F
- the modification comprises a 428L (e.g., M428L) and 434S (e.g., N434S) modification; a 428L, 259I (e.g., V259I), and 308F (e.g., V308F) modification; a 433K (e.g., H433K) and a 434 (e.g., 434Y) modification; a 252, 254, and 256 (e.g., 252Y, 254T, and 256E) modification; a 250Q and 428L modification (e.g., T250Q and M428L); and a 307 and/or 308 modification (e.g., 308F or 308P).
- a 428L e.g., M428L
- 434S e.g., N434S
- 428L, 259I e.g., V259I
- 308F e.g., V308F
- the modification comprises a 265A (e.g., D265A) and/or a 297A (e.g., N297A) modification.
- the present invention includes anti-CoV-S antigen-binding proteins, e.g., antibodies or antigen-binding fragments, comprising an Fc domain comprising one or more pairs or groups of mutations selected from the group consisting of: 250Q and 248L (e.g., T250Q and M248L); 252Y, 254T and 256E (e.g., M252Y, S254T and T256E); 428L and 434S (e.g., M428L and N434S); 257I and 311I (e.g., P257I and Q311I); 257I and 434H (e.g., P257I and N434H); 376V and 434H (e.g., D376V and N434H); 30
- Anti-CoV-S antigen-binding proteins e.g., antibodies and antigen-binding fragments thereof, that comprise a V H and/or V L as set forth herein comprising any possible combinations of the foregoing Fc domain mutations, are contemplated within the scope of the present invention.
- the present invention also includes anti-CoV-S antigen-binding proteins, antibodies or antigen-binding fragments, comprising a V H set forth herein and a chimeric heavy chain constant (CH) region, wherein the chimeric CH region comprises segments derived from the CH regions of more than one immunoglobulin isotype.
- CH heavy chain constant
- the antibodies of the invention may comprise a chimeric C H region comprising part or all of a C H 2 domain derived from a human IgG1, human IgG2 or human IgG4 molecule, combined with part or all of a C H 3 domain derived from a human IgG1, human IgG2 or human IgG4 molecule.
- the antibodies of the invention comprise a chimeric C H region having a chimeric hinge region.
- a chimeric hinge may comprise an “upper hinge” amino acid sequence (amino acid residues from positions 216 to 227 according to EU numbering) derived from a human IgG1, a human IgG2 or a human IgG4 hinge region, combined with a “lower hinge” sequence (amino acid residues from positions 228 to 236 according to EU numbering) derived from a human IgG1, a human IgG2 or a human IgG4 hinge region.
- the chimeric hinge region comprises amino acid residues derived from a human IgG1 or a human IgG4 upper hinge and amino acid residues derived from a human IgG2 lower hinge.
- an antibody comprising a chimeric CH region as described herein may, in certain embodiments, exhibit modified Fc effector functions without adversely affecting the therapeutic or pharmacokinetic properties of the antibody.
- Immunoconjugates [000119]
- the invention encompasses an anti-CoV-S antigen-binding proteins, e.g., antibodies or antigen-binding fragments, conjugated to another moiety, e.g., a therapeutic moiety (an “immunoconjugate”), such as a toxoid or an anti-viral drug to treat influenza virus infection.
- an anti-CoV-S antibody or fragment is conjugated to any of the further therapeutic agents set forth herein.
- immunoconjugate refers to an antigen-binding protein, e.g., an antibody or antigen-binding fragment, which is chemically or biologically linked to a radioactive agent, a cytokine, an interferon, a target or reporter moiety,
- the antigen-binding protein may be linked to the radioactive agent, cytokine, interferon, target or reporter moiety, enzyme, peptide or therapeutic agent at any location along the molecule so long as it is able to bind its target (CoV- S).
- immunoconjugates include antibody-drug conjugates and antibody-toxin fusion proteins.
- the agent may be a second, different antibody that binds specifically to CoV-S.
- the type of therapeutic moiety that may be conjugated to the anti- CoV-S antigen-binding protein e.g., antibody or fragment
- the present invention includes anti-CoV-S antigen-binding proteins, e.g., antibodies and antigen-binding fragments thereof, as well as methods of use thereof and methods of making such antigen-binding proteins.
- anti-CoV-S antigen-binding proteins, e.g., antibodies or antigen-binding fragments, includes multispecific (e.g., bispecific or biparatopic) molecules that include at least one first antigen-binding domain that specifically binds to CoV-S (e.g., an antigen-binding domain from an antibody of Table 1) and at least one second antigen-binding domain that binds to a different antigen or to an epitope in CoV-S which is different from that of the first antigen-binding domain.
- the first antigen-binding domain and the second antigen-binding domain are both selected from the antigen-binding domains of Table 1.
- the first and second epitopes overlap. In another embodiment of the invention, the first and second epitopes do not overlap. For example, in an
- a multispecific antibody is a bispecific IgG antibody (e.g., IgG1 or IgG4) that includes a first antigen-binding domain that binds specifically to CoV-S including the heavy and light immunoglobulin chain of an antibody of Table 1, and a second antigen-binding domain that binds specifically to a different epitope of CoV-S.
- a bispecific IgG antibody e.g., IgG1 or IgG4 includes a first antigen-binding domain that binds specifically to CoV-S and a second binding domain that binds to a host cell protein, e.g., ACE2 or TMPRSS2.
- the antibodies of Table 1 include multispecific molecules, e.g., antibodies or antigen-binding fragments, that include the CDR-Hs and CDR-Ls, V H and V L , or HC and LC of those antibodies, respectively (including variants thereof as set forth herein).
- multispecific molecules e.g., antibodies or antigen-binding fragments, that include the CDR-Hs and CDR-Ls, V H and V L , or HC and LC of those antibodies, respectively (including variants thereof as set forth herein).
- an antigen-binding domain that binds specifically to CoV-S which may be included in a multispecific molecule, comprises: (1) (i) a heavy chain variable domain sequence that comprises CDR-H1, CDR-H2, and CDR-H3 amino acid sequences set forth in Table 1, and (ii) a light chain variable domain sequence that comprises CDR-L1, CDR-L2, and CDR- L3 amino acid sequences set forth in Table 1; or, (2) (i) a heavy chain variable domain sequence comprising an amino acid sequence set forth in Table 1, and (ii) a light chain variable domain sequence comprising an amino acid sequence set forth in Table 1; or, (3) (i) a heavy chain immunoglobulin sequence comprising an amino acid sequence set forth in Table 1, and (ii) a light chain immunoglobulin sequence comprising an amino acid sequence set forth in Table 1.
- the multispecific antibody or fragment includes more than two different binding specificities (e.g., a trispecific
- a bispecific antigen-binding fragment comprises a first scFv (e.g., comprising VH and VL sequences of Table 1) having binding specificity for a first epitope (e.g., CoV-S) and a second scFv having binding specificity for a second, different epitope.
- a first scFv e.g., comprising VH and VL sequences of Table 1 having binding specificity for a first epitope (e.g., CoV-S) and a second scFv having binding specificity for a second, different epitope.
- the first and second scFv are tethered with a linker, e.g., a peptide linker (e.g., a GS linker such as (GGGGS)n (SEQ ID NO: 834) wherein n is, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10).
- a linker e.g., a peptide linker (e.g., a GS linker such as (GGGGS)n (SEQ ID NO: 834) wherein n is, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10).
- a linker e.g., a peptide linker (e.g., a GS linker such as (GGGGS)n (SEQ ID NO: 834) wherein n is, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10).
- Other bispecific antigen-binding fragments include an F(ab) 2 of a bispecific IgG antibody which comprises the
- the present invention provides methods for treating or preventing viral infection (e.g., coronavirus infection) by administering a therapeutically effective amount of anti-CoV-S antigen-binding protein, e.g., antibody or antigen-binding fragment, (e.g., of Table 1) to a subject (e.g., a human) in need of such treatment or prevention.
- a therapeutically effective amount of anti-CoV-S antigen-binding protein e.g., antibody or antigen-binding fragment, (e.g., of Table 1)
- Coronavirus infection may be treated or prevented, in a subject, by administering an anti-CoV-S antigen-binding protein of the present invention to a subject.
- An effective or therapeutically effective dose of anti-CoV-S antigen-binding protein, e.g., antibody or antigen-binding fragment (e.g., of Table 1), for treating or preventing a viral infection refers to the amount of the antibody or fragment sufficient to alleviate one or more signs and/or symptoms of the infection in the treated subject, whether by inducing the regression or elimination of such signs and/or symptoms or by inhibiting the progression of such signs and/or symptoms.
- the dose amount may vary depending upon the age and the size of a subject to be administered, target disease, conditions, route of administration, and the like.
- an effective or therapeutically effective dose of antibody or antigen-binding fragment thereof of the present invention, for treating or preventing viral infection, e.g., in an adult human subject is about 0.01 to about 200 mg/kg, e.g., up to about 150 mg/kg.
- the dosage is up to about 10.8 or 11 grams (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 grams).
- the frequency and the duration of the treatment can be adjusted.
- antigen-binding protein of the present invention can be administered at an initial dose, followed by one or more secondary doses.
- the initial dose may be followed by administration of a second or a plurality of subsequent doses of antibody or antigen-binding fragment thereof in an amount that can be approximately the same or less than that of the initial dose, wherein the subsequent doses are separated by at least 1 day to 3 days; at least one week, at least 2 weeks; at least 3 weeks; at least 4 weeks; at least 5 weeks; at least 6 weeks; at least 7 weeks; at least 8 weeks; at least 9 weeks; at least 10 weeks; at least 12 weeks; or at least 14 weeks.
- the term “subject” refers to a mammal (e.g., rat, mouse, cat, dog, cow, pig, sheep, horse, goat, rabbit), preferably a human, for example, in need of prevention and/or treatment of a disease or disorder such as viral infection or cancer.
- the subject may have a viral infection, e.g., an influenza infection, or be predisposed to developing an infection.
- Subjects predisposed to developing an infection, or subjects who may be at elevated risk for contracting an infection include subjects with compromised immune systems because of autoimmune disease, subjects receiving immunosuppressive therapy (for example, following organ transplant), subjects afflicted with human immunodeficiency syndrome (HIV) or acquired immune deficiency syndrome (AIDS), subjects with forms of anemia that deplete or destroy white blood cells, subjects receiving radiation or chemotherapy, or subjects afflicted with an inflammatory disorder. Additionally, subjects of very young (e.g., 5 years of age or younger) or old age (e.g., 65 years of age or older) are at increased risk.
- immunosuppressive therapy for example, following organ transplant
- HIV human immunodeficiency syndrome
- AIDS acquired immune deficiency syndrome
- subjects with forms of anemia that deplete or destroy white blood cells subjects receiving radiation or chemotherapy, or subjects afflicted with an inflammatory disorder.
- subjects of very young e.g., 5 years of age or younger
- old age e.g., 65 years of age or older
- a subject may be at risk of contracting a viral infection due to proximity to an outbreak of the disease, e.g. subject resides in a densely-populated city or in close proximity to subjects having confirmed or suspected infections of a virus, or choice of employment, e.g. hospital worker, pharmaceutical researcher, traveler to infected area, or frequent flier.
- “Treat” or “treating” means to administer an anti-CoV-S antigen-binding protein, e.g., antibody or antigen-binding fragment of the present invention (e.g., of Table 1), to a subject having one or more signs or symptoms of a disease or infection, e.g., viral infection, for which the antigen-binding protein is effective when administered to the subject at an effective or therapeutically effective amount or dose (as discussed herein).
- an anti-CoV-S antigen-binding protein e.g., antibody or antigen-binding fragment of the present invention (e.g., of Table 1)
- a subject having one or more signs or symptoms of a disease or infection e.g., viral infection
- the present invention also encompasses prophylactically administering an anti-CoV- S antigen-binding protein, e.g., antibody or antigen-binding fragment thereof of the present invention (e.g., of Table 1), to a subject who is at risk of viral infection so as to prevent such infection.
- an anti-CoV- S antigen-binding protein e.g., antibody or antigen-binding fragment thereof of the present invention (e.g., of Table 1)
- Passive antibody-based immunoprophylaxis has proven an effective strategy for preventing subject from viral infection. See e.g., Berry et al., Passive broad-spectrum influenza immunoprophylaxis. Influenza Res Treat.2014; 2014:267594.
- Prevent or “preventing” means to administer an anti-CoV-S antigen-binding protein, e.g., antibody or antigen-binding fragment of the present invention (e.g., of Table 1), to a subject to inhibit the manifestation of a disease or infection (e.g., viral infection) in the body of a subject, for which the antigen-binding protein is effective when administered to the subject at an effective or therapeutically effective amount or dose (as discussed herein).
- an anti-CoV-S antigen-binding protein e.g., antibody or antigen-binding fragment of the present invention (e.g., of Table 1)
- a disease or infection e.g., viral infection
- a sign or symptom of a viral infection in a subject is survival or proliferation of virus in the body of the subject, e.g., as determined by viral titer assay (e.g., coronavirus propagation in embryonated chicken eggs or coronavirus spike protein assay). Other signs and symptoms of viral infection are discussed herein.
- viral titer assay e.g., coronavirus propagation in embryonated chicken eggs or coronavirus spike protein assay.
- Other signs and symptoms of viral infection are discussed herein.
- the subject may be a non-human animal
- the antigen-binding proteins e.g., antibodies and antigen-binding fragments
- the non-human animals e.g., cats, dogs, pigs, cows, horses, goats, rabbits, sheep, and the like.
- the present invention provides a method for treating or preventing viral infection (e.g., coronavirus infection) or for inducing the regression or elimination or inhibiting the progression of at least one sign or symptom of viral infection such as: ⁇ fever or feeling feverish/chills; ⁇ cough; ⁇ sore throat; ⁇ runny or stuffy nose; ⁇ sneezing;
- ⁇ muscle or body aches ⁇ headaches; ⁇ fatigue (tiredness); ⁇ vomiting; ⁇ diarrhea; ⁇ respiratory tract infection; ⁇ chest discomfort; ⁇ shortness of breath; ⁇ bronchitis; and/or ⁇ pneumonia, which sign or symptom is secondary to viral infection, in a subject in need thereof (e.g., a human), by administering a therapeutically effective amount of anti-CoV-S antigen-binding protein (e.g., of Table 1) to the subject, for example, by injection of the protein into the body of the subject.
- a therapeutically effective amount of anti-CoV-S antigen-binding protein e.g., of Table 1
- antigen-binding protein e.g., antibodies and antigen-binding fragments thereof (e.g., of Table 1)
- antigen-binding protein is admixed with a pharmaceutically acceptable carrier or excipient.
- a pharmaceutically acceptable carrier or excipient See, e.g., Remington’s Pharmaceutical Sciences and U.S. Pharmacopeia: National Formulary, Mack Publishing Company, Easton, Pa. (1984); Hardman, et al.
- the pharmaceutical composition is sterile.
- Such compositions are part of the present invention.
- the scope of the present invention includes desiccated, e.g., freeze-dried, compositions comprising an anti-CoV-S antigen-binding proteins, e.g., antibody or antigen-
- a further therapeutic agent that is administered to a subject in association with an anti-CoV-S antigen-binding protein, e.g., antibody or antigen-binding fragment thereof (e.g., of Table 1), disclosed herein is administered to the subject in accordance with the Physicians’ Desk Reference 2003 (Thomson Healthcare; 57 th edition (Nov.1, 2002)).
- the mode of administration can vary.
- Routes of administration include oral, rectal, transmucosal, intestinal, parenteral; intramuscular, subcutaneous, intradermal, intramedullary, intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, intraocular, inhalation, insufflation, topical, cutaneous, transdermal or intra-arterial.
- the present invention provides methods for administering an anti-CoV-S antigen- binding protein, e.g., antibody or antigen-binding fragment thereof (e.g., of Table 1), comprising introducing the protein into the body of a subject.
- the method comprises piercing the body of the subject with a needle of a syringe and injecting the antigen-binding protein into the body of the subject, e.g., into the vein, artery, tumor, muscular tissue or subcutis of the subject.
- the present invention provides a vessel (e.g., a plastic or glass vial, e.g., with a cap or a chromatography column, hollow bore needle or a syringe cylinder) comprising any of the anti-CoV-S antigen-binding proteins, e.g., antibodies or antigen-binding fragments thereof (e.g., of Table 1), polypeptides (e.g., an HC, LC, VH or VL of Table 1) or polynucleotides (e.g., of Table 2) or vectors set forth herein or a pharmaceutical composition thereof comprising a pharmaceutically acceptable carrier.
- a vessel e.g., a plastic or glass vial, e.g., with a cap or a chromatography column, hollow bore needle or a syringe cylinder
- any of the anti-CoV-S antigen-binding proteins e.g., antibodies or antigen-binding fragments thereof (e.g., of Table 1),
- an anti-CoV-S antigen-binding protein e.g., antibody or antigen-binding fragment thereof of the present invention (e.g., of Table 1)
- a further therapeutic agent includes, but is not limited to: an anti-inflammatory agent, an antimalarial agent, a second antibody or antigen-binding fragment thereof that specifically binds TMPRSS2, and a second antibody or antigen-binding fragment thereof that specifically binds to CoV-S.
- an antimalarial agent is chloroquine or hydroxychloroquine.
- an anti-inflammatory agent is an antibody such as sarilumab, tocilizumab, or gimsilumab.
- the further therapeutic agent is a second antibody or antigen-binding fragment disclosed herein, e.g., of Table 1.
- one, two, three, four, or more antibodies, or antigen-binding fragments thereof, of Table 1 can be administered in combination (e.g., concurrently or sequentially).
- a combination of antibodies can be selected from among those binding to different epitope clusters.
- certain antibodies described herein belong to epitope clusters as follows: Cluster 1, mAb 10987, mAbl 0922, mAbl0936, and mAbl0934; Cluster 2, mAbl0989, mAb 10977, and mAb 10933; Cluster 3, mAbl0920; Cluster 4, mAbl0954, mAbl0986, and mAbl0964; and Cluster 5, mAbl0984.
- a combination of two antibodies can be selected from, for example, Cluster I and Cluster 2, Cluster 1 and Cluster 3, Cluster 1 and Cluster 4, Cluster 1 and Cluster 5, Cluster 2 and Cluster 3, Cluster 2 and Cluster 4. Cluster 2 and Cluster 5, Cluster 3 and Cluster 4, Cluster 3 and Cluster 5, and Cluster 4 and Cluster 5.
- an antibody that specifically binds TMPRSS2 is H1H7017N, as described in International Patent Pub. No. WO/2019/147831.
- anti-CoV-S antigen-binding proteins e.g., anti-SARS-CoV- 2-S antibodies or antigen-binding fragments thereof
- the present invention includes a composition comprising two (or more) anti-SARS- CoV-2-S antibodies or antigen-binding fragments comprising variable domains from human subjects, wherein the two (or more) antibodies or antigen-binding fragments are derived from different subjects (e.g., two different human subjects).
- Antibody variable regions derived from human B cells are discussed, e.g., in Examples 1 and 2 (Table 3), which describes that variable domains cloned from such B cells are combined with a constant region not from those B cells to produce hybrid antibodies.
- the source (Donor) of such antibody variable regions is shown in the Table of Exemplary Human-Derived Antibody Variable Regions, below.
- a composition may comprise a combination of an antibody or antigen-binding fragment thereof with variable domains derived from donor 1 and an antibody or antigen-binding fragment thereof with variable domains derived from donor 2.
- a composition may comprise a combination of an antibody or antigen-binding fragment thereof with variable domains derived from donor 1 and an antibody or antigen-binding fragment thereof with variable domains derived from donor 3. In some embodiments, a composition may comprise a combination of an antibody or antigen-binding fragment thereof with variable domains derived from donor 2 and an antibody or antigen-binding fragment thereof with variable domains derived from donor 3.
- a composition may comprise a combination of mAb10987 (e.g., an antibody comprising the CDRs, the variable regions, or the heavy and light chain sequences shown in Table 1) from Donor 1, and mAb10989 (e.g., an antibody comprising the CDRs, the variable regions, or the heavy and light chain sequences shown in Table 1) from Donor 3.
- Table of Exemplary Human-Derived Antibody Variable Regions [000142]
- the further therapeutic agent is an anti-viral drug and/or a vaccine.
- anti-viral drug refers to any anti-infective drug or therapy used to treat, prevent, or ameliorate a viral infection in a subject.
- anti-viral drug includes, but is not limited to a cationic steroid antimicrobial, leupeptin, aprotinin, ribavirin, or interferon-alpha2b.
- Methods for treating or preventing virus (e.g., coronavirus) infection in a subject in need of said treatment or prevention by administering an antibody or antigen-binding fragment of Table 1 in association with a further therapeutic agent are part of the present invention.
- the further therapeutic agent is a vaccine, e.g., a coronavirus vaccine.
- a vaccine is an inactivated/killed virus vaccine, a live attenuated virus vaccine or a virus subunit vaccine.
- the further therapeutic agent is: (camostat mesylate);
- the anti-viral drug is an antibody or antigen- binding fragment that binds specifically to coronavirus, e.g., SARS-CoV-2, SARS-CoV, or MERS-CoV.
- Exemplary anti-CoV-S antibodies include, but are not limited to: H4sH15188P; H1H15188P; H1H15211P; H1H15177P; H4sH15211P; H1H15260P2; H1H15259P2; H1H15203P; H4sH15260P2; H4sH15231P2; H1H15237P2; H1H15208P; H1H15228P2; H1H15233P2; H1H15264P2; H1H15231P2; H1H15253P2; H1H15215P; and H1H15249P2, as set forth in International patent application publication no.
- the antibody or fragment comprises a light chain immunoglobulin that includes CDR-L1, CDR-L2 and CDR-L3 (e.g., the VL or light chain thereof); and a heavy chain that includes CDR-H1, CDR-H2 and CDR-H3 (e.g., the V H or heavy chain thereof) of any of the foregoing anti-CoV-S antibodies.
- the further therapeutic agent is not aprotinin, leupeptin, a cationic steroid antimicrobial, an influenza vaccine (e.g., killed, live,
- an anti-CoV-S antigen- binding protein e.g., antibody or antigen-binding fragment thereof of the present invention
- an anti-CoV-S antigen- binding protein e.g., antibody or antigen-binding fragment thereof of the present invention
- another agent e.g., a single composition, e.g., for simultaneous delivery, or formulated separately into two or more compositions (e.g., a kit).
- Each component can be administered to a subject at a different time than when the other component is administered; for example, each administration may be given non-simultaneously (e.g., separately or sequentially) at intervals over a given period of time.
- kits comprising one or more components that include, but are not limited to, an anti-CoV-S antigen-binding protein, e.g., an antibody or antigen-binding fragment as discussed herein (e.g., of Table 1), in association with one or more additional components including, but not limited to, a further therapeutic agent, as discussed herein.
- an anti-CoV-S antigen-binding protein e.g., an antibody or antigen-binding fragment as discussed herein (e.g., of Table 1)
- additional components including, but not limited to, a further therapeutic agent, as discussed herein.
- the antigen-binding protein and/or the further therapeutic agent can be formulated as a single composition or separately in two or more compositions, e.g., with a pharmaceutically acceptable carrier, in a pharmaceutical composition.
- the kit includes an anti-CoV-S antigen-binding protein, e.g., an antibody or antigen-binding fragment thereof of the invention (e.g., of Table 1), or a pharmaceutical composition thereof in one container (e.g., in a sterile glass or plastic vial) and a further therapeutic agent in another container (e.g., in a sterile glass or plastic vial).
- the kit comprises a combination of the invention, including an anti-CoV-S antigen-binding protein, e.g., antibody or antigen-binding fragment thereof of the invention (e.g., of Table 1), or pharmaceutical composition thereof in combination with one or more further therapeutic agents formulated together, optionally, in a pharmaceutical composition, in a single, common container.
- an anti-CoV-S antigen-binding protein e.g., antibody or antigen-binding fragment thereof of the invention (e.g., of Table 1)
- pharmaceutical composition thereof in combination with one or more further therapeutic agents formulated together, optionally, in a pharmaceutical composition, in a single, common container.
- the kit can include a device (e.g., an injection device) for performing such
- the kit can include one or more hypodermic needles or other injection devices as discussed above containing the anti-CoV-S antigen-binding protein, e.g., antibody or antigen-binding fragment thereof of the present invention (e.g., of Table 1).
- the kit can include a package insert including information concerning the pharmaceutical compositions and dosage forms in the kit. Generally, such information aids patients and physicians in using the enclosed pharmaceutical compositions and dosage forms effectively and safely.
- the following information regarding a combination of the invention may be supplied in the insert: pharmacokinetics, pharmacodynamics, clinical studies, efficacy parameters, indications and usage, contraindications, warnings, precautions, adverse reactions, overdosage, proper dosage and administration, how supplied, proper storage conditions, references, manufacturer/distributor information and patent information. Diagnostic Uses of the Antibodies [000153]
- the anti-CoV-S antigen-binding proteins e.g., antibodies or antigen-binding fragments thereof of the present invention (e.g., of Table 1), may be used to detect and/or measure CoV-S in a sample.
- Exemplary assays for CoV-S may include, e.g., contacting a sample with an anti-CoV-S antigen-binding protein of the invention, wherein the anti-CoV-S antigen-binding protein is labeled with a detectable label or reporter molecule or used as a capture ligand to selectively isolate CoV-S from samples.
- the presence of an anti-CoV-S antigen-binding protein complexed with CoV-S indicates the presence of CoV-S in the sample.
- an unlabeled anti-CoV-S antibody can be used in combination with a secondary antibody which is itself detectably labeled.
- the detectable label or reporter molecule can be a radioisotope, such as 3 H, 14 C, 32 P, 35 S, or 125 I; a fluorescent or chemiluminescent moiety such as fluorescein isothiocyanate, or rhodamine; or an enzyme such as alkaline phosphatase, b- galactosidase, horseradish peroxidase, or luciferase.
- Specific exemplary assays that can be used to detect or measure CoV-S in a sample include neutralization assays, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), and fluorescence-activated cell sorting (FACS).
- the present invention includes a method for detecting the presence of spike protein polypeptide in a sample comprising contacting the sample with an anti-CoV-S antigen-binding protein and detecting the presence of a CoV-S/anti-CoV-S antigen-binding protein wherein the presence of the complex indicates the presence of CoV-S.
- An anti-CoV-S antigen-binding protein of the invention (e.g., of Table 1) may be used in a Western blot or immune-protein blot procedure for detecting the presence of CoV-S or a fragment thereof in a sample.
- Such a procedure forms part of the present invention and includes the steps of e.g.: (1) providing a membrane or other solid substrate comprising a sample to be tested for the presence of CoV-S, e.g., optionally including the step of transferring proteins from a sample to be tested for the presence of CoV-S (e.g., from a PAGE or SDS-PAGE electrophoretic separation of the proteins in the sample) onto a membrane or other solid substrate using a method known in the art (e.g., semi-dry blotting or tank blotting); and contacting the membrane or other solid substrate to be tested for the presence of CoV-S or a fragment thereof with an anti-CoV-S antigen-binding protein of the invention.
- a method known in the art e.g., semi-dry blotting or tank blotting
- Such a membrane may take the form, for example, of a nitrocellulose or vinyl-based (e.g., polyvinylidene fluoride (PVDF)) membrane to which the proteins to be tested for the presence of CoV-S in a non-denaturing PAGE (polyacrylamide gel electrophoresis) gel or SDS- PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis) gel have been transferred (e.g., following electrophoretic separation in the gel).
- PAGE polyacrylamide gel electrophoresis
- SDS- PAGE sodium dodecyl sulfate polyacrylamide gel electrophoresis
- Detection of the bound antigen-binding protein indicates that the CoV-S protein is present on the membrane or substrate and in the sample. Detection of the bound antigen-binding protein may be by binding the antigen-binding protein with a secondary antibody (an anti- immunoglobulin antibody) which is detectably labeled and, then, detecting the presence of the secondary antibody label.
- a secondary antibody an anti- immunoglobulin antibody
- the anti-CoV-S antigen-binding proteins e.g., antibodies and antigen-binding fragments (e.g., of Table 1)
- Such a method forms part of the present invention and comprises, e.g., (1) contacting tissue to be tested for the presence of CoV-S protein with an anti-CoV-S antigen-binding protein of the invention; and
- the antigen-binding protein itself is detectably labeled, it can be detected directly. Alternatively, the antigen-binding protein may be bound by a detectably labeled secondary antibody wherein the label is then detected.
- EXAMPLES The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for.
- SARS-CoV-2-S Human antibodies to SARS-CoV-2 spike protein (SARS-CoV-2-S) were generated in a VELOCIMMUNE ® mouse comprising DNA encoding human immunoglobulin heavy and kappa light chain variable regions or human immunoglobulin heavy and lambda light chain variable regions.
- Each mouse was immunized with a vector expressing the SARS-CoV-2-S receptor binding domain (RBD) (amino acids 1-1273 of NCBI accession number (MN908947.3), SEQ ID NO: 832), followed by a booster with a SARS-CoV-2-S vector or a SARS-CoV-2-S protein.
- the antibody immune response was monitored by a SARS-CoV-2-S-specific immunoassay.
- lymphocytes were harvested and fused with mouse myeloma cells to preserve their viability and form hybridoma cell lines.
- the hybridoma cell lines were screened and selected to identify cell lines that produce SARS-CoV-2- S-specific antibodies.
- Anti-SARS-CoV-2-S antibodies were also isolated directly from antigen- positive mouse B cells without fusion to myeloma cells, as described in U.S. Patent 7582298, herein specifically incorporated by reference in its entirety. Using this method, fully human anti- SARS-CoV-2-S antibodies (i.e., antibodies possessing human variable domains and human constant domains) were obtained. [000161] Antibody variable regions were also isolated from human blood samples. Whole
- One set of the resulting RT products was first amplified by PCR using a 5’ degenerate primer specific for antibody heavy variable region leader sequence or a 5’ degenerate primer specific for antibody light chain variable region leader sequence and a 3’ primer specific for antibody constant region, to form an amplicon.
- the amplicons were then amplified again by PCR using a 5’ degenerate primer specific for antibody heavy variable region framework 1 or a 5’ degenerate primer specific for antibody light chain variable region framework 1 and a 3’ primer specific for antibody constant region, to generate amplicons for cloning.
- the antibody heavy chain and light chain derived PCR products were cloned into expression vectors containing heavy constant region and light constant region, respectively, thereby producing expression vectors for hybrid antibodies.
- Example 2 Heavy and light chain variable region amino acid and nucleotide sequences
- Table 1 sets forth the amino acid sequence identifiers of the heavy and light chain variable regions and CDRs, as well as the heavy chain and light chain sequences, of exemplary anti-SARS-CoV-2-S antibodies. The corresponding nucleic acid sequence identifiers are set forth in Table 2.
- Table 1 Amino Acid Sequence Identifiers
- Antibodies disclosed herein have fully human variable regions but can have mouse constant regions (e.g., a mouse IgG1 Fc or a mouse IgG2 Fc (a or b isotype)) or human constant regions (e.g., a human IgG1 Fc or a human IgG4 Fc).
- mouse constant regions e.g., a mouse IgG1 Fc or a mouse IgG2 Fc (a or b isotype)
- human constant regions e.g., a human IgG1 Fc or a human IgG4 Fc
- variable domains including the CDRs
- Tables 1 and 2 the variable domains (including the CDRs) – which are indicated by the numerical identifiers shown in Tables 1 and 2 will remain the same, and the binding properties to antigen are expected to be identical or substantially similar regardless of the nature of the constant domain.
- VI antibodies utilized VH3-53 paired with VK1-9, VK1-33, or VK1-39 while human-derived antibodies utilized VH3-66 paired with VK1-33 or VH2-70 paired with VK1-39.
- Further analysis of overlaid sequences showed strong overlap in the repertoire of isolated kappa chains between VI and human-derived antibodies.
- the repertoire of Lambda chains did not overlap well, that may be due to only two lambda mice being included in this trial.
- the average CDR length for heavy chain was similar between VI and human derived antibodies with an average length of 13 and 14.5 amino acids, respectively.
- Example 3 Characterization of hybridoma supernatants by binding ELISA [000167] An ELISA binding assay was performed to identify antibody supernatants that bound to the SARS-CoV-2-Spike protein receptor binding domain (RBD). A protein composed of the RBD of SARS-CoV-2 (amino acids 319-541) expressed with a 6X histidine tag and two myc epitope tags at the C-terminus (SARS-CoV-2-S-RBD-mmH; see also NCBI Accession Number MN908947.3) was coated at 1 mg/ml on a 96-well plate in PBS buffer overnight at 4°C. Nonspecific binding sites were subsequently blocked using a 0.5% (w/v) solution of BSA in PBS. Antibody supernatants or media alone were diluted 1:40 or 1 :50 in the PSA+0.5% BSA
- SARS-CoV-2-S-RBD The ability of anti-SARS-CoV-2-S antibodies to bind the receptor binding domain of SARS-CoV-2-S (SARS-CoV-2-S-RBD) was assessed, as described above, using a binding ELISA with the SARS-CoV-2-S-RBD-mmH protein coated on a microplate. Single point antibody supernatant binding to SARS-COV-2-S-RBD-mmH coated on 96-well microtiter plates was detected with an HRP conjugated anti-hFc or anti-mFc antibody. [000169] The binding results of three trials are summarized in Table 4. The SARS-CoV-2 binding signals (absorbance 450nm) are indicated, with the media only background provided as a negative reference per experiment.
- Example 4 Antibody binding to SARS-CoV-2-S-expressing virus-like particle [000170] To investigate the ability of a panel of anti-SARS-CoV-2-S monoclonal antibodies to bind the SARS-CoV-2 spike glycoprotein, an in vitro binding assay utilizing SARS-CoV-2 spike protein-expressing viral-like particles (VLPs) in an electrochemiluminescence based detection platform (MSD) was developed.
- VLPs SARS-CoV-2 spike protein-expressing viral-like particles
- MSD electrochemiluminescence based detection platform
- VSV-SARS- CoV-2-S Vesicular stomatitis virus lacking glycoprotein G
- VSV delta G SARS-CoV-2 spike protein
- VSV-G VSV G protein
- VLPs described above were diluted in PBS, seeded into 96-well carbon electrode plates (MULTI-ARRAY high bind plate, MSD), and incubated overnight at 4 °C to allow the VLPs to adhere. Nonspecific binding sites were blocked by 2% BSA (w/v) in PBS for 1 hour at room temperature. Supernatants containing antibodies produced from SARS CoV-2-immunized mice or infected human sera, along with media-only controls which were diluted 1:10 or 1:20 in 1x PBS + 0.5% BSA buffer, were added to the plate-bound particles.
- the plates were then incubated for 1 hour at room temperature with shaking, after which the plates were washed with 1x PBS to remove the unbound antibodies using an AquaMax2000 plate washer (MDS Analytical Technologies).
- the plate-bound antibodies were detected with a SULFO-TAGTM- conjugated anti-human IgG antibody (Jackson Immunoresearch) or a SULFO-TAGTM- conjugated anti-mouse IgG antibody (Jackson Immunoresearch) for 1 hour at room temperature.
- the plates were developed with the Read Buffer (MSD) according to manufacturer’s recommended procedure and the luminescent signals were recorded with a SECTOR Imager 600 (Meso Scale Development) instrument.
- a signal observed from SARS-COV-2-S-expressing VLPs indicates binding, while comparison with negative VLPs provides a relative background.
- Media alone samples provide baseline signals of secondary antibody binding to samples with no supernatant.
- the ratios of SARS- CoV-2-S-expressing VSV: VSV-VLPs (negative control) ranged from 1.1- 22.7, with many having high background on VSV-VLPs.
- the ratio of mAb11002 of 0.9 is likely due to a low concentration of monoclonal antibody in the supernatant sample.
- Table 5 SARS-CoV-2-S VLP binding
- Example 5 Antibody neutralization of VSV-SARS-CoV-2-S pseudovirus infectivity
- VSV pseudotype viruses were generated by transiently transfecting 293T cells with a plasmid encoding for SARS-CoV-2 spike protein.
- Cells were seeded in 15 cm plates at 1.2x10 7 cells per plate in DMEM complete media one day prior to transfection with 15 ⁇ g/plate spike protein DNA using 125 ⁇ L Lipofectamine LTX, 30 ⁇ L PLUS reagent, and up to 3 mL Opti-Mem. 24 hours post transfection, the cells were washed with 10 mL PBS, then infected with an MOI of 0.1 VSV DG:mNeon virus in 10 mL Opti-Mem. Virus was incubated on cells for 1 hour, with gentle rocking every 10 minutes.
- VSV-SARS-CoV-2-S Neutralization assay with VSV-SARS-CoV-2-S [000177] On day 1, Vero cells were seeded at 80% confluency in T225 flasks.
- the neutralization potency of antibody at each dilution is represented as a percentage compared to mock supernatant control. All antibodies demonstrated neutralization capacity, and particularly for the set of antibodies that were evaluated 1:100, those showing higher neutralization may represent more potent neutralization capacity. Table 6: Neutralization of VLPs
- Target cells were engineered Jurkat T cells expressing human CD20 (used as a positive control with a CD20-targeting human IgG1 antibody) and the full-length SARS-CoV-2 spike protein controlled by a doxycycline-inducible promoter. Reporter cells were incubated with target cells and engagement of FcgR3a via the Fc domain of human IgG1 antibodies bound to target cells led to the activation of the transcription factor NFAT in the reporter cells and drove the expression of luciferase which was then measured via a luminescence readout.
- Jurkat T cells were engineered to constitutively express full length human CD20 (amino acids M1-P297 of NCBI accession number NP_690605.1), Tet3G transactivator protein (cloned using a Takara pEF1a-Tet3G Vector, Catalog # 631167), as well as a doxycycline- inducible full-length SARS-CoV-2 spike protein (amino acids M1-T1273 of NCBI accession number YP_009724390.1).
- Jurkat/Tet3G/hCD20/SARS-CoV2 spike protein- expressing cells were sorted for high expression of the spike protein and subsequently maintained in RPMI + 10% Tet-free FBS + P/S/G + 500 ⁇ g/ml G418 + 1 mg/ml puromycin + 250 ⁇ g/ml hygromycin growth medium.
- NFAT Nuclear Factor of Activated T- cells
- luciferase reporter construct along with the high affinity human FcgR3a 176 Val allotype receptor (amino acids M1-K254 of NCBI accession number P08637 VAR_003960).
- Engineered reporter cells were maintained in RPMI1640 + 10% FBS + P/S/G + 0.5 mg/ml puromycin + 500 mg/ml G418 growth media. [000185] 36 hours prior to the start of the surrogate ADCC assay, 5 x 10 5 target cells/ml were induced in RPMI + 10% Tet-free FBS + P/S/G cell culture media containing 1 ⁇ g/ml doxycycline (Sigma). A day before the experiment, reporter cells were split to a density of 7.5 x 10 5 cells/ml in RPMI 1640 + 10% FBS + P/S/G + 0.5 mg/ml puromycin + 500 mg/ml G418 growth media.
- the target and reporter cells were transferred into assay media (RPMI + 10% Tet-free FBS + P/S/G) and added at a 3:2 ratio (3 x 10 4 /well target cells and 2 x 10 4 /well reporter cells) to 384-well white microtiter plates, followed by the addition of anti-SARS-CoV-2-S antibody supernatant of varying concentrations.
- assay media RPMI + 10% Tet-free FBS + P/S/G
- a positive control CD20 antibody with human IgG1
- a negative control sample containing no antibody was included on each plate to normalize detected ADCC activities of anti-SARS-CoV- 2-S antibody supernatants.
- Table 7 summarizes the results, showing the raw luciferase activity and the calculated % of positive control are indicated. A range of % ADCC activity was observed indicating FcgR3a activation by the antibody supernatants. All samples demonstrated some measure of surrogate ADCC activity, and 10 of the antibody supernatants demonstrated surrogate ADCC activity better than observed in positive controls.
- Table 7 ADCC surrogate activity of anti-SARS-CoV-2-S antibody supernatants.
- Example 7 Anti-SARS-CoV-2-S antibody binding specificity assay [000189]
- a Luminex binding assay was performed to determine the binding of anti-SARS- COV-2-S antibodies to a panel of antigens.
- antigens were amine-coupled or captured by streptavidin to Luminex microspheres as follows: approximately 10 million MagPlex microspheres (Luminex Corp., MagPlex Microspheres, Cat. No. MC10000 and MC12000), were resuspended by vortexing in 500 ⁇ L 0.1M NaPO4, pH 6.2 (activation buffer) and then centrifuged to remove the supernatant. Microspheres were protected from light, as they are light sensitive.
- microspheres were resuspended in 160 ⁇ L of activation buffer and the carboxylate groups (-COOH) were activated by addition of 20 ⁇ L of 50 mg/mL of N- hydroxysuccinimide (NHS, Thermo Scientific, Cat. No.24525) followed by addition of 20 ⁇ L of 50 mg/mL 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide (EDC, ThermoScientific, Cat. No. 22980) at 25 °C.
- NHS N- hydroxysuccinimide
- EDC 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide
- the pH of the reaction was reduced to 5.0 with the addition of 600 ⁇ L 50 mM MES, pH 5 (coupling buffer), and the microspheres were vortexed and centrifuged to remove supernatant.
- the activated microspheres were immediately mixed with 500 ⁇ L of 25 ⁇ g/mL of the protein antigen or Streptavidin in coupling buffer and incubated for two hours at 25 °C.
- the coupling reaction was quenched by addition of 50 ⁇ L of 1M Tris-HCl, pH 8.0 and the microspheres were vortexed, centrifuged, and washed three times with 800 ⁇ L of PBS 0.005% (Tween200.05%), to remove uncoupled proteins and other reaction components.
- Microspheres were resuspended in 1 mL of PBS 2% BSA 0.05% Na Azide at 10 million microspheres/mL.
- 500 ⁇ L of 12.5 ⁇ g/mL of biotinylated protein in PBS was added to Streptavidin-coupled microspheres and incubated for one hour at 25 °C.
- Microspheres were vortexed, centrifuged, and washed three times with 800 ⁇ L of PBS, and then blocked using 500 ⁇ L 30mM Biotin (Millipore-Sigma, Cat. No. B4501) in 0.15M Tris pH 8.0.
- Microspheres were incubated for 30 minutes then vortexed, centrifuged, and washed three times with 800 ⁇ L of PBS. Microspheres were resuspended in 1 mL of PBS 2% BSA 0.05% Na Azide at 10 million microspheres/mL. [000190] Microspheres for the different proteins and biotinylated proteins were mixed at 2700
- microspheres were plated per well on a 96 well ProcartaPlex flat bottom plate (ThermoFisher, Cat. No: EPX-44444-000) and mixed with 25 ⁇ L of individual anti-SARS- CoV-2 supernatant containing antibody. Samples and microspheres were incubated for two hours at 25 o C and then washed twice with 200 ⁇ L of DPBS with 0.05% Tween 20.
- the SARS-CoV-2 proteins used in the assay are as follows: RBD_ (R319-F541).mmh: SEQ ID NO: 829 RBD_ (R319-F541).mFc: SEQ ID NO: 830 RBD_ (R319-F541).hFc): SEQ ID NO: 831 [000191]
- the results of the Luminex binding are shown in Table 8 and Table 9 as median fluorescence intensity (MFI) signal intensities.
- MFI median fluorescence intensity
- Example 8 Anti-SARS-CoV-2-S antibody diversity assay [000192] A binding assay was performed to determine the binding profile of anti-SARS-COV- 2-S antibodies. For this assay, antigens were amine coupled as described for the Luminex binding assay above. Briefly, approximately 9 million MagPlex microspheres for 16 different bead regions (Luminex Corp., MagPLex Microspheres, Cat. No. MagPLex MC10000 and MC12000), were resuspended by vortexing in 500 ⁇ L 0.1M NaPO 4 , pH 6.2 and then centrifuged to remove the supernatant.
- MagPlex microspheres for 16 different bead regions Luminex Corp., MagPLex Microspheres, Cat. No. MagPLex MC10000 and MC12000
- microspheres were resuspended in 160 ⁇ L of activation buffer and the carboxylate groups (-COOH) were activated by addition of 20 ⁇ L of 50 mg/mL of N- hydroxysuccinimide (NHS, Thermo Scientific, Cat# 24525) followed by addition of 20 ⁇ L of 50 mg/mL of 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide (EDC, ThermoScientific, Cat# 22980) at 25°C.
- NHS N- hydroxysuccinimide
- EDC 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide
- the pH of the reaction was reduced to 5.0 with the addition of 600 ⁇ L of 50 mM MES, pH 5 (coupling buffer), and the microspheres were vortexed and centrifuged to remove supernatant.
- the activated microspheres were immediately mixed with 500 ⁇ L of 20 ⁇ g/mL of SARS-CoV-2 Spike Protein (RBD)(R319-F541)-mmH in coupling buffer and incubated for two hours at 25 o C.
- the coupling reaction was quenched by addition of 50 ⁇ L of 1M Tris-HCl, pH 8.0 and the microspheres were vortexed, centrifuged, and washed three times with 1000 ⁇ L of PBS.
- Microspheres were resuspended in 250 ⁇ L of PBS at 9 million microspheres/mL. [000193] 15 out of the 16 microsphere regions with amine-coupled protein were modified for the binning assay as follows: microspheres were washed twice with PBS 5% DMSO, and 500 ⁇ l of a chemical or enzyme were dissolved per manufacturing recommendations and added at 10 nM to the amine-coupled microspheres described above. This was subsequently vortexed and incubated for 2 hours at room temperature with rotation. Wash microspheres 3 times with PBS 2% BSA. Microspheres were resuspended in 1 mL of PBS at 9 million microspheres/mL.
- Protein-modified and protein-unmodified (intact) microspheres were mixed at 2700 beads/ml, and 75 ⁇ L of microspheres were plated per well on a 96 well ProcartaPlex 96 well flat bottom plate (ThermoFisher, Cat. No: EPX-44444-000) and mixed with 25 ⁇ L of individual anti- SARS-CoV-2-S supernatant-containing antibody. Samples and microspheres were incubated for two hours at 25 °C and then washed twice with 200 ⁇ L of DPBS with 0.05% Tween 20.
- Biacore CM5 sensor chip surface was first derivatized by amine coupling with either mouse anti-human Fc specific mAb or rabbit anti-mouse Fcg monoclonal antibody (GE, Catalog # BR-1008-38) to capture anti-SARS-CoV-2 antibodies.
- Binding studies were performed on a human SARS-CoV-2 RBD extracellular domain expressed with a C-terminal myc-myc-hexahistidine tag (SARS-COV-2 RBD-MMH), SARS-CoV-2 RBD extracellular domain expressed with a C-terminal mouse IgG2a (SARS-COV-2 RBD-mFc), or SARS-CoV-2 RBD extracellular domain expressed with a C-terminal human IgG1 (SARS-COV- 2 RBD-hFc).
- the SARS-CoV-2 RBD antibody capture surface was regenerated using either a 10 sec injection of 20mM phosphoric acid for the mouse anti-human Fc specific monoclonal antibody surface or a 40 sec injection of 10mM Glycine, HCl, pH1.5 for the rabbit anti-mouse Fcg specific polyclonal antibody.
- the association rate (ka) and dissociation rate (kd) were determined by fitting the real-time binding sensorgrams to a 1:1 binding model with mass transport limitation using BiaEvaluation software v3.1 or Biacore Insight Evaluation software v2.0. or curve-fitting software.
- Binding dissociation equilibrium constant (K D ) and dissociative half-life (t1 ⁇ 2) were calculated from the kinetic rates as: [000197] Binding kinetics parameters for different SARS-CoV-2 monoclonal antibodies binding to different anti-SARS-COV-2 RBD reagents of the invention at 25°C are shown in Tables 11 and 12.
- Table 11 Binding kinetics of SARS-COV-2 RBD-MMH binding to anti-SARS-CoV-2 monoclonal antibodies at 25 °C
- Table 12 Binding kinetics of SARS-COV-2 RBD-mFc or SARS-COV-2 RBD-hFc binding to anti-SARS-CoV-2-S monoclonal antibodies at 25 °C
- Example 10 Characterization of anti-SARS-CoV-2-S monoclonal antibodies by blocking ELISA [000198] An ELISA-based blocking assay was developed to determine the ability of anti- SARS-CoV2-S antibodies to block the binding of the SARS-CoV-2 spike protein receptor binding domain (RBD) to human angiotensin converting enzyme 2 (hACE2).
- RBD SARS-CoV-2 spike protein receptor binding domain
- hACE2 human angiotensin converting enzyme 2
- the SARS-CoV-2 protein used in the experiments was comprised of the receptor binding domain (RBD) portion of the SARS-CoV-2 spike protein (amino acids Arg319 to Phe541) expressed with the Fc portion of the human IgG1 at the c-terminus (SARS-CoV-2 RBD- hFc; see NCBI accession number MN908947.3)
- the human ACE2 protein used in the experiments was purchased from R&D systems and is comprised of amino acids glutamine 18 to serine 740 with a c-terminal 10X-Histidine tag (hACE2-His; NCBI accession number Q9BYF1). [000200] Experiments were carried out using the following procedure.
- a monoclonal anti- Penta-His antibody (Qiagen) was coated at 1 ⁇ g/ml in PBS on a 96-well microtiter plate overnight at 4 °C.
- the hACE2-His receptor was added at 0.2 ⁇ g/ml in PBS and bound for 2 hours at room temperature. Nonspecific binding sites were subsequently blocked using a 0.5% (w/v) solution of BSA in PBS.
- a constant amount of 10 pM or 15 pM (as indicated in Table 13) of SARS-CoV-2 RBD-hFc protein was bound with antibodies diluted 1:10 or 1:20 in PBS + 0.5% BSA.
- binding signal of the sample of the constant SARS-CoV-2-S RBD- hFc without the presence of the antibody for each plate was referenced as 100% binding or 0% blocking; and the baseline signal of the sample of media only without the presence of SARS- CoV-2 RBD-hFc was referenced as 0% binding or 100% blocking.
- the ability of anti-SARS-CoV-2-S antibodies to block SARS-CoV-2-S RBD from binding to human ACE2 was assessed using a blocking ELISA format.
- Example 11 Epitope mapping of anti-SARS-CoV-2-S monoclonal antibodies to spike glycoprotein by Hydrogen-Deuterium Exchange Mass Spectrometry
- Hydrogen-Deuterium Exchange Mass Spectrometry was performed to determine the amino acid residues of the SARS-CoV-2 Spike Protein Receptor Binding Domain (RBD (amino acids R319-F541)) that interact with mAb10989, mAb10987, mAb10934, mAb10933, mAb10920, mAb10922, mAb10936, mAb10954, mAb10964, mAb10977, mAb10984, and mAb10986.
- RBD amino acids R319-F541
- HDX-MS A general description of the HDX-MS method is set forth in e.g., Ehring (1999) Analytical Biochemistry 267(2):252-259; and Engen and Smith (2001) Anal. Chem.73:256A-265A.
- the HDX-MS experiments were performed on an integrated HDX-MS platform, consisting of a Leaptec HDX PAL system for the deuterium labeling and quenching, a Waters Acquity I-Class (Binary Solvent Manager) for the sample digestion and loading, a Waters Acquity I-Class (Binary Solvent Manager) for the analytical gradient, and a Thermo Q Exactive HF mass spectrometer for peptide mass measurement.
- the labeling solution was prepared as PBS buffer in D2O at pD 7.0 (10 mM phosphate buffer, 140 mM NaCl, and 3 mM KCl, equivalent to pH 7.4 at 25°C).
- pD 7.0 10 mM phosphate buffer, 140 mM NaCl, and 3 mM KCl, equivalent to pH 7.4 at 25°C.
- 10 mL of the RBD protein or RBD protein premixed with each one of the 12 antibodies listed above were incubated at 20 °C with 90 mL of D 2 O labeling solution for various timepoints, in duplicate.
- the time points were 0 min (non-deuterated control), 5 min, and 10 min.
- mAb10920, mAb10922, mAb10936, mAb10954, mAb10964, mAb10977, mAb10984, and mAb10986 the time points were 0 min (non-deuterated control) and 10 min.
- the deuteration reaction was quenched by adding 90 mL of pre-chilled quench buffer (0.5 M TCEP-HCl, 4 M urea and 0.5% formic acid) to each sample for a 90 second incubation at 20 °C.
- the quenched samples were then injected into the Leaptec HDX PAL system for online pepsin/protease XIII digestion.
- the digested peptides were trapped by a C18 column (2.1 mm x 5 mm, Waters) and separated by another C18 column (2.1 mm x 50 mm, Waters) at -5 °C with a 20 minute gradient (for mAb10989, mAb10987, mAb10934, and mAb10933) or a 10 minute gradient (for mAb10920, mAb10922, mAb10936, mAb10954, mAb10956, mAb10964, mAb10977, and mAb10984) from 0% to 90% of movbile phase B solution (mobile phase A solution: 0.5% formic acid and 4.5% acetonitrile in water, mobile phase B solution: 0.5% formic acid in acetonitrile).
- the eluted peptides were analyzed by a Thermo Q Exactive HF mass spectrometry in LC-MS/MS or LC-MS mode.
- the LC-MS/MS data from the undeuterated RBD protein sample were searched against a database including amino acid sequences of the RBD protein, pepsin, protease XIII, and their reversed sequences using Byonic search engine (Protein Metrics).
- the search parameters were set as default using non-specific enzymatic digestion and human glycosylation as common variable modification.
- Any peptide that exhibited a reduction in deuterium uptake of 5% or greater (i.e., a D%D value of less than -5%, such as -6%, -10%, and so on) upon mAb binding was defined as significantly protected.
- Peptides corresponding to amino acids 467-513 (DISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVL) (SEQ ID NO: 835) of the RBD were significantly protected by mAb10989.
- a total of 187 peptides from the RBD were identified from both RBD alone and RBD in complex with mAb10987 samples, representing 86.06% sequence coverage of RBD. Any peptide that exhibited a reduction in deuterium uptake of 5% or greater (i.e., a D%D value of less than -5%, such as -6%, -10%, and so on) upon mAb binding was defined as significantly protected.
- Peptides corresponding to amino acids 432-452 (CVIAWNSNNLDSKVGGNYNYL) (SEQ ID NO: 836) of the RBD were significantly protected by mAb10987.
- a total of 188 peptides from the RBD were identified from both RBD alone and RBD in complex with mAb10934 samples, representing 86.06% sequence coverage of the RBD. Any peptide that exhibited a reduction in deuterium uptake of 5% or greater (i.e., a D%D value of less than -5%, such as -6%, -10%, and so on) upon mAb binding was defined as significantly protected.
- Any peptide that exhibited a reduction in deuterium uptake of 5% or greater (i.e., a D%D value of less than -5%, such as -6%, -10%, and so on) upon mAb binding was defined as significantly protected.
- Peptides corresponding to amino acids 467-510 (DISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRV) (SEQ ID NO: 839) of the RBD were significantly protected by mAb10933.
- a total of 75 peptides from the RBD were identified from both RBD alone and RBD in complex with mAb10920 samples, representing 83.27% sequence coverage of the RBD.
- Any peptide that exhibited a reduction in deuterium uptake of 5% or greater (i.e., a D%D value of less than -5%, such as -6%, -10%, and so on) upon mAb binding was defined as significantly protected.
- Peptides corresponding to amino acids 471-486 (EIYQAGSTPCNGVEGF) (SEQ ID NO: 840), and 491-515 (PLQSYGFQPTNGVGYQPYRVVVLSF) (SEQ ID NO: 841) of the RBD were significantly protected by mAb10920.
- a total of 86 peptides from the RBD were identified from both RBD alone and RBD in complex with mAb10922 samples, representing 87.25% sequence coverage of the RBD. Any peptide that exhibited a reduction in deuterium uptake of 5% or greater (i.e., a D%D value of less
- any peptide that exhibited a reduction in deuterium uptake of 5% or greater (i.e., a D%D value of less than -5%, such as -6%, -10%, and so on) upon mAb binding was defined as significantly protected.
- Peptides corresponding to amino acids 400-422 (FVIRGDEVRQIAPGQTGKIADYN) (SEQ ID NO: 845), 453-486 (YRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGF) (SEQ ID NO: 846), and 490-515 (FPLQSYGFQPTNGVGYQPYRVVVLSF) (SEQ ID NO: 847) of the RBD were significantly protected by mAb10954.
- a total of 109 peptides from the RBD were identified from both RBD alone and RBD in complex with mAb10964 samples, representing 83.67% sequence coverage of RBD. Any peptide that exhibited a reduction in deuterium uptake of 5% or greater (i.e., a D%D value of less than -5%, such as -6%, -10%, and so on) upon mAb binding was defined as significantly protected.
- peptide that exhibited a reduction in deuterium uptake of 5% or greater i.e., a D%D value of less than -5%, such as -6%, -10%, and so on
- Peptides corresponding to amino acids 351-364 (YAWNRKRISNCVAD) (SEQ ID NO: 850), and 471-486 (EIYQAGSTPCNGVEGF) (SEQ ID NO: 840) of the RBD were significantly protected by mAb10977.
- a total of 88 peptides from the RBD were identified from both RBD alone and RBD in complex with mAb10984 samples, representing 87.25% sequence coverage of RBD.
- Any peptide that exhibited a reduction in deuterium uptake of 5% or greater (i.e., a D%D value of less than -5%, such as -6%, -10%, and so on) upon mAb binding was defined as significantly protected.
- Peptides corresponding to amino acids 400-422 (FVIRGDEVRQIAPGQTGKIADYN) (SEQ ID NO: 845), and 453-486 (YRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGF) (SEQ ID NO: 846) of the RBD were significantly protected by mAb10984.
- a total of 84 peptides from the RBD were identified from both RBD alone and RBD in complex with mAb10986 samples, representing 87.25% sequence coverage of the RBD. Any peptide that exhibited a reduction in deuterium uptake of 5% or greater (i.e., a D%D value of less than -5%, such as -6%, -10%, and so on) upon mAb binding was defined as significantly protected.
- Table 18 RBD peptides with significant protection upon formation of RBD-mAb10920 complex comparing to RBD alone
- Table 19 RBD peptides with significant protection upon formation of RBD-mAb10922 complex comparing to RBD alone
- Table 20 RBD peptides with significant protection upon formation of RBD-mAb10936 complex comparing to RBD alone
- Table 21 RBD peptides with significant protection upon formation of RBD-mAb10954 complex comparing to RBD alone
- Table 23 RBD peptides with significant protection upon formation of RBD-mAb10977 complex comparing to RBD alone
- Table 24 RBD peptides with significant protection upon formation of RBD-mAb10984 complex comparing to RBD alone
- Example 12 Neutralization of SARS-CoV-2 wild-type and variant spike proteins [000221] To test whether anti-SARS-CoV-2 spike protein antibodies can neutralize SARS- CoV-2 variants, these antibodies were screened against a panel of VSV pseudotype viruses expressing wild-type and variant spike proteins. VSV pseudotype viruses were generated by transiently transfecting 293T cells with a plasmid encoding the SARS-CoV-2 spike protein or the same plasmid containing nucleotide variations that encode for known variants of the SARS- CoV-2 spike protein amino acid sequence. All plasmids were confirmed by Sanger sequencing.
- VSV DG:mNeon /Spike pseudovirus or VSV DG:mNeon /Spike_(variant amino acid mutation) (for example, VSV DG:mNeon /Spike_H49Y).
- Vero cells were seeded to 80% confluency in T225 flasks, the cells were washed with PBS (Gibco: 20012-043), TrypLE was added to detach cells from the flask, and Complete DMEM was added to inactivate trypsin.20,000 Vero cells were plated in in 100 ⁇ L of prewarmed Complete DMEM per well in 96 Well Black Polystyrene Microplate (Corning: 3904). On Day 2, VSV DG:mNeon /Spike pseudovirus was thawed on ice and diluted with Infection media.
- Antibodies were diluted in a U-bottom 96 well plate, generating a dilution of each antibody in 210 ⁇ l Infection media at 2X assay concentration.120 ⁇ L of diluted antibodies were transferred to a fresh U-bottom plate, and media and an IgG1 control antibody were added to each plate.120 ⁇ l of diluted pseudovirus was added to every well except the media control wells. To those wells, 120 ⁇ L of Infection media was added. Pseudovirus with antibodies were incubated for 30 minutes at room temperature, then media was removed from Vero cells.100 ⁇ L of antibody/pseudovirus mixture were added to the cells, and then incubated at 37 °C, 5% CO2 for 24 hours.
- Monoclonal antibodies and antibody combinations were serially diluted in DMEM (Quality Biological), supplemented with 10% (v/v) heat inactivated fetal bovine serum (Sigma), 1% (v/v) penicillin/streptomycin (Gemini Bio-products) and 1% (v/v) L-glutamine (2 mM final concentration, Gibco) (VeroE6 media) to a final volume of 250 mL.
- 250 mL of VeroE6 media containing SARS-CoV-2 (WA-1) 1000 PFU/mL
- the virus-antibody mixtures were incubated for 60 min at 37 °C.
- plaque reduction neutralization titer (PRNT50) values the serum dilutions at which plaque formation was reduced by 50% relative to that of the untreated control
- PRNT50 plaque reduction neutralization titer
- Amino acid variants in spike (S) protein were identified from over 7000 publicly available SARS-CoV-2 sequences, representing globally circulating isolates, and cloned into VSV pseudoparticles. Neutralization assays with variant-encoding pseudoparticles were performed to assess the impact of each variant on neutralization potency of the monoclonal antibodies.
- Table 27 illustrates the relative neutralization potency of monoclonal antibodies against variant encoding pseudoparticles relative to SARS-CoV-2 spike (S-wt) at a single concentration of 5 ⁇ g/ml. Percent of neutralization relative to S-wt was captured for each individual antibody and variant.
- the Biacore CM5 sensor chip surface was first derivatized by amine coupling with either mouse anti-human Fc specific mAb (Regeneron, mAb2567) to capture anti-SARS-COV-2bmAbs. Binding studies were performed on human SARS-COV-2 RBD extracellular domain expressed with a C-terminal
- SARS-COV-2 RBD-MMH myc-myc-hexahistidine
- SARS-COV-2 RBD-mFc SARS-COV-2 RBD extracellular domain expressed with a C-terminal mouse IgG2a
- association rate (ka) and dissociation rate (kd) were determined by fitting the real-time binding sensorgrams to a 1:1 binding model with mass transport limitation using BiaEvaluation software v3.1 or Biacore Insight Evaluation software v2.0. or curve-fitting software. Binding dissociation equilibrium constant (KD) and dissociative half-life (t1 ⁇ 2) were calculated from the kinetic rates as: [000230] Binding kinetics parameters for different SARS-COV-2 mAbs binding to different anti-SARS-COV-2 RBD reagents of the invention at 25 °C and 37 °C are shown in Tables 29 through 32, respectively. Table 29: Binding kinetics parameters of SARS-COV-2 RBD-MMH binding to anti-SARS- COV-2-S monoclonal antibodies at 25 °C.
- Table 30 Binding kinetics parameters of SARS-COV-2 RBD-MMH binding to anti-SARS- COV-2-S monoclonal antibodies at 37 °C.
- Table 31 Binding kinetics parameters of SARS-COV-2 RBD-mFc binding to anti-SARS- COV-2-S monoclonal antibodies at 25 °C.
- Example 14 Anti-SARS-CoV-2 Antibodies block RBD binding to hACE2 as determined by ELISA [000231] An ELISA-based blocking assay was used to determine the ability of anti-SARS- CoV-2 antibodies to block the binding of the SARS-COV-2 Spike protein receptor binding domain (RBD) to its receptor, human angiotensin converting enzyme 2 (hACE2).
- RBD SARS-COV-2 Spike protein receptor binding domain
- hACE2 human angiotensin converting enzyme 2
- the SARS-CoV-2 protein used in this assay was comprised of the receptor binding domain (RBD) portion of the SARS-CoV-2 Spike protein (amino acids Arg319-Phe541) expressed with the Fc portion of the human IgG1 at the c-terminus (SARS-CoV-2 RBD-hFc)
- the human ACE2 protein used in the experiments was purchased from R&D Systems and was comprised of amino acids Gln18-Ser740 with a C-terminal 10X-Histidine tag (hACE2-His; NCBI Accession No. Q9BYF1). [000233] Experiments were carried out using the following procedure.
- a monoclonal anti- Penta-His antibody (Qiagen) was coated at 1 ⁇ g/ml in PBS on a 96-well microtiter plate overnight at 4 °C.
- the hACE2-His receptor was added at 0.2ug/ml in PBS and bound for two hours at room temperature (RT). Nonspecific binding sites were subsequently blocked using a 0.5% (w/v) solution of BSA in PBS.
- a constant amount of 100pM of SARS-CoV-2 RBD-hFc protein was bound with anti-SARS-COV-2 antibodies and an isotype IgG1 antibody control at dilutions from 0.0008nM to 50nM in PBS +0.5% BSA.
- the calculated IC50 value defined as the concentration of antibody required to block 50% of SARS-CoV-2 RBD-hFc binding to plate-coated hACE2-His, was used as an indicator of blocking potency. Percent blocking was defined based on the background-corrected binding signal observed at the highest antibody concentration tested using this formula and reported for all tested antibodies: [000235] Antibodies that blocked binding less than or equal to 50% at the highest concentration tested were classified as non-blockers and IC50 values were not reported for those antibodies. [000236] The ability of anti-SARS-CoV-2 antibodies to block SARS-CoV-2 RBD binding to human ACE2 was assessed using a blocking ELISA. In this assay 100pM SARS-COV-2 RBD- hFc was titrated with a wide range of the concentrations of the anti-SARS-CoV-2-S antibody and
- RBD-hFc at 100 pM was titrated with anti-SARS-COV-2-S antibodies in serial dilutions from 50nM and bound RBD-hFc on immobilized hACE2 with a 10x histidine tag, and detected with HRP-conjugated anti-hFc antibody. NBD; no blocking detected.
- Example 15 Cross-competition between mAb10987, mAb10989, mAb10933, and mAb10934
- mAb10987, mAb10989, mAb10933, and mAb10934 were examined in cross- competition binding assays ( Figure 11), identifying several pairs of non-competing mAbs with picomolar neutralization potency that could potentially be combined to form antibody cocktails, e.g., mAb10987 and mAb0933.
- Epitope binning of the anti-SARS-CoV-2-S mAbs was conducted in a pre-mix sandwich format involving competing mAbs against one another in a pairwise combinatorial manner for binding to SARS-CoV-2 RBD-MMH protein using a ForteBio Octet HTX biolayer interferometry instrument (Molecular Devices ForteBio LLC, Fremont, CA) with running buffer of 10 mM HEPES, 150 mM NaCl, 0.05% (v/v) Tween-20, pH 7.4, 1 mg/mL BSA. Assays were performed at 30 oC with continuous agitation at 1000 rpm.
- mAb10933 targets the spike-like loop region on one edge of the ACE2 interface. Within that region, the residues that show the most significant HDX protection by mAb10933 face upward, suggesting that the Fab region of mAb10933 binds the RBD from the top direction, where mAb10933 will have significant collisions with ACE2. In order to avoid competition with mAb10933, mAb10987 only binds to the HDX-defined protected regions from the front or the lower left side (in the front view of mAb10987 in Figure 12). This is consistent with the neutralization data described above, as mAb10987 would orient it in a position that has high probability to interfere with ACE2.
- Example 16 Structure determination of antibody-bound spike protein [000241] To better understand the binding of mAb10933 and mAb10987 to the spike protein RBD, structural analysis was performed via cryo-electron microscopy (cryoEM). Fab fragments of mAb10933 and mAb10987 were isolated using FabALACTICA kit (Genovis).600 ⁇ g of the mAb10933 Fab and 600 ⁇ g of mAb10987 Fab were mixed with 300 ⁇ g of SARS-CoV-2-S RBD and incubated on ice for ⁇ 1 hour then injected into a Superdex 200 increase gel filtration column equilibrated to 50 mM Tris pH 7.5, 150 mM NaCl.
- Peak fractions containing the mAb10933 Fab - mAb10987 Fab - RBD complex were collected and concentrated using a 10 kDa MWCO centrifugal filter.
- the protein sample was diluted to 1.5 mg/mL and 0.15% PMAL-C8 amphipol was added.3.5 ⁇ L of protein was deposited onto a freshly plasma cleaned UltrHommeoil grid (1.2/1.3, 300 mesh). Excess solution was blotted away using filter paper and plunge frozen into liquid ethane using a Vitrobot Mark IV.
- the cryoEM grid was transferred to a Titan Krios (Thermo Fisher) equipped with a K3 detector (Gatan). Movies were collected using EPU (Thermo Fisher) at 105,000x magnification, corresponding to a pixel size of 0.85 ⁇ .
- cryoSPARC v2.14.2.2,821 movies were aligned using patch motion correction and patch CTF estimation.2,197 aligned micrographs were selected for further processing on the basis of estimated defocus values and CTF fit resolutions.
- An initial set of particles picked using blob picker were subjected to 2D classification to generate templates for template picking.989,553 particles picked by template picking were subjected to multiple rounds of 2D classification to remove unbound fabs and particles containing an incomplete complex.
- Example 17 Cross-competition between anti-SARS-CoV-2-S mAbs
- Binding competition between anti-SARS-CoV-2-S monoclonal antibodies (mAbs) was determined using a real time, label-free bio-layer interferometry (BLI) assay on the Octet HTX biosensor platform (Pall ForteBio Corp.). The entire experiment was performed at 25 °C in 10mM HEPES, 150mM NaCl, 3mM EDTA, and 0.05% v/v Surfactant Tween-20, 1mg/mL BSA,
- SARS-COV-2 RBD-MMH pH 7.4 (HBS-EBT) buffer with the plate shaking at a speed of 1000rpm.
- SARS-COV-2 RBD-MMH C-terminal myc-myc-hexahistidine
- ⁇ 0.51nm of SARS-COV-2-S RBD-MMH was first captured onto anti-Penta-His antibody coated Octet biosensor tips (Fortebio Inc, # 18-5122) by submerging the biosensor tips for 1 minute in wells containing a 10 ⁇ g/mL solution of SARS-COV-2-S RBD- MMH.
- the SARS-COV-2-S RBD-MMH captured biosensor tips were then saturated with a first anti-SARS-CoV-2-S monoclonal antibody (subsequently referred to as mAb-1) by dipping into wells containing 50 ⁇ g/mL solution of mAb-1 for 5 minutes.
- the biosensor tips were then subsequently dipped into wells containing 50 ⁇ g/mL solution of a second anti-SARS-CoV-2 monoclonal antibody (subsequently referred to as mAb-2) for 5 minutes.
- the biosensor tips were washed in HBS-ETB buffer in between every step of the experiment. The real-time binding response was monitored during the entire course of the experiment and the binding response at the end of every step was recorded.
- Example 18 pH sensitivity of anti-SARS-CoV-2-S monoclonal antibodies binding to monomeric SARS-CoV-2-S RBD reagents measured at 37 oC [000245]
- the dissociation rate constants (k d ) for different anti-SARS-CoV-2-S monoclonal antibodies in pH 7.4, pH 6.0, and pH5.0 buffers were determined using a real-time surface plasmon resonance (SPR)-based Biacore T200 biosensor.
- SPR surface plasmon resonance
- Binding studies were performed on human SARS- COV-2-S RBD extracellular domain expressed with a C-terminal myc-myc-hexahistidine (SARS-COV-2 RBD-MMH), Single concentrations of SARS-COV-2-S RBD-MMH (90nM) prepared in PBS-T-pH 7.4 buffer were injected at a flow rate of 25 ⁇ L/min for 3 minutes followed by the dissociation of bound SARS-COV-2-S RBD-MMH in PBS-T-pH 7.4, PBS-T- pH 6.0 or PBS-T PBS-T-pH 5.0 running buffers for 5 minutes.
- SARS-COV-2 RBD-MMH Single concentrations of SARS-COV-2-S RBD-MMH (90nM) prepared in PBS-T-pH 7.4 buffer were injected at a flow rate of 25 ⁇ L/min for 3 minutes followed by the dissociation of bound SARS-COV-2-S RBD-MMH in PBS-
- the dissociation rate constants (k d ) in four pH running buffers were determined by fitting the real-time binding sensorgrams to a 1:1 binding model using Scrubber 2.0c curve- fitting software.
- the dissociative half-life (t1 ⁇ 2) was calculated from the kd values as: [000247]
- the k d and t1 ⁇ 2 values for SARS-COV-2-S RBD-MMH binding to different anti- SARS-CoV-2-S monoclonal antibodies in PBS-T-pH 7.4 followed by dissociation in PBS-T-pH 7.4 and PBS-T-pH 6.0 at 37 °C are shown in Table 35.
- Example 19 Anti-SARS-CoV-2-S antibodies binding to virus-like particles [000248] To investigate the ability of a panel of anti-SARS-CoV-2 monoclonal antibodies to bind SARS-CoV-2 Spike glycoprotein, an in vitro binding assay utilizing vesicular stomatitis virus (VSV) pseudotyped with SARS-CoV-2 Spike protein in an electrochemiluminescence based detection platform (MSD) was developed.
- VSV vesicular stomatitis virus
- VLPs viral like particles
- Nonspecific binding sites were blocked by 2% BSA (w/v) in PBS for 1 hour at room temperature.
- BSA w/v
- anti-SARS-CoV-2 antibodies and a non-binding human IgG1 control diluted in PBS + 0.5% BSA at a range of concentrations from 0.0008nM to 50nM, and buffer with no antibody were added in duplicate and the plates incubated for 1 hour at room temperature with shaking.
- the plates were then washed with 1X PBS to remove the unbound antibodies using an AquaMax2000 plate washer (MDS Analytical Technologies).
- the plate-bound antibodies were detected with a SULFO-TAGTM-conjugated anti-human IgG antibody (Jackson Immunoresearch) for 1 hour at room temperature.
- Binding to the immobilized VLPs on 96-well High Bind plates was performed with a series of antibody dilutions and the bound antibodies were detected using SULFO-TAGTM-conjugated anti-human IgG.
- the binding signals from electrochemiluminescence were recorded on a Sector Imager 600 (MSD). RLU values were determined for the antibody binding to VLPs. All antibodies displayed a concentration-
- Example 20 Anti-SARS-CoV-2-S antibodies binding to spike protein-expressing cells [000253] To investigate the ability of a panel of anti-SARS-CoV-2-S monoclonal antibodies to bind to SARS-CoV-2-S expressing cells, an in vitro binding assay utilizing SARS-CoV-2-S expressing cells in an electrochemiluminescence based detection platform (MSD) was developed.
- MSD electrochemiluminescence based detection platform
- Jurkat/Tet3G/hCD20/Tet-3G inducible cells were engineered to transiently express the SARS-CoV-2 Spike Protein (Accession number MN908947.3, amino acids 16-1211, Jurkat/Tet3G/hCD20/Tet-On 3G Inducible COVID-19 Spike Protein High Sorted), and flow cytometry sorted for selection of high expression of the SARS-CoV-2 protein.
- Parental Jurkat/Tet3G/hCD20/Tet-3G were also included in the experiments as a negative binding control.
- Nonspecific binding sites were blocked by 2% BSA (w/v) in PBS for one hour at room temperature.
- BSA w/v
- anti-SARS-CoV-2 antibodies and a non-binding human IgG1 control diluted in PBS + 0.5% BSA at a range of concentrations from 0.0008nM to 50nM, and buffer with no antibody were added in duplicate and the plates incubated for one hour at room temperature with shaking.
- the plates were then washed with 1X PBS to remove the unbound antibodies using an AquaMax2000 plate washer (MDS Analytical Technologies).
- the plate-bound antibodies were detected with a SULFO-TAGTM-conjugated anti-human IgG antibody (Jackson Immunoresearch) for one hour at room temperature.
- Binding to the immobilized cells on 96-well high bind plates was performed with a series of antibody dilutions and the bound antibodies were detected using SULFO-TAGTM-conjugated anti-human IgG.
- the binding signals from electrochemiluminescence were recorded on a Sector Imager 600 (MSD). All antibodies displayed a concentration-dependent binding and the ratio of the binding on spike expressing cells to the parental cells were analyzed at the concentration of 5.5nM and 0.20nM.
- the binding results of the anti-SARS-COV-2-S mAbs at the two concentrations to Spike protein expressing and parental Jurkat cells are summarized in Table 38.
- Table 38 Specificity of anti-SARS-CoV-2-S antibodies binding to spike protein-expressing Jurkat cells vs parental cells by electrochemiluminescence
Abstract
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JP2021518800A JP7116256B1 (en) | 2020-04-02 | 2020-06-25 | Anti-SARS-COV-2-Spike Glycoprotein Antibodies and Antigen-Binding Fragments |
BR122023004078-3A BR122023004078B1 (en) | 2020-04-02 | 2020-06-25 | PHARMACEUTICAL COMPOSITION, ITS USE AND METHOD FOR MANUFACTURING AN ANTIBODY OR ANTIGEN BINDING FRAGMENT THEREOF |
CR20220552A CR20220552A (en) | 2020-04-02 | 2020-06-25 | Anti-sars-cov-2-spike glycoprotein antibodies and antigen-binding fragments |
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CA3115553A CA3115553C (en) | 2020-04-02 | 2020-06-25 | Anti-sars-cov-2-spike glycoprotein antibodies and antigen-binding fragments |
PE2022002139A PE20221893A1 (en) | 2020-04-02 | 2020-06-25 | ANTIBODIES AGAINST SARS-COV-2 SPICLE GLYCOPROTEIN AND ANTIGEN-BINDING FRAGMENTS |
AU2020340881A AU2020340881A1 (en) | 2020-04-02 | 2020-06-25 | Anti-SARS-CoV-2-spike glycoprotein antibodies and antigen-binding fragments |
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CN202080005771.3A CN113766928A (en) | 2020-04-02 | 2020-06-25 | anti-SARS-COV-2 fiber process glycoprotein antibody and antigen binding fragment |
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