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WO2023036986A2 - Anticorps à chaîne lourde uniquement anti-sars-cov-2 (sars2, covid-19) - Google Patents

Anticorps à chaîne lourde uniquement anti-sars-cov-2 (sars2, covid-19) Download PDF

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WO2023036986A2
WO2023036986A2 PCT/EP2022/075300 EP2022075300W WO2023036986A2 WO 2023036986 A2 WO2023036986 A2 WO 2023036986A2 EP 2022075300 W EP2022075300 W EP 2022075300W WO 2023036986 A2 WO2023036986 A2 WO 2023036986A2
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seq
heavy chain
sars2
nos
antibody
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PCT/EP2022/075300
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WO2023036986A3 (fr
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Franklin Gerardus Grosveld
Berend Jan Bosch
Bartholomeus Leonard HAAGMANS
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Harbour Antibodies Bv
Universiteit Utrecht Holding Bv
Erasmus University Medical Center Rotterdam
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Publication of WO2023036986A2 publication Critical patent/WO2023036986A2/fr
Publication of WO2023036986A3 publication Critical patent/WO2023036986A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1002—Coronaviridae
    • C07K16/1003—Severe acute respiratory syndrome coronavirus 2 [SARS‐CoV‐2 or Covid-19]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • SARS-Cov-2 (SARS2, COVID-19) HEAVY CHAIN ONLY ANTIBODIES
  • the invention relates to heavy chain only antibodies (HCAbs) and antigen-binding fragments thereof that recognize the spike (S) protein of SARS-Cov-2 coronavirus (Covid-19), hereafter called SARS2 or SARS-CoV-2.
  • HCAbs heavy chain only antibodies
  • SARS2 or SARS-CoV-2 SARS-Cov-2 coronavirus
  • Coronavirus disease 19 (COVID-19) is caused by the zoonotic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  • SARS-CoV-2 zoonotic severe acute respiratory syndrome coronavirus 2
  • the virus infects humans and human-to-human transmission is efficient, it occurs at close contact and via airway expelled micro-droplets. It is a lower airway infection with fever, coughing and shortness of breath as the primary symptoms and leads in ⁇ 2% of cases to a lethal pneumonia.
  • Elderly people and patients with an impaired immune system are particularly vulnerable, (the WHO, in 2020).
  • the first case was documented in Wuhan China in late 2019 and has since spread to other parts of Asia, Africa, the Americas and Europe (https://coironaviiirus.jhu.edu/; https://www.who.
  • SARS-CoV-2 belongs to the Sarbecovirus subgenus along with another zoonotic coronavirus SARS-CoV1 (originally termed SARS-CoV; hereafter referred to as SARS-1 or SARS-CoV-1) that emerged in 2002/2003 displaying a -10% fatality rate.
  • the invention further provides an anti-SARS2-SlB heavy chain-only antibody.
  • the antibody competes for binding to SARS2-S with a reference heavy chain-only (lgG1) antibody consisting of two heavy chains, wherein each heavy chain has a heavy chain variable region of the amino acid sequence of:
  • the invention further provides an anti-SARS2-SlA heavy chain-only antibody.
  • SARS2-S1A has the sequence of SEQ ID NO: 123.
  • the antibody competes for binding to SARS2-S with a reference heavy chain-only (lgG1) antibody consisting of two heavy chains, wherein each heavy chain has a heavy chain variable region of the amino acid sequence of SEQ ID NO: 60.
  • the invention further provides a multispecific anti-SARS2-S antibody comprising a first heavy chain variable region and a second heavy chain variable region, optionally wherein the antibody comprises one or more additional heavy chain variable regions.
  • the invention further provides a combination of antibodies comprising a first anti-SARS2-S antibody, wherein the antibody is according to the invention, and a second anti-SARS2-S antibody, wherein the first and second antibodies do not bind to the same epitope.
  • the invention further provides an isolated nucleic acid encoding an antibody of the invention.
  • the invention further provides a vector comprising a nucleic acid of the invention.
  • the invention further provides a host cell comprising a vector of the invention.
  • the invention further provides a pharmaceutical composition comprising an antibody of the invention, or a combination of antibodies of the invention, and a pharmaceutically acceptable carrier.
  • the invention further provides an antibody, combination of antibodies or composition of the invention for use in therapy, optionally wherein the therapy is preventing, treating or ameliorating coronavirus infection, optionally betacoronavirus infection, such as SARS2 infection.
  • FIG. 1 Immunisation of HCAb transgenic mice to generate antibodies containing human heavy chain only variable regions.
  • A Immunization scheme for generating heavy chain-only antibodies against SARS2-S.
  • SED trimeric SARS2-S ectodomain
  • CD138 + (plasma) cells were collected from bone marrow and spleens of the immunized mice and B cells were collected from the lymph nodes of the immunized mice. RNA was purified and cDNA was synthesised. Amplified heavy chain variable region sequeences were cloned into a eukaryotic vector containing human Fc (pCAG delta CH1hG1). The vector contains VH323 leader sequence that provides secretion of the HCAb. The ligated vectors were transfected into two bacterial libraries for amplification. The vectors were then isolated (960 minipreps from each library) and transfected into HEK cells.
  • Each of the HEK cell wells was grown for 48 hours and the medium tested twice for the production of antibodies binding the SARS2-S protein. Strep tag reacting antibodies were ruled out using a non-related RVFV-ST protein. This resulted in the identificaiton of >600 anti-SARS2 positive wells.
  • Each of the 600 supernatants was tested for neutralization of SARS-2 pseudovirus, of which approximately 150 supernatants showed >50% neutralizing activity. These were sequences which resulted in 9 groups of HCAbs that had a different CDR3 recombination. These were used to map their binding to the different domains of the spike protein. 14 HCAbs with high pseudovirus (PSV) neutralization potency were selected for purification and further analysis. These HCAbs were profiled for epitope binding kinetics, binding competition, ACE2 binding inhibition, post-translational modification liabilities. The IC50 values of these HCAbs was determined using PSV and live virus assays.
  • the 16 most promising clones from the pseudovirus neutralization assay were selected and their sequences compared to their respective germline sequence.
  • Three different VH germline were used (VH3-11 , VH3-53 and VH3-48).
  • Two of the HCAbs had identical sequences (3H6 and 8H9) or nearly identical (2C6 and 6E2), while others differ in somatic hypermutations and CDR3 to greater extent). 8H9 and 8C7 were left out of further analysis, leaving 14 HCAbs for further analysis.
  • HCAbs were expressed at similar levels in HEK293 freestyle cells purified on protein A columns, eluted and run on SDS page gels under non reducing conditions leaving the heavy chain dimers intact.
  • the spike protein is bound to the tips of an Octet BLI instrument to determine the competition between different HCAbs to bind to their epitopes.
  • (xi)-(xv): 7D1 binds to a different epitope from that of 11C12 and 10D12, but to an overlapping or identical epitope to that bound by 2H4, 14D2 and 10H7.
  • the binding and dissociation curves also allow affinity measurements of each of the antibodies.
  • 14D2 has the same epitope as 7D1 and an overlapping epitope with 2H4 and 10H7. 14D2 binds to a different epitope from that bound by 11C12 or 10D12.
  • 10H7 has a different epitope from that bound by 11C12 or 10D12. 10H7 has the same epitope as 2H4 and an overlapping epitope with 14D2 and 7D1 .
  • the HCAb were grouped into Groups 1 a, 1 b, 2 and 3.
  • the division of Group 1 into Groups 1 a and 1 b was based on there being two sub-groups that exhibit a partially overlapping region of binding to the S1B protein. 10D12 and 11C12 bind to distinct epitopes, and define Groups 2 and 3, respectively.
  • Recombinant soluble human ACE2 was coated on NUNC Maxisorp plates (Thermo Scientific) at 4°C overnight. Plates were washed three times with PBS containing 0.05% Tween-20 and blocked with 3% BSA in PBS containing 0.1% Tween-20 at room temperature for 2 hours.
  • Recombinant S1 B of SARS2-S 300 ng
  • serially diluted HCAbs (1 D6, 3H3, 10D12, 7D1 , 10H7, 3H6, 14D2, 2C6, 6A3, 1 E10, 2C8, 2H4, 6E2, 11C12) were mixed for 1h at RT, added to the plate for 1 hour at room temperature, after which the plates were washed three times. Binding to ACE2 was detected using HRP-conjugated StrepMAb (IBA) that recognizes the C-terminal Streptag on the S1 B proteins.11C12 binding the S1A domain was used as the negative control.
  • IBA HRP-conju
  • REGN 10987 and 10933 positive blocking control monoclonal H2L2 antibodies from Regeneron.
  • the spike S1 B protein is bound to the tips of an Octet BLI instrument to determine the kinetics of binding of the different HCAbs using different concentratios of HCAb.
  • Kdis and KD are shown below each panel. Binding curves are provided for: (A) 1 D6, (B) 3H3, (C) 10D12, (D) 7D1 , (E) 10H7, and (F) 3H6.
  • the spike protein S1 B is bound to the tips of an Octet BLI instrument to determine the kinetics of binding of the different HCAbs using different concentratios of HCAb. Below each panel the K on , Kdis and KD are shown. Binding curves are provided for: (A) 14D2, (B) 2C6, (C) 6A3, (D) 1 E10, (E) 2C8 and (F) 2H4.
  • the spike protein S1 B or Secto is bound to the tips of an Octet BLI instrument to determine the kinetics of binding of the different HCAbs using different concentratios of HCAb.
  • Below each panel the Kon, Kdis and K D are shown. Binding curves are provided for: (A) 6E2 (SARS2-S1 B), (B) 11C12 (SARS2-S ect o), (C) 3H6 (SARS2-S ect0 ) and (D) 3H6 (SARS2-S1 B ).
  • the S1 B domain binds the ACE2 receptor on the cell membrane.
  • VeroE6 cells were seeded with density of 10 5 cells per ml. After reaching 70-80% confluency, cells were transfected with plasmids encoding full length SARS2-S - C-terminally fused to GFP - using Lipofectamine 2000 (Invitrogen). The furin recognition site in the SARS2-S was mutated (R 682 RAR to A 682 AAR) to inhibit cleavage of the protein by endogenous furin and allow trypsin-induced syncytia formation.
  • the different HCAbs contained potential glycosylation sites that could be disadvantageous in the context of therapeutic applications and/or the manufacture of a consistent product. All antibodies were therefore treated with N-Glycosidase F (PNGase F) which catalyzes the cleavage of N-linked oligosaccharides according to the manufacturer’s instructions. These were subsequently analysed by SDS PAGE to monitor whether the HCAbs had been deglycosylated resulting in a shift of gel mobility (panel A). They were subsequently tested for binding the SARS-2 spike protein versus the same mock treated glycosylated HCAb and the EC50 (effective half-maximal concentration of binding) determined (panels B and C). The result shows that only 2C6 and 6E2 are significantly affected by deglycosylation.
  • Multi-valent HCAbs can consist of two heavy chains of identical amino acid sequence. Hence, production in cell culture results in a single product, rather than a mixture of products, as seen when more than one chain is involved (e.g. with regular heavy and light chain antibodies). In addition having two or more VH binding sites on the same HCAb will increase the avidity of the HCAb and potentially lock the Spike protein in a non-infectious conformation.
  • FIG. 1 Diagram of a tetravalent bispecific HCAb, in which the second heavy chain variable region (VH2) has been added C-terminally to a conventional divalent monospecific HCAb.
  • C Bispecific HCAb constructs. These constructs were expressed in HEK cells and the supernatants analysed by gel elctrophoresis and compared to the five monospecific antibodies that were used to make the different bi-specific antibodies.
  • Figure 19 Blocking activity of SARS2-spike VSV pseudovirus infection by bi-specific HCAbs
  • SEQ ID NO: 115 The sequence of SEQ ID NO: 115 is set out below in ST.25 format.
  • the Examples show that 1 D6, 3H3, 10H7, 3H6, 2C8 and 2H4 bind to the same epitope on SARS2-S1 B (Group 1a).
  • Each of these antibodies binds strongly to SARS2-S1 B (ECso of 5.2-21.7 ng/ml; Ko of 2.8 nM - 1.28 pM as measured by biolayer interferometry), strongly inhibits ACE2 binding to SARS2-S1 B (IC50 of 0.215-2.274 pg/ml), potently neutralizes in vitro infection of primate cells by vesicular stomatitis virus pseudotyped with SARS2-S (IC50 of 0.082-2.274 pg/ml), and potently neutralizes SARS2 virus infection of primate cells (PRNT50 of 0.078-0.469 pg/ml). Similar functional properties can be expected to be associated with the heavy chain-only antibodies defined below which share characteristics with these exemplified antibodies.
  • the invention provides an anti-SARS2-S heavy chain-only antibody that competes for binding to SARS2-S with a reference heavy chain-only (I gG 1 ) antibody consisting of two heavy chains, wherein each heavy chain has a heavy chain variable region of the amino acid sequence of one of SEQ ID NOs: 2, 6, 10, 14, 19 and 27.
  • competition for binding is assessed by biolayer interferometry at 25°C, optionally wherein SARS2-S is bound to the biosensor tip, the reference antibody is bound to the SARS2-S (in binding buffer) to saturation, the binding tip is washed and a second binding step is performed with the test antibody.
  • a second binding step is performed with the reference antibody as a control.
  • a test antibody competes with a reference antibody if the level of binding of the test antibody is ⁇ 30% higher than the control reference antibody.
  • the anti-SARS2-S heavy chain-only antibody does not compete for binding to SARS2-S with a reference heavy chain-only (I gG 1 ) antibody consisting of two heavy chains, wherein each heavy chain has a heavy chain variable region of the amino acid sequence of one of SEQ ID NOs: 47 and 60.
  • competition for binding is assessed by biolayer interferometry at 25°C, optionally wherein SARS2-S is bound to the biosensor tip, the reference antibody is bound to the SARS2-S (in binding buffer) to saturation, the binding tip is washed and a second binding step is performed with the test antibody.
  • a second binding step is performed with the reference antibody as a control.
  • a test antibody competes with a reference antibody if the level of binding of the test antibody is ⁇ 30% higher than the control reference antibody.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a KD of 1.5 pM or less (e.g 100 nM or less, such as 20 nM or less) as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-S1 B with an ICso of 3.5 pg/ml or less (e.g. an ICso of 1.75 pg/ml or less).
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 2.5 pg/ml or less (e.g. an ICso of 0.5 pg/ml or less).
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control
  • an ICso of 2.5 pg/ml or less e.g. an ICso of 0.5 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.5 pg/ml or less (e.g. a PRNT50 of 0.3 pg/ml or less).
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control)
  • the antibody has a PRNT50 of 0.5 pg/ml or less (e.g. a PRNT50 of 0.3 pg/ml or less).
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (a) binds to SARS2-S1 B with a KD of 1.5 pM or less (e.g 100 nM or less, such as 20 nM or less) as measured by biolayer interferometry at 25°C, and/or
  • (b) inhibits ACE2 binding to SARS2-SlBwith an ICso of 3.5 pg/ml or less (e.g. an ICso of 1.75 pg/ml or less), and/or
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 2.5 pg/ml or less (e.g. an ICso of 0.5 pg/ml or less), and/or
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.5 pg/ml or less (e.g. a PRNT50 of 0.3 pg/ml or less).
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.5 pg/ml or less (e.
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 2.5 pg/ml or less (e.g. an IC50 of 0.5 pg/ml or less), and
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.5 pg/ml or less (e.g. a PRNT50 of 0.3 pg/ml or less).
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control)
  • the antibody has a PRNT50 of 0.5 pg/ml or less (e.g. a PRNT50 of 0.3 pg/ml or less).
  • the invention provides an anti-SARS2-S heavy chain-only antibody that binds to the same epitope as a reference heavy chain-only (lgG1) antibody consisting of two heavy chains, wherein each heavy chain has a heavy chain variable region of the amino acid sequence of one of SEQ ID NOs: 2, 6, 10, 14, 19 and 27.
  • binding to the same epitope is determined by biolayer interferometry at 25°C, optionally wherein SARS2-S is bound to the biosensor tip, the reference antibody is bound to the SARS2-S (in binding buffer) to saturation, the binding tip is washed and a second binding step is performed with the test antibody.
  • a second binding step is performed with the reference antibody as a control.
  • a test antibody binds to the same epitope as a reference antibody if the level of binding of the test antibody is ⁇ 10% higher than the control reference antibody.
  • the anti-SARS2-S heavy chain-only antibody does not compete for binding to SARS2-S with a reference heavy chain-only (I gG 1 ) antibody consisting of two heavy chains, wherein each heavy chain has a heavy chain variable region of the amino acid sequence of one of SEQ ID NOs: 47 and 60.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a KD of 1.5 pM or less (e.g 100 nM or less, such as 20 nM or less) as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-S1 B with an IC 5 o of 3.5 pg/ml or less (e.g. an IC 5 o of 1.75 pg/ml or less).
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 2.5 pg/ml or less e.g. an IC50 of 0.5 pg/ml or less).
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells ⁇ e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.5 pg/ml or less ⁇ e.g. a PRNT50 of 0.3 pg/ml or less).
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 2.5 pg/ml or less ⁇ e.g. an IC50 of 0.5 pg/ml or less), and/or
  • (d) is capable of neutralizing in vitro infection of primate cells ⁇ e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.5 pg/ml or less ⁇ e.g. a PRNT50 of 0.3 pg/ml or less).
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 2.5 pg/ml or less ⁇ e.g. an IC50 of 0.5 pg/ml or less), and (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.5 pg/ml or less (e.g. a PRNT50 of 0.3 pg/ml or less).
  • the Examples show that the 1D6 heavy chain-only antibody binds strongly to SARS2-S1 B (ECSO of 21.7 ng/ml; Ko of 212 nM as measured by biolayer interferometry), strongly inhibits ACE2 binding to SARS2-S1 B (ICso of 3.3 pg/ml), potently neutralizes in vitro infection of primate cells by vesicular stomatitis virus pseudotyped with SARS2-S (IC50 of 2.274 pg/ml), and potently neutralizes SARS2 virus infection of primate cells (PRNT50 of 0.469 pg/ml).
  • Deglycosylation of 1D6 by PNGase F treatment has no impact on 1 D6 binding to SARS2-S. Similar functional properties can be expected to be associated with the heavy chain-only antibodies defined below which share structural and functional characteristics with the 1D6 heavy chain-only antibody.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody that binds to the same epitope as a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 14.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody that competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 14.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 15 for CDR1 of the heavy chain; ii. SEQ ID NO: 16 for CDR2 of the heavy chain; and iii. SEQ ID NO: 17 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a KD of 250 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICso of 3.5 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 2.5 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.5 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.5 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 2.5 pg/ml or less, and/or
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control)
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.5 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.5 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 2.5 pg/ml or less, and
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.5 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.5 pg/ml or less.
  • the heavy chain-only antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 14.
  • the heavy chain-only antibody comprises an amino acid sequence that is at least 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a heavy chain variable region of the amino acid sequence of SEQ ID NO: 14.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. a sequence that is at least 90% identical to SEQ ID NO: 15 for CDR1 of the heavy chain; ii. a sequence that is at least 90% identical to SEQ ID NO: 16 for CDR2 of the heavy chain; and iii. a sequence that is at least 90% identical to SEQ ID NO: 17 for CDR3 of the heavy chain, wherein the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 14.
  • CDRs complementarity determining regions
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. a sequence that is at least 95% identical to SEQ ID NO: 15 for CDR1 of the heavy chain; ii. a sequence that is at least 95% identical to SEQ ID NO: 16 for CDR2 of the heavy chain; and iii. a sequence that is at least 95% identical to SEQ ID NO: 17 for CDR3 of the heavy chain, wherein the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 14.
  • CDRs complementarity determining regions
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with: i. a sequence consisting of X1X2X3X4X5X6X7X8X9 for CDR1 of the heavy chain, wherein:
  • Xi is F, W or Y
  • X 2 is T, S, C, U or M
  • X 3 is F, W or Y
  • X 4 is S, C, T, U or M
  • X5 is D, E, N or Q
  • X 6 is Y, F or W
  • X 7 is Y, F or W
  • Xs is M, S, C, T or II
  • X 9 is S, C, T, U or M; ii. a sequence consisting of X1X2X3X4X5X6X7X8X9X10X11X12X13 for CDR2 of the heavy chain, wherein:
  • Xi is S, C, T, U or M
  • X 2 is N, D, E or Q
  • X 3 is I, A, G, L or V
  • X 4 is N, D, E or Q
  • X 5 is A, G, I, L or V
  • X 6 is S, C, T, U or M
  • X 7 is G, A, L, V or I
  • X 8 is S, C, T, U or M
  • X is T, S, C, U or M
  • Xu is Y, F or W
  • X12 is Y, F or W
  • X13 is A, G, I, L or V; and iii. a sequence consisting of X1X2X3X4X5X6X7X8X9X10 for CDR3 of the heavy chain, wherein:
  • Xi is A, G, I, L or ,
  • X 2 is R, H or K
  • X 3 is L, A, G, I or V,
  • X 4 is D, E, N or Q
  • X 5 is G, A, L, V or I
  • X 6 is S, C, T, U or M
  • X 7 is G, A, L, V or I
  • X 8 is N, D, E or Q
  • X 9 is S, C, T, U or M
  • X10 is D, E, N or Q.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 2.5 pg/ml or less, and/or
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • (d) is capable of neutralizing in vitro infection of primate cells e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.5 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.5 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitr
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 2.5 pg/ml or less, and
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • (d) is capable of neutralizing in vitro infection of primate cells e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.5 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • the antibody has a PRNT50 of 0.5 pg/ml or less.
  • the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 14.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody consisting of two heavy chains, wherein each heavy chain comprises complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 15 for CDR1 of the heavy chain; ii. SEQ ID NO: 16 for CDR2 of the heavy chain; and iii. SEQ ID NO: 17 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • each of the heavy chains comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 14.
  • the 3H3 heavy chain-only antibody binds strongly to SARS2-S1 B (ECSO of 13.1 ng/ml; Ko of 770 nM as measured by biolayer interferometry), strongly inhibits ACE2 binding to SARS2-S1 B (ICso of 1.63 pg/ml), potently neutralizes in vitro infection of primate cells by vesicular stomatitis virus pseudotyped with SARS2-S (IC50 of 0.974 pg/ml), and potently neutralizes SARS2 virus infection of primate cells (PRNT50 of 0.313 pg/ml).
  • Deglycosylation of 3H3 by PNGase F treatment has no impact on 3H3 binding to SARS2-S. Similar functional properties can be expected to be associated with the heavy chain-only antibodies defined below which share structural and functional characteristics with the 3H3 heavy chain-only antibody.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody that binds to the same epitope as a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 10.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody that competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 10.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 11 for CDR1 of the heavy chain; ii. SEQ ID NO: 12 for CDR2 of the heavy chain; and iii. SEQ ID NO: 13 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a KD of 800 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICso of 2 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC 5 o of 1 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 1 pg/ml or less, and/or
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control)
  • an IC50 of 1 pg/ml or less
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody (a) binds to SARS2-S1 B with a K D of 800 nM or less as measured by biolayer interferometry at 25°C,
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 1 pg/ml or less, and
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • (d) is capable of neutralizing in vitro infection of primate cells e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • the antibody has a PRNT50 of 0.4 pg/ml or less.
  • the heavy chain-only antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 10.
  • the heavy chain-only antibody comprises an amino acid sequence that is at least 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a heavy chain variable region of the amino acid sequence of SEQ ID NO: 10.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. a sequence that is at least 90% identical to SEQ ID NO: 11 for CDR1 of the heavy chain; ii. a sequence that is at least 90% identical to SEQ ID NO: 12 for CDR2 of the heavy chain; and iii. a sequence that is at least 90% identical to SEQ ID NO: 13 for CDR3 of the heavy chain, wherein the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 10.
  • CDRs complementarity determining regions
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. a sequence that is at least 95% identical to SEQ ID NO: 11 for CDR1 of the heavy chain; ii. a sequence that is at least 95% identical to SEQ ID NO: 12 for CDR2 of the heavy chain; and iii. a sequence that is at least 95% identical to SEQ ID NO: 13 for CDR3 of the heavy chain, wherein the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 10.
  • CDRs complementarity determining regions
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with: i. a sequence consisting of X1X2X3X4X5X6X7X8X9 for CDR1 of the heavy chain, wherein:
  • X 2 is T, S, C, U orM
  • X 3 is F, WorY,
  • X 4 is G, A, L, Vor I,
  • X5 is D, E, N or Q
  • Xe is D, E, N or Q
  • X 7 is Y, F or W
  • Xs is M, S, C, T or II
  • X 9 is S, C, T, U orM; ii. a sequence consisting of X1X2X3X4X5X6X7X8X9X10X11X12X13 for CDR2 of the heavy chain, wherein:
  • Xi is S, C, T, U orM
  • X 2 is N, D, EorQ,
  • X 3 is I, A, G, LorV,
  • X 4 is N, D, E or Q
  • X 5 is A, G, I, LorV,
  • X 6 is S, C, T, U orM
  • X 7 is G, A, L, Vor I,
  • X 8 is S, C, T, U orM
  • X10 is T, S, C, UorM
  • X11 is Y, F orW
  • X12 is Y, F or W
  • Xi 3 is A, G, I, L or V; and iii. a sequence consisting of X- ⁇ X ⁇ XsXeXyXsXgX-io for CDR3 of the heavy chain, wherein:
  • Xi is A, G, I, LorV,
  • X 2 is R, H or K
  • X 3 is L, A, G, I or V,
  • X 4 is D, E, N or Q
  • X 5 is E, D, N or Q
  • X 6 is S, C, T, U or M
  • X 7 is G, A, L, V or I
  • X 8 is K, H or R
  • X9 is S, C, T, II or M
  • X10 is D, E, N or Q.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a KD of 800 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICso of 2 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 1 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • an IC50 of 1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 1 pg/ml or less, and/or
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • (d) is capable of neutralizing in vitro infection of primate cells ⁇ e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 1 pg/ml or less, and
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • (d) is capable of neutralizing in vitro infection of primate cells e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • the antibody has a PRNT50 of 0.4 pg/ml or less.
  • the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 10.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody consisting of two heavy chains, wherein each heavy chain comprises complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 11 for CDR1 of the heavy chain; ii. SEQ ID NO: 12 for CDR2 of the heavy chain; and iii. SEQ ID NO: 13 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • each of the heavy chains comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 10.
  • the Examples show that the 10H7 heavy chain-only antibody binds strongly to SARS2-S1 B (ECSO of 5.2 ng/ml; KD of 2.8 nM as measured by biolayer interferometry), strongly inhibits ACE2 binding to SARS2-S1 B (ICso of 0.86 pg/ml), potently neutralizes in vitro infection of primate cells by vesicular stomatitis virus pseudotyped with SARS2-S (IC50 of 0.215 pg/ml), and potently neutralizes SARS2 virus infection of primate cells (PRNT50 of 0.078 pg/ml).
  • the invention further provides an anti-SARS2-S heavy chain-only antibody that binds to the same epitope as a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 19.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody that competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 19.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 20 for CDR1 of the heavy chain; ii. SEQ ID NO: 21 for CDR2 of the heavy chain; and iii. SEQ ID NO: 22 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a KD of 5 nM or less ⁇ e.g. 3 nM or less) as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICso of 1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.3 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control
  • an IC50 of 0.3 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.3 pg/ml or less, and/or
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control)
  • an IC50 of 0.3 pg/ml or less
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (b) inhibits ACE2 binding to SARS2-SlBwith an ICso of 1 pg/ml or less
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.3 pg/ml or less, and
  • (d) is capable of neutralizing in vitro infection of primate cells e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the heavy chain-only antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 19.
  • the heavy chain-only antibody comprises an amino acid sequence that is at least 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a heavy chain variable region of the amino acid sequence of SEQ ID NO: 19.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. a sequence that is at least 90% identical to SEQ ID NO: 20 for CDR1 of the heavy chain; ii. a sequence that is at least 90% identical to SEQ ID NO: 21 for CDR2 of the heavy chain; and iii. a sequence that is at least 90% identical to SEQ ID NO: 22 for CDR3 of the heavy chain, wherein the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 19.
  • CDRs complementarity determining regions
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. a sequence that is at least 95% identical to SEQ ID NO: 20 for CDR1 of the heavy chain; ii. a sequence that is at least 95% identical to SEQ ID NO: 21 for CDR2 of the heavy chain; and iii. a sequence that is at least 95% identical to SEQ ID NO: 22 for CDR3 of the heavy chain, wherein the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 19.
  • CDRs complementarity determining regions
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with: i. a sequence consisting of X1X2X3X4X5X6X7X8X9 for CDR1 of the heavy chain, wherein:
  • X 2 is T, S, C, U orM
  • X 3 is V, G, A, I or L
  • X 4 is S, C, T, U orM
  • X5 is N, D, E or Q
  • Xe is N, D, E or Q
  • X 7 is Y, F or W
  • Xs is M, S, C, T or II
  • X 9 is A, G, I, LorV; ii. a sequence consisting of X1X2X3X4X5X6X7X8X9X10X11X12X13 for CDR2 of the heavy chain, wherein:
  • Xi is S, C, T, U orM
  • X 2 is V, G, A, I or L
  • X 3 is I, G, A, LorV,
  • X 4 is Y, F or W
  • X 5 is A, G, I, Lor ,
  • X 6 is N, D, E or Q
  • X 7 is N, D, EorQ,
  • X 8 is N, D, EorQ,
  • X 9 is T, S, C, UorM
  • X10 is Y, F or W
  • X11 is Y, F orW
  • X12 is A, G, I, L or V, and
  • X13 is D, N, E or Q; and iii. a sequence consisting of X ⁇ XsX ⁇ sXeXyXsXgXioXi 1X12X13X1 4 for CDR3 of the heavy chain, wherein:
  • Xi is S, C, T, U orM
  • X 2 is S, C, T, U orM
  • X 3 is R, H or K
  • X 4 is Y, W or F
  • X 5 is G, A, I, LorV,
  • X 6 is S, C, T, U orM
  • X 7 is G, A, I, LorV,
  • X 8 is S, C, T, U orM
  • X 9 is E, D, N or Q
  • X is E, D, N or Q
  • Xn is L, G, A, I or V
  • X12 is Y, F, or W
  • X13 is D, E, N, or Q
  • X14 is I, G, A, L, or V.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a KD of 5 nM or less ⁇ e.g. 3 nM or less) as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICso of 1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 0.3 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control
  • an ICso of 0.3 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 0.3 pg/ml or less, and/or
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (b) inhibits ACE2 binding to SARS2-SlBwith an ICso of 1 pg/ml or less
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.3 pg/ml or less, and
  • (d) is capable of neutralizing in vitro infection of primate cells e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 19.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody consisting of two heavy chains, wherein each heavy chain comprises complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 20 for CDR1 of the heavy chain; ii. SEQ ID NO: 21 for CDR2 of the heavy chain; and iii. SEQ ID NO: 22 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • each of the heavy chains comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 19.
  • N55G, N55A and N55Q variants of the 10H7 heavy chain-only antibody bind to SARS2-S ec to with similarly high affinity to the 10H7 antibody (KD of 15.4-18.6 nM as measured by biolayer interferometry at 25°C). Similar functional properties can be expected to be associated with the heavy chain-only antibodies defined below which share structural and functional characteristics with the 10H7 heavy chain-only antibody (and these N55 mutants).
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 20 for CDR1 of the heavy chain; ii. SEQ ID NO: 69 for CDR2 of the heavy chain; and iii. SEQ ID NO: 22 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • the heavy chain-only antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 68.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a K D of 5 nM or less ⁇ e.g. 3 nM or less) as measured by biolayer interferometry at 25°C. In some embodiments, the anti-SARS2-S heavy chain-only antibody binds to SARS2-S ec to with a K D of 20 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICso of 1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 0.3 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • an ICso of 0.3 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 0.3 pg/ml or less, and/or
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • (d) is capable of neutralizing in vitro infection of primate cells ⁇ e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 0.3 pg/ml or less, and
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • (d) is capable of neutralizing in vitro infection of primate cells ⁇ e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody consisting of two heavy chains, wherein each heavy chain comprises complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 20 for CDR1 of the heavy chain; ii. SEQ ID NO: 69 for CDR2 of the heavy chain; and iii. SEQ ID NO: 22 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • each of the heavy chains comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 68.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 20 for CDR1 of the heavy chain; ii. SEQ ID NO: 83 for CDR2 of the heavy chain; and iii. SEQ ID NO: 22 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • the heavy chain-only antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 82.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a KD of 5 nM or less (e.g. 3 nM or less) as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S ec to with a KD of 20 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICso of 1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 0.3 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control
  • an ICso of 0.3 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody (a) binds to SARS2-S ec to with a K D of 20 nM or less as measured by biolayer interferometry at 25°C, and/or
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 0.3 pg/ml or less, and/or
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • (d) is capable of neutralizing in vitro infection of primate cells e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 0.3 pg/ml or less, and
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • (d) is capable of neutralizing in vitro infection of primate cells ⁇ e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody consisting of two heavy chains, wherein each heavy chain comprises complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 20 for CDR1 of the heavy chain; ii. SEQ ID NO: 83 for CDR2 of the heavy chain; and iii. SEQ ID NO: 22 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • each of the heavy chains comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 82.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 20 for CDR1 of the heavy chain; ii. SEQ ID NO: 85 for CDR2 of the heavy chain; and iii. SEQ ID NO: 22 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a KD of 5 nM or less ⁇ e.g. 3 nM or less) as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S ec to with a KD of 20 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICso of 1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.3 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control
  • an IC50 of 0.3 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.3 pg/ml or less, and/or
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control)
  • an IC50 of 0.3 pg/ml or less
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (b) inhibits ACE2 binding to SARS2-SlBwith an ICso of 1 pg/ml or less
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.3 pg/ml or less, and
  • (d) is capable of neutralizing in vitro infection of primate cells e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the heavy chain-only antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 84.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody consisting of two heavy chains, wherein each heavy chain comprises complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 20 for CDR1 of the heavy chain; ii. SEQ ID NO: 85 for CDR2 of the heavy chain; and iii. SEQ ID NO: 22 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • each of the heavy chains comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 84.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with: i. a sequence consisting of X1X2X3X4X5X6X7X8X9 for CDR1 of the heavy chain, wherein:
  • Xi is F, W or Y
  • X 2 is T, S, C, U or M
  • X 3 is V, G, A, I or L
  • X 4 is S, C, T, U or M
  • X5 is N, D, E or Q
  • Xe is N, D, E or Q
  • X 7 is Y, F or W
  • Xs is M, S, C, T or II
  • X 9 is A, G, I, L or V; ii. a sequence consisting of X1X2X3X4X5X6X7X8X9X10X11X12X13 for CDR2 of the heavy chain, wherein:
  • Xi is S, C, T, U or M
  • X 2 is V, G, A, I or L
  • X 3 is I, G, A, L or V
  • X 4 is Y, F or W
  • X 5 is A, G, I, L or V
  • Xe is N, D, E or Q
  • X? is G, A or Q
  • X 8 is N, D, E or Q
  • X 9 is T, S, C, U or M
  • X10 is Y, F or W
  • X11 is Y, F or W
  • X12 is A, G, I, L or V, and
  • X13 is D, N, E or Q; and iii. a sequence consisting of X1X2X3X4X5X6X7X8X9X10X11X12X13X14 for CDR3 of the heavy chain, wherein:
  • Xi is S, C, T, U or M
  • X 2 is S, C, T, U or M
  • X 3 is R, H or K
  • X 4 is Y, W or F
  • X 5 is G, A, I, L or ,
  • X 6 is S, C, T, U or M
  • X 7 is G, A, I, L or V,
  • X 8 is S, C, T, U or M
  • X 9 is E, D, N or Q
  • X10 is E, D, N or Q
  • X11 is L, G, A, I or V
  • X12 is Y, F, or W
  • X13 is D, E, N, or Q
  • Xi 4 is I, G, A, L, or V.
  • the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 68.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a KD of 5 nM or less ⁇ e.g. 3 nM or less) as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S ec t 0 with a
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICso of 1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.3 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • an IC50 of 0.3 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC 5 o of 0.3 pg/ml or less, and/or
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • (d) is capable of neutralizing in vitro infection of primate cells ⁇ e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.3 pg/ml or less, and
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • (d) is capable of neutralizing in vitro infection of primate cells ⁇ e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the Examples show that the 3H6 heavy chain-only antibody binds strongly to SARS2-S1 B (ECSO of 2.8 ng/ml; Ko of 12.4 nM as measured by biolayer interferometry) and SARS2-S ec to (KD of 5.69 nM as measured by biolayer interferometry), strongly inhibits ACE2 binding to SARS2-S1 B (ICSO of 0.28 pg/ml), potently neutralizes in vitro infection of primate cells by vesicular stomatitis virus pseudotyped with SARS2-S (ICso of 0.082 pg/ml), and potently neutralizes SARS2 virus infection of primate cells (PRNT50 of 0.234 pg/ml).
  • the invention further provides an anti-SARS2-S heavy chain-only antibody that binds to the same epitope as a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 2.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody that competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 2.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 3 for CDR1 of the heavy chain; ii. SEQ ID NO: 4 for CDR2 of the heavy chain; and iii. SEQ ID NO: 5 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a KD of 15 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S ec to with a KD of 10 nM or less (e.g. 6 nM or less) as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICso of 1 pg/ml or less (e.g. 0.3 pg/ml or less).
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 0.1 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control
  • an ICso of 0.1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.25 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.25 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus
  • (b) binds to SARS2-S ec to with a KD of 10 nM or less ⁇ e.g. 6 nM or less) as measured by biolayer interferometry at 25°C, and/or
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 0.1 pg/ml or less, and/or
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control
  • (e) is capable of neutralizing in vitro infection of primate cells ⁇ e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.25 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 0.1 pg/ml or less, and
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • (e) is capable of neutralizing in vitro infection of primate cells ⁇ e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.25 pg/ml or less.
  • the heavy chain-only antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 2.
  • the heavy chain-only antibody comprises an amino acid sequence that is at least 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a heavy chain variable region of the amino acid sequence of SEQ ID NO: 2.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. a sequence that is at least 90% identical to SEQ ID NO: 3 for CDR1 of the heavy chain; ii. a sequence that is at least 90% identical to SEQ ID NO: 4 for CDR2 of the heavy chain; and iii. a sequence that is at least 90% identical to SEQ ID NO: 5 for CDR3 of the heavy chain, wherein the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 2.
  • CDRs complementarity determining regions
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. a sequence that is at least 95% identical to SEQ ID NO: 3 for CDR1 of the heavy chain; ii. a sequence that is at least 95% identical to SEQ ID NO: 4 for CDR2 of the heavy chain; and iii. a sequence that is at least 95% identical to SEQ ID NO: 5 for CDR3 of the heavy chain, wherein the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 2.
  • CDRs complementarity determining regions
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with: i. a sequence consisting of X1X2X3X4X5X6X7X8X9 for CDR1 of the heavy chain, wherein:
  • Xi is F, W orY
  • X 2 is T, S, C, U or M
  • X 3 is F, W orY
  • X 4 is S, C, T, U or M
  • X5 is D, E, N or Q
  • X 6 is H, K or R
  • X 7 is Y, F or W
  • X 8 is M, S, C, T or II
  • X 9 is S, C, T, U or M; ii. a sequence consisting of X1X2X3X4X5X6X7X8X9X10X11X12X13 for CDR2 of the heavy chain, wherein:
  • Xi is S, C, T, U or M
  • X 2 is Y, F or W
  • X 3 is I, A, G, L or V
  • X4 is N, D, E or Q
  • X 5 is S, C, T, U or M
  • X 6 is S, C, T, U or M
  • X 7 is N, D, E or Q
  • X 8 is T, S, C, U or M
  • X 9 is A, G, L, I or V,
  • X10 is I, G, A, L or V
  • X11 is Y, F or W
  • X12 is Y, F or W
  • X13 is A, G, I, L or V; and iii. a sequence consisting of X1X2X3X4X5X6X7X8X9X10 for CDR3 of the heavy chain, wherein:
  • Xi is A, G, I, L or ,
  • X 2 is R, H or K
  • X 3 is H, K or R
  • X4 is D, E, N or Q
  • X5 is D, E, N or Q
  • X 6 is S, C, T, U or M
  • X 7 is G, A, L, V or I
  • X 8 is S, C, T, U or M
  • X 9 is W, F or Y, and
  • X10 is I, A, G, L or V.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a KD of 15 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S ec to with a
  • KD 10 nM or less ⁇ e.g. 6 nM or less) as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICso of 1 pg/ml or less ⁇ e.g. 0.3 pg/ml or less).
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.25 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.25 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (b) binds to SARS2-S ec to with a KD of 10 nM or less (e.g. 6 nM or less) as measured by biolayer interferometry at 25°C, and/or
  • (c) inhibits ACE2 binding to SARS2-SlBwith an ICso of 1 pg/ml or less (e.g. 0.3 pg/ml or less), and/or
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.1 pg/ml or less, and/or
  • (e) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.25 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.25 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (b) binds to SARS2-S ec to with a KD of 10 nM or less (e.g. 6 nM or less) as measured by biolayer interferometry at 25°C,
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.1 pg/ml or less, and
  • (e) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.25 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.25 pg/ml or less.
  • the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 2.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody consisting of two heavy chains, wherein each heavy chain comprises complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 3 for CDR1 of the heavy chain; ii. SEQ ID NO: 4 for CDR2 of the heavy chain; and iii. SEQ ID NO: 5 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • each of the heavy chains comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 2.
  • the Examples show that the 2C8 heavy chain-only antibody binds strongly to SARS2-S1 B (EC 5 O of 7.6 ng/ml; K D of 1.28 pM as measured by biolayer interferometry), strongly inhibits ACE2 binding to SARS2-S1 B (ICso of 1.41 pg/ml), potently neutralizes in vitro infection of primate cells by vesicular stomatitis virus pseudotyped with SARS2-S (IC50 of 0.478 pg/ml), and potently neutralizes SARS2 virus infection of primate cells (PRNT50 of 0.313 pg/ml).
  • the invention further provides an anti-SARS2-S heavy chain-only antibody that binds to the same epitope as a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 27.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody that competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 27.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 28 for CDR1 of the heavy chain; ii. SEQ ID NO: 29 for CDR2 of the heavy chain; and iii. SEQ ID NO: 30 for CDR3 of the heavy chain.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a K D of 1.5 pM or less ⁇ e.g. 1.3 pM or less) as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICso of 1.5 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.5 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control
  • an IC50 of 0.5 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.5 pg/ml or less, and/or
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control)
  • an IC50 of 0.5 pg/ml or less
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC 5 o of 0.5 pg/ml or less, and
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control)
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • the heavy chain-only antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 27.
  • the heavy chain-only antibody comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a heavy chain variable region of the amino acid sequence of SEQ ID NO: 27.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. a sequence that is at least 90% identical to SEQ ID NO: 28 for CDR1 of the heavy chain; ii. a sequence that is at least 90% identical to SEQ ID NO: 29 for CDR2 of the heavy chain; and iii. a sequence that is at least 90% identical to SEQ ID NO: 30 for CDR3 of the heavy chain, wherein the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 27.
  • CDRs complementarity determining regions
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. a sequence that is at least 95% identical to SEQ ID NO: 28 for CDR1 of the heavy chain; ii. a sequence that is at least 95% identical to SEQ ID NO: 29 for CDR2 of the heavy chain; and iii. a sequence that is at least 95% identical to SEQ ID NO: 30 for CDR3 of the heavy chain, wherein the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 27.
  • CDRs complementarity determining regions
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with: i. a sequence consisting of X1X2X3X4X5X6X7X8X9 for CDR1 of the heavy chain, wherein:
  • Xi is F, W orY
  • X 2 is T, S, C, U or M
  • X 3 is V, G, A, I or L
  • X 4 is S, C, T, U or M
  • X 5 is N, D, E or Q
  • X 6 is N, D, E or Q
  • X 7 is Y, F or W
  • Xs is M, S, C, T or II
  • X 9 is A, G, L, I or V; ii. a sequence consisting of X1X2X3X4X5X6X7X8X9X10X11X12X13 for CDR2 of the heavy chain, wherein:
  • Xi is S, C, T, U orM
  • X 2 is V, G, A, I or L
  • X 3 is I, G, A, LorV,
  • X 4 is Y, F or W
  • X 5 is A, G, I, LorV,
  • Xe is N, D, E or Q
  • X 7 is N, D, EorQ,
  • X 8 is D, E, N or Q
  • X 9 is T, S, C, UorM
  • X is Y, F or W
  • X11 is Y, F orW
  • X12 is A, G, I, L or V, and
  • X13 is D, N, E or Q; and iii. a sequence consisting of X ⁇ XsXiXsXeXyXsXgXi 0X11X12X13X14 for CDR3 of the heavy chain, wherein:
  • Xi is S, C, T, U orM
  • X 2 is S, C, T, U orM
  • X 3 is R, H or K
  • X 4 is Y, W or F
  • X 5 is G, A, I, Lor ,
  • X 6 is S, C, T, U orM
  • X 7 is G, A, I, LorV,
  • X 8 is S, C, T, U orM
  • X 9 is E, D, N or Q
  • X10 is E, D, N or Q
  • X11 is L, G, A, I orV
  • X12 is F, Y or W
  • X13 is D, E, N, or Q
  • Xi 4 is I, G, A, L, orV.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a K D of 1.5 pM or less ⁇ e.g. 1.3 pM or less) as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICso of 1.5 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.5 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control
  • an IC50 of 0.5 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.5 pg/ml or less, and/or
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control)
  • an IC50 of 0.5 pg/ml or less
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC 5 o of 0.5 pg/ml or less, and
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control)
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 27.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody consisting of two heavy chains, wherein each heavy chain comprises complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 28 for CDR1 of the heavy chain; ii. SEQ ID NO: 29 for CDR2 of the heavy chain; and iii. SEQ ID NO: 30 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • each of the heavy chains comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 27.
  • the Examples show that the 2H4 heavy chain-only antibody binds strongly to SARS2-S1 B (EC 5 O of 9.5 ng/ml; K D of 95.1 nM as measured by biolayer interferometry), strongly inhibits ACE2 binding to SARS2-S1 B (ICso of 1.22 pg/ml), potently neutralizes in vitro infection of primate cells by vesicular stomatitis virus pseudotyped with SARS2-S (IC50 of 0.269 pg/ml), and potently neutralizes SARS2 virus infection of primate cells (PRNT50 of 0.156 pg/ml). Similar functional properties can be expected to be associated with the heavy chain-only antibodies defined below which share structural and functional characteristics with the 2H4 heavy chain-only antibody.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody that binds to the same epitope as a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 6.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody that competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 6.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 7 for CDR1 of the heavy chain; ii. SEQ ID NO: 8 for CDR2 of the heavy chain; and iii. SEQ ID NO: 9 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a K D of 100 nM or less as measured by biolayer interferometry at 25°C. In some embodiments, the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICso of 1.5 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.3 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control
  • an IC50 of 0.3 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC 5 o of 0.3 pg/ml or less, and/or
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control)
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.3 pg/ml or less, and
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control)
  • an IC50 of 0.3 pg/ml or less
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • the heavy chain-only antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 6.
  • the heavy chain-only antibody comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a heavy chain variable region of the amino acid sequence of SEQ ID NO: 6.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. a sequence that is at least 90% identical to SEQ ID NO: 7 for CDR1 of the heavy chain; ii. a sequence that is at least 90% identical to SEQ ID NO: 8 for CDR2 of the heavy chain; and iii. a sequence that is at least 90% identical to SEQ ID NO: 9 for CDR3 of the heavy chain, wherein the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 6.
  • CDRs complementarity determining regions
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. a sequence that is at least 95% identical to SEQ ID NO: 7 for CDR1 of the heavy chain; ii. a sequence that is at least 95% identical to SEQ ID NO: 8 for CDR2 of the heavy chain; and iii. a sequence that is at least 95% identical to SEQ ID NO: 9 for CDR3 of the heavy chain, wherein the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 6.
  • CDRs complementarity determining regions
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with: i. a sequence consisting of X1X2X3X4X5X6X7X8X9 for CDR1 of the heavy chain, wherein:
  • X 2 is T, S, C, U or M
  • X 3 is F, W orY
  • X 4 is S, C, T, U or M
  • X 5 is D, E, N or Q
  • X 6 is F, W orY
  • X 7 is Y, F or W
  • X 8 is M, S, C, T or II
  • X 9 is Y, F or W; ii. a sequence consisting of X1X2X3X4X5X6X7X8X9X10X11X12X13 for CDR2 of the heavy chain, wherein:
  • Xi is S, C, T, U orM
  • X 2 is Y, F or W
  • X3 is I, G, L, AorV
  • X 4 is S, C, T, U orM
  • X 5 is T, S, C, UorM, Xe is N, D, E or Q
  • X 7 is G, A, I, LorV
  • X 8 is T, S, C, UorM
  • X 9 is T, S, C, UorM
  • X is I, G, A, LorV
  • X11 is Y, F orW
  • X12 is Y, F or W
  • X13 is A, G, I, L or V
  • Xi is A, G, I, Lor ,
  • X 2 is R, H or K
  • X 3 is I, G, A, LorV,
  • X 4 is D, E, N or Q
  • X 5 is S, C, T, U orM
  • X 6 is S, C, T, U orM
  • X 7 is G, A, L
  • Vor I is Q, D, E or Q
  • X 9 is S, C, T, U or M
  • X10 is S, C, T, U orM.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1B with a KD of 100 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICsoof 1.5 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.3 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control
  • an IC50 of 0.3 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.3 pg/ml or less, and/or
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control)
  • an IC50 of 0.3 pg/ml or less
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.3 pg/ml or less, and
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control)
  • an IC50 of 0.3 pg/ml or less
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 6.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody consisting of two heavy chains, wherein each heavy chain comprises complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 7 for CDR1 of the heavy chain; ii. SEQ ID NO: 8 for CDR2 of the heavy chain; and iii. SEQ ID NO: 9 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • each of the heavy chains comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 6.
  • N54Q, N54G, N54L and N54Y variants of the 2H4 heavy chain-only antibody bind to SARS2-S ec to with similarly high affinity to the 2H4 antibody (KD of 10.2-13.0 nM as measured by biolayer interferometry at 25°C). Similar functional properties can be expected to be associated with the heavy chain-only antibodies defined below which share structural and functional characteristics with the 2H4 heavy chain-only antibody (and these N54 mutants).
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 7 for CDR1 of the heavy chain; ii. SEQ ID NO: 65 for CDR2 of the heavy chain; and iii. SEQ ID NO: 9 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a KD of 100 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S ec to with a KD of 15 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICso of 1.5 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 0.3 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control
  • an ICso of 0.3 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody (a) binds to SARS2-S1 B with a K D of 100 nM or less as measured by biolayer interferometry at 25°C, and/or
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.3 pg/ml or less, and/or
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • (e) is capable of neutralizing in vitro infection of primate cells e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.3 pg/ml or less, and
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • (e) is capable of neutralizing in vitro infection of primate cells ⁇ e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • the heavy chain-only antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 64.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody consisting of two heavy chains, wherein each heavy chain comprises complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 7 for CDR1 of the heavy chain; ii. SEQ ID NO: 65 for CDR2 of the heavy chain; and iii. SEQ ID NO: 9 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • each of the heavy chains comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 64.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 7 for CDR1 of the heavy chain; ii. SEQ ID NO: 87 for CDR2 of the heavy chain; and iii. SEQ ID NO: 9 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S ec to with a KD of 15 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICso of 1.5 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC 5 o of 0.3 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC 5 o of 0.3 pg/ml or less, and/or
  • (e) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 0.3 pg/ml or less, and
  • (e) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • the heavy chain-only antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 86.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody consisting of two heavy chains, wherein each heavy chain comprises complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 7 for CDR1 of the heavy chain; ii. SEQ ID NO: 87 for CDR2 of the heavy chain; and iii. SEQ ID NO: 9 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • each of the heavy chains comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 86.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 7 for CDR1 of the heavy chain; ii. SEQ ID NO: 89 for CDR2 of the heavy chain; and iii. SEQ ID NO: 9 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a K D of 100 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S ec to with a KD of 15 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICso of 1.5 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.3 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control
  • an IC50 of 0.3 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.3 pg/ml or less, and/or
  • (e) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) inhibits ACE2 binding to SARS2-SlBwith an ICso of 1.5 pg/ml or less
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.3 pg/ml or less, and
  • (e) is capable of neutralizing in vitro infection of primate cells e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • the heavy chain-only antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 88.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody consisting of two heavy chains, wherein each heavy chain comprises complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 7 for CDR1 of the heavy chain; ii. SEQ ID NO: 89 for CDR2 of the heavy chain; and iii. SEQ ID NO: 9 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • each of the heavy chains comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 88.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 7 for CDR1 of the heavy chain; ii. SEQ ID NO: 91 for CDR2 of the heavy chain; and iii. SEQ ID NO: 9 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a KD of 100 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S ec to with a KD of 15 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICso of 1.5 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.3 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g.
  • VeroE6 cells in a plaque reduction neutralization test by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 0.3 pg/ml or less, and/or
  • (e) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 0.3 pg/ml or less, and
  • the heavy chain-only antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 90.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody consisting of two heavy chains, wherein each heavy chain comprises complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 7 for CDR1 of the heavy chain; ii. SEQ ID NO: 91 for CDR2 of the heavy chain; and iii. SEQ ID NO: 9 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • each of the heavy chains comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 90.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with: i. a sequence consisting of X1X2X3X4X5X6X7X8X9 for CDR1 of the heavy chain, wherein:
  • Xi is F, W or Y
  • X 2 is T, S, C, U or M
  • X 3 is F, W or Y
  • X 4 is S, C, T, U or M
  • X5 is D, E, N or Q
  • X 6 is F, W or Y
  • X 7 is Y, F or W
  • Xs is M, S, C, T or II
  • X 9 is Y, F or W; ii. a sequence consisting of X1X2X3X4X5X6X7X8X9X10X11X12X13 for CDR2 of the heavy chain, wherein:
  • Xi is S, C, T, U or M
  • X 2 is Y, F or W
  • X3 is I, G, L, A or V
  • X 4 is S, C, T, U or M
  • X 5 is T, S, C, U or M
  • X 6 is Q, G or L
  • X 7 is G, A, I, L or V,
  • X 8 is T, S, C, U or M
  • X 9 is T, S, C, U or M, X is I, G, A, L or V,
  • Xn is Y, F or W
  • X12 is Y, F or W
  • X13 is A, G, I, L or V
  • iii a sequence consisting of X1X2X3X4X5X6X7X8X9X10 for CDR3 of the heavy chain, wherein:
  • Xi is A, G, I, L or V
  • X 2 is R, H or K
  • X 3 is I, G, A, L or ,
  • X4 is D, E, N or Q
  • X 5 is S, C, T, U or M
  • X 6 is S, C, T, U or M
  • X 7 is G, A, L, V or I
  • Xs is Q, D, E or Q
  • X9 is S, C, T, U or M, and X is S, C, T, U or M.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a K D of 100 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S ec to with a KD of 15 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICso of 1.5 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.3 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control
  • an IC50 of 0.3 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.3 pg/ml or less, and/or
  • (e) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.3 pg/ml or less, and
  • (e) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.2 pg/ml or less.
  • the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 64.
  • SARS2-S1 B (Group 1 b). Each of these antibodies binds strongly to SARS2-S1 B (EC50 of 5.0-10.7 ng/ml; K D of 4.12 - 38.4 nM as measured by biolayer interferometry), strongly inhibits ACE2 binding to SARS2-S1B (IC50 of 0.83-2.81 pg/ml), potently neutralizes in vitro infection of primate cells by vesicular stomatitis virus pseudotyped with SARS2-S (IC50 of 0.015-0.902 pg/ml), and potently neutralizes SARS2 virus infection of primate cells (PRNT50 of 0.039-0.469 pg/ml). Similar functional properties can be expected to be associated with the heavy chain-only antibodies defined below which share characteristics with these exemplified antibodies.
  • the invention provides an anti-SARS2-S heavy chain-only antibody that competes for binding to SARS2-S with a reference heavy chain-only (I gG 1 ) antibody consisting of two heavy chains, wherein each heavy chain has a heavy chain variable region of the amino acid sequence of one of SEQ ID NOs: 31 , 35, 39, 43, 51 and 55.
  • competition for binding is assessed by biolayer interferometry at 25°C, optionally wherein SARS2-S is bound to the biosensor tip, the reference antibody is bound to the SARS2-S (in binding buffer) to saturation, the binding tip is washed and a second binding step is performed with the test antibody.
  • a second binding step is performed with the reference antibody as a control.
  • a test antibody competes with a reference antibody if the level of binding of the test antibody is ⁇ 30% higher than the control reference antibody.
  • the anti-SARS2-S heavy chain-only antibody does not compete for binding to SARS2-S with a reference heavy chain-only (I gG 1 ) antibody consisting of two heavy chains, wherein each heavy chain has a heavy chain variable region of the amino acid sequence of one of SEQ ID NOs: 47 and 60.
  • competition for binding is assessed by biolayer interferometry at 25°C, optionally wherein SARS2-S is bound to the biosensor tip, the reference antibody is bound to the SARS2-S (in binding buffer) to saturation, the binding tip is washed and a second binding step is performed with the test antibody.
  • a second binding step is performed with the reference antibody as a control.
  • a test antibody competes with a reference antibody if the level of binding of the test antibody is ⁇ 30% higher than the control reference antibody.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a KD of 40 nM or less (e.g. 20 nM or less, such as 10 nM or less) as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICso of 3 pg/ml or less (e.g. an IC50 of 1.5 pg/ml or less).
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 1 pg/ml or less e.g. an ICso of 0.4 pg/ml or less).
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells ⁇ e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.5 pg/ml or less ⁇ e.g. a PRNT50 of 0.1 pg/ml or less).
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (a) binds to SARS2-S1 B with a KD of 40 nM or less e.g. 20 nM or less, such as 10 nM or less) as measured by biolayer interferometry at 25°C, and/or
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC 5 o of 1 pg/ml or less ⁇ e.g. an IC 5 o of 0.4 pg/ml or less), and/or
  • (d) is capable of neutralizing in vitro infection of primate cells ⁇ e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.5 pg/ml or less ⁇ e.g. a PRNT50 of 0.1 pg/ml or less).
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 1 pg/ml or less ⁇ e.g. an ICso of 0.4 pg/ml or less), and
  • (d) is capable of neutralizing in vitro infection of primate cells ⁇ e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.5 pg/ml or less ⁇ e.g. a PRNT50 of 0.1 pg/ml or less).
  • the invention provides an anti-SARS2-S heavy chain-only antibody that binds to the same epitope as a reference heavy chain-only (lgG1) antibody consisting of two heavy chains, wherein each heavy chain has a heavy chain variable region of the amino acid sequence of one of SEQ ID NOs: 31 , 35, 39, 43, 51 and 55.
  • binding to the same epitope is determined by biolayer interferometry at 25°C, optionally wherein SARS2-S is bound to the biosensor tip, the reference antibody is bound to the SARS2-S (in binding buffer) to saturation, the binding tip is washed and a second binding step is performed with the test antibody.
  • a second binding step is performed with the reference antibody as a control.
  • a test antibody binds to the same epitope as a reference antibody if the level of binding of the test antibody is ⁇ 10% higher than the control reference antibody.
  • the anti-SARS2-S heavy chain-only antibody does not compete for binding to SARS2-S with a reference heavy chain-only (I gG 1 ) antibody consisting of two heavy chains, wherein each heavy chain has a heavy chain variable region of the amino acid sequence of one of SEQ ID NOs: 47 and 60.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a KD of 40 nM or less (e.g. 20 nM or less, such as 10 nM or less) as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICso of 3 pg/ml or less (e.g. an IC50 of 1.5 pg/ml or less).
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 1 pg/ml or less (e.g. an IC50 of 0.4 pg/ml or less).
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control
  • an IC50 of 1 pg/ml or less e.g. an IC50 of 0.4 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.5 pg/ml or less (e.g. a PRNT50 of 0.1 pg/ml or less).
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.5 p
  • (b) inhibits ACE2 binding to SARS2-SlBwith an ICso of 3 pg/ml or less (e.g. an ICso of 1.5 pg/ml or less), and/or
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 1 pg/ml or less (e.g. an ICso of 0.4 pg/ml or less), and/or
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.5 pg/ml or less (e.g. a PRNT50 of 0.1 pg/ml or less).
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control)
  • the antibody has a PRNT50 of 0.5 pg/ml or less (e.g. a PRNT50 of 0.1 pg/ml or less).
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 1 pg/ml or less (e.g. an ICso of 0.4 pg/ml or less), and
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.5 pg/ml or less (e.g. a PRNT50 of 0.1 pg/ml or less).
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control)
  • the antibody has a PRNT50 of 0.5 pg/ml or less (e.g. a PRNT50 of 0.1 pg/ml or less).
  • the Examples show that the 6A3 heavy chain-only antibody binds strongly to SARS2-S1 B (ECSO of 6.7 ng/ml; K D of 38.4 nM as measured by biolayer interferometry), strongly inhibits ACE2 binding to SARS2-S1 B (ICSO of 0.83 pg/ml), potently neutralizes in vitro infection of primate cells by vesicular stomatitis virus pseudotyped with SARS2-S (ICso of 0.902 pg/ml), and potently neutralizes SARS2 virus infection of primate cells (PRNT50 of 0.313 pg/ml).
  • Deglycosylation of 6A3 by PNGase F treatment has no impact on 6A3 binding to SARS2-S. Similar functional properties can be expected to be associated with the heavy chain-only antibodies defined below which share structural and functional characteristics with the 6A3 heavy chain-only antibody.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody that binds to the same epitope as a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 55.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody that competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 55.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 56 for CDR1 of the heavy chain; ii. SEQ ID NO: 57 for CDR2 of the heavy chain; and iii. SEQ ID NO: 58 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a KD of 50 nM or less (e.g. 40 nM or less) as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an IC 5 o of 1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 1 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (a) binds to SARS2-S1 B with a KD of 50 nM or less (e.g. 40 nM or less) or less as measured by biolayer interferometry at 25°C, and/or
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC 5 o of 1 pg/ml or less, and/or (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 1 pg/ml or less, and
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control)
  • ICso 1 pg/ml or less
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • the heavy chain-only antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 55.
  • the heavy chain-only antibody comprises an amino acid sequence that is at least 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a heavy chain variable region of the amino acid sequence of SEQ ID NO: 55.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. a sequence that is at least 90% identical to SEQ ID NO: 56 for CDR1 of the heavy chain; ii. a sequence that is at least 90% identical to SEQ ID NO: 57 for CDR2 of the heavy chain; and iii. a sequence that is at least 90% identical to SEQ ID NO: 58 for CDR3 of the heavy chain, wherein the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 55.
  • CDRs complementarity determining regions
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. a sequence that is at least 95% identical to SEQ ID NO: 56 for CDR1 of the heavy chain; ii. a sequence that is at least 95% identical to SEQ ID NO: 57 for CDR2 of the heavy chain; and iii. a sequence that is at least 95% identical to SEQ ID NO: 58 for CDR3 of the heavy chain, wherein the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 55.
  • CDRs complementarity determining regions
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with: i. a sequence consisting of X1X2X3X4X5X6X7X8X9 for CDR1 of the heavy chain, wherein:
  • Xi is L, A, G, I or V
  • X 2 is N, D, E or Q
  • X 3 is V, G, A, I or L
  • X 4 is S, C, T, U or M
  • X 5 is N, D, E or Q
  • X 6 is D, E, N or Q
  • X 7 is Y, F or W
  • X 8 is M, S, C, T or II
  • X 9 is S, C, T, U or M; ii. a sequence consisting of X1X2X3X4X5X6X7X8X9X10X11X12X13 for CDR2 of the heavy chain, wherein:
  • Xi is S, C, T, U or M
  • X 2 is V, G, A, I or L
  • X 3 is I, G, A, L or V
  • X 4 is Y, F or W
  • X 5 is S, C, T, U or M
  • X 6 is G, A, I, L or V,
  • X 7 is G, A, I, L or ,
  • X 8 is N, D, E or Q
  • X 9 is T, S, C, U or M
  • X10 is F, W or Y
  • X11 is Y, F or W
  • X12 is A, G, I, L or V, and
  • X13 is D, N, E or Q; and iii. a sequence consisting of X1X2X3X4X5X6X7X8X9X10X11X12X13 for CDR3 of the heavy chain, wherein:
  • X 2 is S, C, T, U or M
  • X 3 is R, H or K
  • X 4 is Y, W or F
  • X 5 is G, A, I, L or V
  • X 6 is S, C, T, U or M
  • X 7 is G, A, I, L or V,
  • X 8 is D, E, N or Q
  • X9 is D, E, N or Q
  • X10 is L, G, A, I or V
  • X11 is F, W or Y
  • X12 is D, E, N, or Q
  • X13 is I, G, A, L, or .
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a K D of 50 nM or less ⁇ e.g. 40 nM or less) as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICso of 1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 1 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (a) binds to SARS2-S1 B with a KD of 50 nM or less (e.g. 40 nM or less) or less as measured by biolayer interferometry at 25°C, and/or
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 1 pg/ml or less, and/or
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control)
  • an IC50 of 1 pg/ml or less
  • (d) is capable of neutralizing in vitro infection of primate cells ⁇ e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 1 pg/ml or less, and
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • (d) is capable of neutralizing in vitro infection of primate cells ⁇ e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.4 pg/ml or less.
  • the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 23.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody consisting of two heavy chains, wherein each heavy chain comprises complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 24 for CDR1 of the heavy chain; ii. SEQ ID NO: 25 for CDR2 of the heavy chain; and iii. SEQ ID NO: 26 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • each of the heavy chains comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 23.
  • the Examples show that the 7D1 heavy chain-only antibody binds strongly to SARS2-S1 B (EC50 of 5.0 ng/ml; K D of 4.12 nM as measured by biolayer interferometry), strongly inhibits ACE2 binding to SARS2-S1 B (IC50 of 2.81 pg/ml), potently neutralizes in vitro infection of primate cells by vesicular stomatitis virus pseudotyped with SARS2-S (IC50 of 0.136 pg/ml), and potently neutralizes SARS2 virus infection of primate cells (PRNT50 of 0.098 pg/ml).
  • Deglycosylation of 7D1 by PNGase F treatment has no impact on 7D1 binding to SARS2-S. Similar functional properties can be expected to be associated with the heavy chain-only antibodies defined below which share structural and functional characteristics with the 7D1 heavy chain-only antibody.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody that binds to the same epitope as a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 43.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody that competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 43.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 44 for CDR1 of the heavy chain; ii. SEQ ID NO: 45 for CDR2 of the heavy chain; and iii. SEQ ID NO: 46 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a KD of 5 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an IC 5 o of 3 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.2 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control
  • an IC50 of 0.2 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC 5 o of 0.2 pg/ml or less, and/or (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 0.2 pg/ml or less, and
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the heavy chain-only antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 43.
  • the heavy chain-only antibody comprises an amino acid sequence that is at least 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a heavy chain variable region of the amino acid sequence of SEQ ID NO: 43.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. a sequence that is at least 90% identical to SEQ ID NO: 44 for CDR1 of the heavy chain; ii. a sequence that is at least 90% identical to SEQ ID NO: 45 for CDR2 of the heavy chain; and iii. a sequence that is at least 90% identical to SEQ ID NO: 46 for CDR3 of the heavy chain, wherein the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 43.
  • CDRs complementarity determining regions
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. a sequence that is at least 95% identical to SEQ ID NO: 44 for CDR1 of the heavy chain; ii. a sequence that is at least 95% identical to SEQ ID NO: 45 for CDR2 of the heavy chain; and iii. a sequence that is at least 95% identical to SEQ ID NO: 46 for CDR3 of the heavy chain, wherein the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 43.
  • CDRs complementarity determining regions
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with: i. a sequence consisting of X1X2X3X4X5X6X7X8X9 for CDR1 of the heavy chain, wherein:
  • Xi is F, W or Y
  • X 2 is N, D, E or Q
  • X 3 is V, G, A, I or L
  • X 4 is S, C, T, U or M
  • X 5 is S, C, T, U or M
  • X 6 is S, C, T, U or M
  • X 7 is Y, F or W
  • X 8 is M, S, C, T or II
  • X 9 is S, C, T, U or M; ii. a sequence consisting of X1X2X3X4X5X6X7X8X9X10X11X12X13 for CDR2 of the heavy chain, wherein:
  • Xi is S, C, T, U or M
  • X 2 is V, G, A, I or L
  • X 3 is I, G, A, L or V
  • X 4 is Y, F or W
  • X 5 is S, C, T, U or M
  • X 6 is G, A, I, L or V,
  • X 7 is G, A, I, L or ,
  • X 8 is G, A, I, L or V,
  • X 9 is T, S, C, U or M
  • X10 is Y, F or W
  • X11 is Y, F or W
  • X12 is A, G, I, L or V, and
  • X13 is D, N, E or Q; and iii. a sequence consisting of X ⁇ XsX ⁇ XeXyXsXgX XnX ⁇ Xis for CDR3 of the heavy chain, wherein:
  • Xi is A, G, I, L or V
  • X 2 is R, H or K
  • X 3 is G, A, I, L or V,
  • X 4 is W, F or Y
  • X 5 is T, S, C, U or M
  • X 6 is G, A, I, L or V
  • X 7 is V
  • X 8 is T
  • X 9 is A, G, I, L or
  • X is T, S, C, U or M
  • Xu is T, S, C, U or M
  • X12 is G, A, I, L or V
  • X13 is P.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a KD of 5 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICso of 3 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 0.2 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • an ICso of 0.2 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 0.2 pg/ml or less, and/or
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • (d) is capable of neutralizing in vitro infection of primate cells ⁇ e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (c) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 0.2 pg/ml or less, and
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the antibody competes for binding to SARS2-S with a heavy chain-only antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 43.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody consisting of two heavy chains, wherein each heavy chain comprises complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 44 for CDR1 of the heavy chain; ii. SEQ ID NO: 45 for CDR2 of the heavy chain; and iii. SEQ ID NO: 46 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • each of the heavy chains comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 43.
  • N28Q, N28A, N28G and N28L variants of the 7D1 heavy chain-only antibody bind to SARS2-S ec to with similarly high affinity to the 7D1 antibody (KD of 27.9-41 .4 nM as measured by biolayer interferometry at 25°C). Similar functional properties can be expected to be associated with the heavy chain-only antibodies defined below which share structural and functional characteristics with the 7D1 heavy chain-only antibody (and these N28 mutants).
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 67 for CDR1 of the heavy chain; ii. SEQ ID NO: 45 for CDR2 of the heavy chain; and iii. SEQ ID NO: 46 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a KD of 5 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S ec to with a KD of 50 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICso of 3 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.2 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control
  • an IC50 of 0.2 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.2 pg/ml or less, and/or
  • (e) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 0.2 pg/ml or less, and
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • (e) is capable of neutralizing in vitro infection of primate cells e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the heavy chain-only antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 66.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody consisting of two heavy chains, wherein each heavy chain comprises complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 67 for CDR1 of the heavy chain; ii. SEQ ID NO: 45 for CDR2 of the heavy chain; and iii. SEQ ID NO: 46 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • each of the heavy chains comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 66.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 93 for CDR1 of the heavy chain; ii. SEQ ID NO: 45 for CDR2 of the heavy chain; and iii. SEQ ID NO: 46 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a KD of 5 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S ec to with a K D of 50 nM or less ⁇ e.g. 30 nM or less) as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an IC50 of 3 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.2 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (b) binds to SARS2-S ec to with a KD of 50 nM or less ⁇ e.g. 30 nM or less) as measured by biolayer interferometry at 25°C, and/or
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC 5 o of 0.2 pg/ml or less, and/or
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • (e) is capable of neutralizing in vitro infection of primate cells ⁇ e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC 5 o of 0.2 pg/ml or less, and
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • (e) is capable of neutralizing in vitro infection of primate cells ⁇ e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the heavy chain-only antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 92.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody consisting of two heavy chains, wherein each heavy chain comprises complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 93 for CDR1 of the heavy chain; ii. SEQ ID NO: 45 for CDR2 of the heavy chain; and iii. SEQ ID NO: 46 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • each of the heavy chains comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 92.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 95 for CDR1 of the heavy chain; ii. SEQ ID NO: 45 for CDR2 of the heavy chain; and iii. SEQ ID NO: 46 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a KD of 5 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S ec to with a KD of 50 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an ICso of 3 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an ICso of 0.2 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control
  • an ICso of 0.2 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.2 pg/ml or less, and/or
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • (e) is capable of neutralizing in vitro infection of primate cells e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.2 pg/ml or less, and
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control
  • (e) is capable of neutralizing in vitro infection of primate cells ⁇ e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the heavy chain-only antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 94.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody consisting of two heavy chains, wherein each heavy chain comprises complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 95 for CDR1 of the heavy chain; ii. SEQ ID NO: 45 for CDR2 of the heavy chain; and iii. SEQ ID NO: 46 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • each of the heavy chains comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 94.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 97 for CDR1 of the heavy chain; ii. SEQ ID NO: 45 for CDR2 of the heavy chain; and iii. SEQ ID NO: 46 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S1 B with a KD of 5 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody binds to SARS2-S ec to with a KD of 50 nM or less as measured by biolayer interferometry at 25°C.
  • the anti-SARS2-S heavy chain-only antibody inhibits ACE2 binding to SARS2-SlBwith an IC 5 o of 3 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.2 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control
  • an IC50 of 0.2 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • primate cells e.g. VeroE6 cells
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 (e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.2 pg/ml or less, and/or
  • (e) is capable of neutralizing in vitro infection of primate cells ⁇ e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the anti-SARS2-S heavy chain-only antibody is anti-SARS2-S heavy chain-only antibody:
  • (d) is capable of neutralizing in vitro infection of primate cells (e.g. VeroE6 cells) by vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control), optionally with an IC50 of 0.2 pg/ml or less, and
  • primate cells e.g. VeroE6 cells
  • SARS2-S having the sequence of SEQ ID NO: 81 e.g. reducing infection by at least 80% relative to an untreated control
  • (e) is capable of neutralizing in vitro infection of primate cells ⁇ e.g. VeroE6 cells) (in a plaque reduction neutralization test) by SARS2 virus, wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 81 ⁇ e.g. reducing infection by at least 80% relative to an untreated control), optionally wherein the antibody has a PRNT50 of 0.1 pg/ml or less.
  • the heavy chain-only antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 96.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody consisting of two heavy chains, wherein each heavy chain comprises complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 97 for CDR1 of the heavy chain; ii. SEQ ID NO: 45 for CDR2 of the heavy chain; and iii. SEQ ID NO: 46 for CDR3 of the heavy chain.
  • CDRs complementarity determining regions
  • each of the heavy chains comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 96.
  • the invention further provides an anti-SARS2-S heavy chain-only antibody comprising complementarity determining regions (CDRs) with: i. a sequence consisting of X1X2X3X4X5X6X7X8X9 for CDR1 of the heavy chain, wherein:
  • X2 is Q, A, G or L
  • X 3 is V, G, A, I or L
  • X 4 is S, C, T, U orM
  • X 5 is S, C, T, U orM
  • X 6 is S, C, T, U orM
  • X 7 is Y, F or W
  • Xs is M, S, C, T or II

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Virology (AREA)
  • Biochemistry (AREA)
  • Immunology (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pulmonology (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne des anticorps à chaîne lourde uniquement qui reconnaissent la protéine spike du SARS-CoV-2 (SARS2-S). Dans certains modes de réalisation, les anticorps se lient à SARS2-S avec une affinité élevée et/ou inhibent l'infection par le SARS-Cov-2 de cellules humaines. Dans certains modes de réalisation, les anticorps fournissent un moyen de prévention, de traitement ou d'amélioration d'une infection par le SARS2. Dans certains modes de réalisation, les anticorps sont utilisés dans des dosages diagnostiques (p. ex. des dosages sérodiagnostiques pour le SARS2).
PCT/EP2022/075300 2021-09-10 2022-09-12 Anticorps à chaîne lourde uniquement anti-sars-cov-2 (sars2, covid-19) WO2023036986A2 (fr)

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