Antibodies against SARS-COV2 spike protein

Abstract

The invention relates to antibodies useful for the prevention, treatment and / or diagnosis of coronavirus infections, and diseases and / or complications associated with coronavirus infections, including COVID-19.

Description

[0001] ANTIBODIES AGAINST SARS-COV2 SPIKE PROTEIN

[0002] Field of invention

[0003] The invention relates to antibodies useful for the prevention, treatment and / or diagnosis of coronavirus infections, and diseases and / or complications associated with coronavirus infections, including COVID-19.

[0004] Background of the invention

[0005] Since emerging in late 2019 severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is estimated to have led to 757 million infections and 6.9 million deaths. Effective vaccines and increasing herd immunity from natural infection have greatly reduced the mortality from SARS-CoV-2 infection but are less effective at preventing infection. SARS-CoV-2 therefore still causes significant mortality in high-risk groups such as the immunosuppressed or elderly who show reduced or absent responses to vaccination.

[0006] Initially two domains of the SI region of spike, the N-terminal domain (NTD) and the receptor binding domain (RBD), have been described as binding sites for potent neutralizing mAbs. All commercially developed mAbs to date target the RBD (Westendorf et al. Cell Rep 39, 110812 (2022); Weinreich et al. N Engl J Med 384, 238- 251 (2021); Dong, et al bioRxiv (2021)), whilst anti-NTD mAbs are frequently SARS- CoV-2 variant specific because of the extensive mutation of the supersite between variants. Subsequently, another domain of SI, named SD1 was described as a binding site for antibodies that could neutralise infection in vitro, albeit poorly with respect to breadth of variants neutralised or with poor potency as defined by neutralisation IC50 (Hong et al PMID: 35228716, Seow et al PMID: 35981534 and Bianchini et al PMID: 36701425).

[0007] Both RBD and NTD are hot spots of mutation in SARS-CoV-2. RBD mutations can impart selective advantages to the virus, firstly some can increase the affinity to ACE2 and are believed to drive increased transmissibility, the N501 Y mutation found in the Alpha variant is an example of this. Secondly, mutations in the RBD and NTD may also lead to escape from neutralizing antibody responses. As population level immunity from vaccination and natural infection increases there is intense selective pressure to allow the virus to break through pre-existing immunity. Evolution of S has therefore been rapid with many mutations mapping closely to the sites of interaction of potent mAbs in the RBD and NTD. SARS-CoV-2, in a period of 3 years since its emergence, evolved variants that escape all mAbs that have been developed for clinical use. The arrival of Omicron in late 2021 often caused profound drops in neutralization titres in serum from vaccinees and from natural infection, leading Omicron to spread globally with a large wave of infection and become the dominant variant in a matter of weeks.

[0008] However, Omicron has continued to evolve rapidly, BA.1 was replaced by BA.1.1 and BA.2 which were in turn replaced by BA.4 / 5, BA.4.6 and BF.7. Since late 2022, an increasing number of BA.2 sub-variants have begun to cocirculate, with convergent evolution leading to the acquisition of subsets of common mutations in related variants. Currently XBB.1.5 and CH.1.1 are the dominant strains, with frequently several strains cocirculating such as XBF, BQ.1.1, BF.7, showing large differences in frequency in different geographical locations. Despite the evolution of variants that escape polyclonal and monoclonal antibodies, the SD1 domain remains more conserved and is therefore an excellent candidate domain for neutralising antibodies (Bianchini et al PMID: 36701425).

[0009] Therefore, it is an object of the invention to identify further and improved antibodies useful for preventing, treating and / or diagnosing coronavirus infections, and diseases and / or complications associated with coronavirus infections (e.g. COVID-19), especially those caused by the Omicron variants of concern (VoCs) and variants having further mutations in the spike protein of SARS-CoV-2.

[0010] Summary of the invention

[0011] The inventors have identified 4 potent spike binding mAbs from vaccinees who suffered vaccine breakthrough infections with Omicron sublineages BA.4 / 5.

[0012] Accordingly, the invention provides an antibody capable of binding to the spike protein of coronavirus SARS-CoV-2, wherein the antibody comprises the six CDRs of antibody SD1-1, SD1-2, SD1-3 or SD1-6 described herein.

[0013] In a further embodiment, the invention provides an antibody capable of binding to the spike protein of coronavirus SARS-CoV-2, wherein the antibody comprises CDRH1, CDRH2 and CDRH3 from a first antibody selected from one of antibodies SD1-1, SD1-2, SD1-3 or SD1-6 and CDRL1, CDRL2 and CDRL3 from a second antibody selected from another of antibodies SD1-1, SD1-2, SD1-3 or SD1-6.

[0014] In a further embodiment, the invention provides one or more polynucleotides encoding one or both of the heavy chain and / or light chain of an antibody according to the invention, one or more vectors comprising a polynucleotide of the invention, or a host cell comprising one or more polynucleotides or vectors of the invention.

[0015] In a further embodiment, the invention provides a method for producing an antibody that is capable of binding to the spike protein of coronavirus SARS-CoV-2, the method comprising culturing the host cell and isolating the antibody from said culture.

[0016] In a further embodiment, the invention provides a pharmaceutical composition comprising: (a) the antibody, and (b) at least one pharmaceutically acceptable diluent or carrier.

[0017] In a further embodiment, the invention provides the antibody or the pharmaceutical composition for use in a method of treatment of a human or animal by therapy, or for use in a method of treating or preventing coronavirus infection, or a disease or complication associated with coronavirus infection.

[0018] In a further embodiment, the invention provides a method of treating or preventing coronavirus infection, or a disease or complication associated with coronavirus infection in a subject, comprising administering a therapeutically effective amount of the antibody or the pharmaceutical composition to said subject.

[0019] In a further embodiment, the invention provides a method of identifying the presence of coronavirus, or a protein fragment thereof, in a sample, comprising: (i) contacting the sample with the antibody; and (ii) detecting the presence or absence of an antibody-antigen complex, wherein the presence of the antibody-antigen complex indicates the presence of coronavirus, or a fragment thereof, in the sample.

[0020] In a further embodiment, the invention provides a method of treating or preventing coronavirus infection, or a disease or complication associated therewith, in a subject, the method comprising identifying the presence of coronavirus according to the method above, and treating the subject with the antibody, an anti-viral drug or an anti-inflammatory agent.

[0021] In a further embodiment, the invention provides the use of the antibody or the pharmaceutical composition for preventing, treating and / or diagnosing coronavirus infection, or a disease or complication associated therewith.

[0022] In a further embodiment, the invention provides the use of the antibody or the pharmaceutical composition for the manufacture of a medicament for treating or preventing coronavirus infection, or a disease or complication associated therewith. Brief description of the figures

[0023] Figure 1. Neutralisation assays against SARS-CoV-2 variants. (A) Pseudovirus neutralisation curves of SD1-2 against Victoria (an early pandemic strain), Alpha, Beta, Gamma, Delta, BA. l, BA.2, BA.4 / 5, BA.2.75, BA.2.75.2, BA.2.3.20, BA.2.10.4, and BA.4.6. IC50 values shown in table 4. (B) Pseudovirus neutralisation curves of SD1-2 against BF.7, B J.1, BN. l, BN.1.2, BQ. l, BQ.l, BQ.1.1, SBS.l, CA.3.1, CH.1.1, CK. l, DS. l, EG.l, FK. l, XBB, XBB. l, XBB.1.16, XBB.1.16.1, XBB.1.5 and XBF. IC50 values shown in table 4 . (C) Neutralisation curves of SD1-2 against authentic virus Victoria, Alpha, Beta, Gamma, Delta, BA. l, BA.1.1, BA.2, BA.2.12.1, BA.2.75, BA.2.75.2, BA.2.75.5, BA.2.3.20, BA.4.6, BA.5, BQ. l, BQ.1.1, BN.l, and XBB.1.5. IC50 values shown in table 5.

[0024] Figure 2. Neutralisation assays against SARS-CoV-2 variants. (A) Pseudovirus neutralisation curves of SD1-6 against Alpha, Victoria (an early pandemic strain), XBB.1.16, XBB.1.16.1, XBB.1.5, XBB.1.5.10 and XBB.2.3. IC50 values shown in table 6 (B) Neutralisation curves of SD1-6 against authentic virus Alpha, BA.l, BA.1.1, BA.2, BA.2.12.1, BA.2.3.20, BA.2.75, BA.2.75.2, BA.4.6, Beta, BN.l, BQ.l, BQ.1.1, Delta, Victoria and XBB.1.5. IC50 values shown in table 7.

[0025] Figure 3. Neutralisation assays against SARS-CoV-2 variant XBB.1.5.70. (A) Pseudovirus neutralisation curves of SD1-2 against XBB.1.5.70. (B) Pseudovirus neutralisation curves of SD1-6 against XBB.1.5.70.

[0026] Detailed description of the invention

[0027] Antibodies of the invention

[0028] An antibody of the invention specifically binds to the spike protein of SAR-CoV-2. In particular, it specifically binds to the SI subunit of the spike protein. Preferably, it binds to the SD1 domain of the SI subunit.

[0029] An antibody of the invention may comprise all six CDRs of antibody SD1-1, SD1- 2, SD1-3, or SD1-6. The antibody may comprise a heavy chain variable domain comprising or consisting of an amino acid sequence having at least 80% sequence identity, such as at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity, to the heavy chain variable domain of antibody SD1-1, SD1-2, SD1-3 or SD1-6. The antibody may comprise a light chain variable domain comprising or consisting of an amino acid sequence having at least 80% sequence identity, such as at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity, to the light chain variable domain of antibody SD1-1, SD1-2, SD1-3 or SD1-6. The antibody may comprise a heavy chain variable domain and a light chain variable domain comprising or consisting of an amino acid sequence having at least 80% sequence identity, such as at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity, to the heavy chain variable domain and light chain domain, respectively, of antibody SD1-1, SD1-2, SD1-3 or SD1-6. The antibody may comprise mutations in the framework regions of the variable domains compared to the sequences of antibody SD1-1, SD1-2, SD1-3 or SD1-6, as shown in Table 1. For example, the antibody may comprise a heavy chain variable domain comprising the CDRH1, CDRH2 and CDRH3 of an antibody in Table 1, and a light chain variable domain comprising the CDRL1, CDRL2 and CDRL3 of the antibody in Table 1, wherein the heavy chain variable domain and the light chain variable domain comprises or consists of an amino acid sequence having at least 80% sequence identity, such as at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity, to the heavy chain variable domain and light chain variable domain, respectively of the antibody in Table 1. The antibody may be any one of the antibodies in Table 1.

[0030] Table 1 lists 4 individual antibodies that were identified from recovered BA.4 / 5 SARS-CoV-2 infected patients. Table 1 also lists the SEQ ID NOs for the heavy chain variable domain and light chain variable domain nucleotide and amino acid sequences, and the complementarity determining regions (CDRs) of the variable domains, of each of the antibodies.

[0031] The antibody in Table 1 may be selected from the group consisting of SD1-1, SD1- 2, SD1-3 and SD1-6. These antibodies were surprisingly found to retain strong neutralisation of authentic viruses and pseudoviral constructs of multiple SARS-CoV-2 variant strains, including strains selected from Victoria, Alpha, Beta, Gamma, Delta, BA. l, BA.1.1, BA.2, BA.2.12.1, BA.4 / 5, BA.2.75, BA.2.75.2, BA.2.75.5, BA.2.3.20, BA.2.10.4, BA.4.6, BA.5, BQ. l, BQ.1.1, DS. l, CK. l, EG.l, FK. l BN. l, BN.1.2.1, BS. l, BJ. l, BF.7, CH.1.1, CA.3.1, XBB, XBB. l, XBB.1.5, XBB.2.3 XBB.1.5.10, XBB.1.16, XBB.1.16.1, XBF, and XBB.1.5.70.

[0032] The neutralisation data presented herein were performed in vitro and may underestimate in vivo neutralization due to antibody dependent cell mediated cytotoxicity and complement activity. In one embodiment, the antibody in Table 1 may be SD1-2. SD1-2 was found to neutralise the SARS-CoV-2 variant strains Victoria, Alpha, Beta, Gamma, Delta, BA.l, BA.2, 75, BA.2.75.2, BA.2.75.5, BA.2.10.4, BA.2.3.20, BA.4.6, BA.4 / 5, BA.5, BQ.l, BQ.1.1, BN.l, DS.l, CK.l, BN.1.2.1, BS.l, BJ.l, BF.7, CH.1.1, CA.3.1, XBB, XBB.l, XBB.1.5, XBB.1.16, XBB.1.16.1, XBF, FK.l, EG.l, and XBB.1.5.70.

[0033] In one embodiment, an antibody of the invention may comprise a CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs: 20, 21 and 22, respectively, and a CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOs: 29, 30 and 31, respectively. In one embodiment, an antibody of the invention may comprise a heavy chain variable domain comprising or consisting of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the heavy chain variable domain of antibody SD1-2 (i.e. SEQ ID NO: 11). In one embodiment, an antibody of the invention may comprise a light chain variable domain comprising or consisting of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the light chain variable domain of antibody SD1-2 (i.e. SEQ ID NO: 12). In one embodiment, an antibody of the invention may comprise a heavy chain variable domain and a light chain variable domain comprising or consisting of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the heavy chain variable domain and light chain variable domain, respectively, of antibody SD1-2 (i.e. SEQ ID NOs: 11 and 12, respectively). In one embodiment, an antibody of the invention may comprise a heavy chain variable domain comprising a CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs: 20, 21 and 22, respectively, and a CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOs: 29, 30 and 31, respectively, wherein the heavy chain variable domain and the light chain variable domain comprises or consists of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the heavy chain variable domain and light chain variable domain, respectively, of antibody SD1-2 (i.e. SEQ ID NOs: 11 and 12, respectively). In one embodiment, the antibody may be a full-length antibody, for example, the antibody may comprise a heavy chain variable domain and a light chain variable domain as set out in SEQ ID NOs: 11 and 12, respectively, and a constant region, such as an IgA, IgD, IgE, IgG (IgGl, IgG2, IgG3 or IgG4) or IgM constant region.

[0034] In some embodiments, an antibody of the invention may comprise the heavy chain of SD1-2, and not the light chain of SD1-2. The heavy chain domain of SD 1-2 is derived from a IGHV3-23 v-region. The inventors have previously demonstrated that switching of the heavy chains and light chains between antibodies derived from the same v-region may result in an antibody that is particularly useful with the invention (Dejnirattisai et al. 2021, PMID: 33852911). For example, the antibody may comprise a CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs: 20, 21 and 22, respectively. The antibody may comprise a heavy chain variable domain comprising or consisting of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the heavy chain variable domain of antibody SD1-2 (i.e. SEQ ID NO: 11). The antibody may comprise a heavy chain variable domain comprising or consisting of SEQ ID NO: 11.

[0035] Alternatively, in an embodiment of the invention, the antibody may comprise the light chain of SD1-2, and not the heavy chain of SD1-2. The light chain domain of SD1-2 is derived from an IGLV3-1 region. For example, the antibody may comprise a CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOs: 29, 30 and 31, respectively. The antibody may comprise a light chain variable domain comprising or consisting of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the light chain variable domain of antibody SD1-2 (i.e. SEQ ID NO: 12). The antibody may comprise a light chain variable domain comprising or consisting of SEQ ID NO: 12.

[0036] In one embodiment, the antibody in Table 1 may be SD1-1. In one embodiment, an antibody of the invention may comprise a CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs: 17, 18 and 19, respectively, and a CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOs: 26, 27 and 28, respectively. In one embodiment, an antibody of the invention may comprise a heavy chain variable domain comprising or consisting of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the heavy chain variable domain of antibody SD1-1 (i.e. SEQ ID NO: 9). In one embodiment, an antibody of the invention may comprise a light chain variable domain comprising or consisting of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the light chain variable domain of antibody SD1-1 (i.e. SEQ ID NO: 10). In one embodiment, an antibody of the invention may comprise a heavy chain variable domain and a light chain variable domain comprising or consisting of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the heavy chain variable domain and light chain variable domain, respectively, of antibody SD1-1 (i.e. SEQ ID NOs: 9 and 10, respectively). In one embodiment, an antibody of the invention may comprise a heavy chain variable domain comprising a CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs: 17, 18 and 19, respectively, and a CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOs: 26, 27 and 28, respectively, wherein the heavy chain variable domain and the light chain variable domain comprises or consists of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the heavy chain variable domain and light chain variable domain, respectively, of antibody SD1-1 (i.e. SEQ ID NOs: 9 and 10, respectively). In one embodiment, the antibody may be a full-length antibody, for example, the antibody may comprise a heavy chain variable domain and a light chain variable domain as set out in SEQ ID NOs: 9 and 10, respectively, and a constant region, such as an IgA, IgD, IgE, IgG (IgGl, IgG2, IgG3 or IgG4) or IgM constant region.

[0037] In some embodiments, an antibody of the invention may comprise the heavy chain of SD1-1, and not the light chain of SD1-1. The heavy chain domain of SD1-1 is derived from an IGHV5-51*03 region. The inventors have previously demonstrated that switching of the heavy chains and light chains between antibodies derived from the same v-region may result in an antibody that is particularly useful with the invention (Dejnirattisai 2021, PMID: 33852911).

[0038] For example, the antibody may comprise a CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs: 17, 18 and 19, respectively. The antibody may comprise a heavy chain variable domain comprising or consisting of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the heavy chain variable domain of antibody SD1-1 (i.e. SEQ ID NO: 9). The antibody may comprise a heavy chain variable domain comprising or consisting of SEQ ID NO: 9.

[0039] Alternatively, in an embodiment of the invention, the antibody may comprise the light chain of SD1-1, and not the heavy chain of SD1-1. The light chain domain of SD1-1 is derived from an IGKV1-39*O1 or IGKV1-39D*O1 region. For example, the antibody may comprise a CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID Nos 26, 27 and 28, respectively. The antibody may comprise a light chain variable domain comprising or consisting of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the light chain variable domain of antibody SD1-1 (i.e. SEQ ID NO: 10). The antibody may comprise a light chain variable domain comprising or consisting of SEQ ID NO: 10.

[0040] In one embodiment, the antibody in Table 1 may be SD1-3. In one embodiment, an antibody of the invention may comprise a CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs: 23, 24 and 25, respectively, and a CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOs: 32, 33 and 34, respectively. In one embodiment, an antibody of the invention may comprise a heavy chain variable domain comprising or consisting of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the heavy chain variable domain of antibody SD1-3 (i.e. SEQ ID NO: 13). In one embodiment, an antibody of the invention may comprise a light chain variable domain comprising or consisting of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the light chain variable domain of antibody SD1-3 (i.e. SEQ ID NO: 14). In one embodiment, an antibody of the invention may comprise a heavy chain variable domain and a light chain variable domain comprising or consisting of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the heavy chain variable domain and light chain variable domain, respectively, of antibody SD1-3 (i.e. SEQ ID NOs: 13 and 14, respectively). In one embodiment, an antibody of the invention may comprise a heavy chain variable domain comprising a CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs: 23, 24 and 25, respectively, and a CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOs: 32, 33 and 34, respectively, wherein the heavy chain variable domain and the light chain variable domain comprises or consists of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the heavy chain variable domain and light chain variable domain, respectively, of antibody SD1-3 (i.e. SEQ ID NOs: 13 and 14, respectively). In one embodiment, the antibody may be a full-length antibody, for example, the antibody may comprise a heavy chain variable domain and a light chain variable domain as set out in SEQ ID NOs: 13 and 14, respectively, and a constant region, such as an IgA, IgD, IgE, IgG (IgGl, IgG2, IgG3 or IgG4) or IgM constant region.

[0041] In some embodiments, an antibody of the invention may comprise the heavy chain of SD1-3, and not the light chain of SD1-3. The heavy chain domain of SD1-3 is derived from an IGHV1 -46*01 or IGHV1 -46*02 region. The inventors have previously demonstrated that switching of the heavy chains and light chains between antibodies derived from the same v-region may result in an antibody that is particularly useful with the invention (Dejnirattisai 2021, PMID: 33852911).

[0042] For example, the antibody may comprise a CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs: 23, 24 and 25, respectively. The antibody may comprise a heavy chain variable domain comprising or consisting of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the heavy chain variable domain of antibody SD1-3 (i.e. SEQ ID NO: 13). The antibody may comprise a heavy chain variable domain comprising or consisting of SEQ ID NO: 13.

[0043] Alternatively, in an embodiment of the invention, the antibody may comprise the light chain of SD1-3, and not the heavy chain of SD1-3. The light chain domain of SD1-3 is derived from an IGLV7-46*01 region. For example, the antibody may comprise a CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOs: 32, 33 and 34, respectively. The antibody may comprise a light chain variable domain comprising or consisting of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the light chain variable domain of antibody SD1-3 (i.e. SEQ ID NO: 14). The antibody may comprise a light chain variable domain comprising or consisting of SEQ ID NO: 14.

[0044] In one embodiment, the antibody in Table 1 may be SD1-6. SD1-6 was found to neutralise the SARS-CoV-2 variant strains Victoria (an early pandemic strain), Alpha, Beta, Delta, BA.l, BA.2.12.1, BA.4.6, BN.l, BQ.l, BA.1.1., BA.2, BA.2.3.20, BA.2.75, BA.2.75.2, BQ1.1 XBB.1.5, XBB.1.5.10, XBB.1.16, XBB.1.16.1 XBB.2.3, and XBB.1.5.70. In one embodiment, an antibody of the invention may comprise a CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs: 20, 21 and 22, respectively, and a CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOs: 29, 30 and 31, respectively. In one embodiment, an antibody of the invention may comprise a heavy chain variable domain comprising or consisting of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the heavy chain variable domain of antibody SD1-6 (i.e. SEQ ID NO: 15). In one embodiment, an antibody of the invention may comprise a light chain variable domain comprising or consisting of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the light chain variable domain of antibody SD1-6 (i.e. SEQ ID NO: 16). In one embodiment, an antibody of the invention may comprise a heavy chain variable domain and a light chain variable domain comprising or consisting of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the heavy chain variable domain and light chain variable domain, respectively, of antibody SD1-6 (i.e. SEQ ID NOs: 15 and 16, respectively). In one embodiment, an antibody of the invention may comprise a heavy chain variable domain comprising a CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs: 20, 21 and 22, respectively, and a CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOs: 29, 30 and 31, respectively, wherein the heavy chain variable domain and the light chain variable domain comprises or consists of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the heavy chain variable domain and light chain variable domain, respectively, of antibody SD1-6 (i.e. SEQ ID NOs: 15 and 16, respectively). In one embodiment, the antibody may be a full-length antibody, for example, the antibody may comprise a heavy chain variable domain and a light chain variable domain as set out in SEQ ID NOs: 15 and 16, respectively, and a constant region, such as an IgA, IgD, IgE, IgG (IgGl, IgG2, IgG3 or IgG4) or IgM constant region.

[0045] In some embodiments, an antibody of the invention may comprise the heavy chain of SD1-6, and not the light chain of SD1-6. The heavy chain domain of SD 1-6 is derived from an IGHV3-23*04 region. The inventors have previously demonstrated that switching of the heavy chains and light chains between antibodies derived from the same v-region may result in an antibody that is particularly useful with the invention (Dejnirattisai 2021, PMID: 33852911).

[0046] For example, the antibody may comprise a CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs: 20, 21 and 22, respectively. The antibody may comprise a heavy chain variable domain comprising or consisting of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the heavy chain variable domain of antibody SD1-6 (i.e. SEQ ID NO: 15). The antibody may comprise a heavy chain variable domain comprising or consisting of SEQ ID NO: 15.

[0047] Alternatively, in an embodiment of the invention, the antibody may comprise the light chain of SD1-6, and not the heavy chain of SD1-6. The light chain domain of SD1-6 is derived from an IGLV3-l*01 region. For example, the antibody may comprise a CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOs: 29, 30 and 31, respectively. The antibody may comprise a light chain variable domain comprising or consisting of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the light chain variable domain of antibody SD1-6 (i.e. SEQ ID NO: 16). The antibody may comprise a light chain variable domain comprising or consisting of SEQ ID NO: 16.

[0048] Mixed chain antibodies of the invention

[0049] An antibody of the invention may comprise a light chain variable domain comprising CDRL1, CDRL2 and CDRL3 from a first antibody in Table 1 and a heavy chain variable domain comprising CDRH1, CDRH2 and CDRH3 from a second antibody in Table 1, with the proviso that the first and second antibodies are different. Such antibodies are referred to as mixed chain antibodies herein.

[0050] Examples of the mixed chain antibodies useful with the invention are provided in Table 3. Table 3 shows examples of mixed chain antibodies generated from antibodies in Table 1.

[0051] Hence, in one embodiment, an antibody of the invention comprises a heavy chain variable domain comprising CDRH1, CDRH2 and CDRH3 from a first antibody in Table 1 and a light chain variable domain comprising CDRL1, CDRL2 and CDRL3 from a second antibody in Table 1, with the proviso that the first and second antibodies are different. The antibody may comprise a heavy chain variable domain amino acid sequence having at least 80% sequence identity to the heavy chain variable domain from a first antibody in Table 1, and a light chain variable domain amino acid sequence having at least 80% sequence identity to the light chain variable domain from a second antibody in Table 1, with the proviso that the first and second antibodies are different. For example, the antibody may comprise a heavy chain variable domain comprising or consisting of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the heavy chain variable domain of an antibody in Table 1, and a light chain variable domain comprising or consisting of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the light chain variable domain of an antibody in Table 1, with the proviso that the first and second antibodies are different. In some embodiments, an antibody of the invention comprises a heavy chain variable domain comprising CDRH1, CDRH2 and CDRH3 from a first antibody in Table 1 and a light chain variable domain comprising CDRL1, CDRL2 and CDRL3 from a second antibody in Table 1, and comprise a heavy chain variable domain comprising or consisting of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the heavy chain variable domain of the first antibody in Table 1, and a light chain variable domain comprising or consisting of an amino acid sequence having >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity to the light chain variable domain of the second antibody in Table 1, with the proviso that the first and second antibodies are different.

[0052] The antibody in Table 1 may be selected from the group consisting of: SD1-1, SD1-2, SD1-3 and SD1-6.

[0053] In one embodiment, the first antibody and the second antibody are SD1-1 and SD1-

[0054] 2. The resulting mixed chain antibodies are set out in Table 3. Hence, the antibody of the invention may comprise six CDRs (CDRH1-3 and CDRL1-3): three from a variable domain of SD1-1 and three from a variable domain of SD1-2, and / or a heavy chain variable domain and a light chain variable domain, each comprising or consisting of an amino acid sequence having at least 80% (e.g. >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the corresponding variable domain of SD1-1 and SD1-2.

[0055] In one embodiment, the first antibody and the second antibody SD1-1 and SD1-3. Hence, the antibody of the invention may comprise six CDRs (CDRH1-3 and CDRL1-3): three from a variable domain of SD1-1 and three from a variable domain of SD1-3, and / or a heavy chain variable domain and a light chain variable domain, each comprising or consisting of an amino acid sequence having at least 80% (e.g. >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to corresponding variable domain of SD1- 1 and SD1-2.

[0056] In one embodiment, the first antibody and the second antibody SD1-1 and SD1-6. Hence, the antibody of the invention may comprise six CDRs (CDRH1-3 and CDRL1-3): three from a variable domain of SD1-1 and three from a variable domain of SD1-6, and / or a heavy chain variable domain and a light chain variable domain, each comprising or consisting of an amino acid sequence having at least 80% (e.g. >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to corresponding variable domain of SD1- 1 and SD1-2.

[0057] In one embodiment, the first antibody and the second antibody are SD1-2 and SD1-

[0058] 3. Hence, the antibody of the invention may comprise six CDRs (CDRH1-3 and CDRL1- 3): three from a variable domain of SD1-2 and three from a variable domain of SD1-3, and / or a heavy chain variable domain and a light chain variable domain, each comprising or consisting of an amino acid sequence having at least 80% sequence identity to the corresponding variable domain of corresponding variable domain of SD1-1 and SD1-3. In one embodiment, the first antibody and the second antibody are SD1-2 and SD1- 6. Hence, the antibody of the invention may comprise six CDRs (CDRH1-3 and CDRL1- 3): three from a variable domain of SD1-2 and three from a variable domain of SD1-6, and / or a heavy chain variable domain and a light chain variable domain, each comprising or consisting of an amino acid sequence having at least 80% sequence identity to the corresponding variable domain of corresponding variable domain of SD1-2 and SD1-6.

[0059] In one embodiment, the first antibody and the second antibody are SD1-3 and SD1- 6. Hence, the antibody of the invention may comprise six CDRs (CDRH1-3 and CDRL1- 3): three from a variable domain of SD1-3 and three from a variable domain of SD1-6, and / or a heavy chain variable domain and a light chain variable domain, each comprising or consisting of an amino acid sequence having at least 80% sequence identity to the corresponding variable domain of corresponding variable domain of SD1-3 and SD1-6.

[0060] The constant region domains of an antibody molecule of the invention, if present, may be selected having regard to the proposed function of the antibody molecule, and in particular the effector functions which may be required. For example, the constant region domains may be human IgA, IgD, IgE, IgG or IgM domains. Typically, the constant regions are of human origin. In particular, human IgG (i.e. IgGl, IgG2, IgG3 or IgG4) constant region domains may be used. Typically, the constant region is a human IgGl constant region.

[0061] Properties of the antibodies of the invention

[0062] An antibody of the invention may be or may comprise a modification from the amino acid sequence of an antibody in Table 1 or 3, whilst maintaining the activity and / or function of the antibody. The modification may a substitution, deletion and / or addition. For example, the modification may comprise 1, 2, 3, 4, 5, up to 10, up to 20, up to 30 or more amino acid substitutions and / or deletions from the amino acid sequence of an antibody in Table 1 or 3. For example, the modification may comprise an amino acid substituted with an alternative amino acid having similar properties. Some properties of the 20 main amino acids, which can be used to select suitable substituents, are as follows:

[0063] The modification may comprise a derivatised amino acid, e.g. a labelled or nonnatural amino acid, providing the function of the antibody is not significantly adversely affected.

[0064] Modification of antibodies of the invention as described above may be prepared during synthesis of the antibody or by post-production modification, or when the antibody is in recombinant form using the known techniques of site-directed mutagenesis, random mutagenesis, or enzymatic cleavage and / or ligation of nucleic acids.

[0065] Antibodies of the invention may be modified (e.g. as described above) to improve the potency of said antibodies or to adapt said antibodies to new SARS-CoV-2 variants. The modifications may be amino acid substitutions to adapt the antibody to substitutions in a virus variant. For example, the known mode of binding of an antibody to the spike protein (e.g. by crystal structure determination, or modelling) may be used to identify the amino acids of the antibody that interact with the substitution in the virus variant. This information can then be used to identify possible substitutions of the antibody that will compensate for the change in the epitope characteristics. For example, a substitution of a hydrophobic amino acid in the spike protein to a negatively changes amino acid may be compensated by substituting the amino acid from the antibody that interacts with said amino acid in the spike protein to a positively charged amino acid. Methods for identifying residues of an antibody that may be substituted are encompassed by the present disclosure, for example, by determining the structure of antibody-antigen complexes as described herein.

[0066] The antibodies of the invention may contain one or more modifications to increase their cross-lineage neutralisation property.

[0067] The term 'antibody' as used herein may relate to whole antibodies (i.e. comprising the elements of two heavy chains and two light chains inter-connected by disulphide bonds) as well as antigen-binding fragments thereof. Antibodies typically comprise immunologically active portions of immunoglobulin (Ig) molecules, i.e., molecules that contain an antigen binding site that specifically binds (immunoreacts with) an antigen. By "specifically binds" or "immunoreacts with", it is meant that the antibody reacts with one or more antigenic determinants of the desired antigen and does not react with other polypeptides. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and at least one heavy chain constant region. Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Antibodies may include, but are not limited to, polyclonal, monoclonal, chimeric, dAb (domain antibody), single chain, Fab, Fab’ and F(ab’)2 fragments, scFvs, and Fab expression libraries.

[0068] An antibody of the invention may be a monoclonal antibody. Monoclonal antibodies (mAbs) of the invention may be produced by a variety of techniques, including conventional monoclonal antibody methodology, for example those disclosed in “Monoclonal Antibodies: a manual of techniques” (Zola H, 1987, CRC Press) and in “Monoclonal Hybridoma Antibodies: techniques and applications” (Hurrell JGR, 1982 CRC Press).

[0069] An antibody of the invention may be multispecific, such as bispecific. A bispecific antibody of the invention binds two different epitopes. The epitopes may be in the same protein (e.g. two epitopes in spike protein of SARS-CoV-2) or different proteins (e.g. one epitope in spike protein and one epitope in another protein (such as coat protein) of SARS- CoV-2).

[0070] In one embodiment, a bispecific antibody of the invention may bind to two separate epitopes on the spike protein of SARS-CoV-2. For example, the bispecific antibody may bind to a first epitope on the SD1 of the spike protein, and a second epitope on the NTD of the spike protein or the RBD of the spike protein. Alternatively, the bispecific antibody may bind to two different epitopes in the SD1 domain of the spike protein.

[0071] One or more (e.g. two) antibodies of the invention can be coupled to form a multispecific (e.g. bispecific) antibody. Methods to prepare multispecific, e.g. bispecific, manufactured dimeric IgA or manufactured IgM antibodies are well known in the art.

[0072] An antibody may be selected from the group consisting of single chain antibodies, single chain variable fragments (scFvs), variable fragments (Fvs), fragment antigenbinding regions (Fabs), recombinant antibodies, monoclonal antibodies, fusion proteins comprising the antigen-binding domain of a native antibody or an aptamer, single-domain antibodies (sdAbs), also known as VHH antibodies, nanobodies (Camelid-derived singledomain antibodies), shark IgNAR-derived single-domain antibody fragments called VNAR, diabodies, triabodies, Anticalins, aptamers (DNA or RNA) and active components or fragments thereof.

[0073] The constant region domains of an antibody molecule of the invention, if present, may be selected having regard to the proposed function of the antibody molecule, and in particular the effector functions which may be required. For example, the constant region domains may be human IgA, IgD, IgE, IgG or IgM domains. Typically, the constant regions are of human origin. In particular, human IgG (i.e. IgGl, IgG2, IgG3 or IgG4) constant region domains may be used. Typically, the constant region is a human IgGl constant region.

[0074] The light chain constant region may be either lambda or kappa.

[0075] Antibodies of the invention may be mono-specific or multi-specific (e.g. bispecific). A multi-specific antibody comprises at least two different variable domains, wherein each variable domain is capable of binding to a separate antigen or to a different epitope on the same antigen.

[0076] An antibody of the invention may be a chimeric antibody, a CDR-grafted antibody, a nanobody, a human or humanised antibody. Typically, the antibody is a human antibody. Fully human antibodies are those antibodies in which the variable regions and the constant regions (where present) of both the heavy and the light chains are all of human origin, or substantially identical to sequences of human origin, but not necessarily from the same antibody.

[0077] The antibody of the invention may be a full-length antibody. For example, the antibody may comprise a heavy chain variable domain of an antibody in Table 1, a light chain variable domain of an antibody in Table 1, and a constant region, such as an IgA, IgD, IgE, IgG (IgGl, IgG2, IgG3 or IgG4) or IgM constant region.

[0078] The antibody of the invention may be an antigen-binding fragment. An antigenbinding fragment of the invention binds to the same epitope of the parent antibody, i.e. the antibody from which the antigen-binding fragment is derived. An antigen-binding fragment of the invention typically retains the parts of the parent antibody that interact with the epitope. The antigen-binding fragment typically comprise the complementaritydetermining regions (CDRs) that interact with the antigen, such as one, two, three, four, five or six CDRs. In some embodiments, the antigen-binding fragment further comprises the structural scaffold surrounding the CDRs of the parent antibody, such as the variable region domains of the heavy and / or light chains. Typically, the antigen-binding fragment retains the same or similar binding affinity to the antigen as the parent antibody.

[0079] An antigen-binding fragment does not necessarily have an identical sequence to the parent antibody. In one embodiment, the antigen-binding fragment may have >70%, >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity with the respective CDRs of the parent antibody. In one embodiment, the antigen-binding fragment may have >70%, >80%, >90%, >95%, >96%, >97%, >98%, >99% or 100% sequence identity with the respective variable region domains of the parent antibody. Typically, the non-identical amino acids of a variable region are not in the CDRs.

[0080] The antigen-binding fragments of antibodies of the invention retain the ability to selectively bind to an antigen. Antigen-binding fragments of antibodies include single chain antibodies (i.e. a full-length heavy chain and light chain); Fab, modified Fab, Fab', modified Fab', F(ab')2, Fv, Fab-Fv, Fab-dsFv, single domain antibodies (e.g. VH or VL or VHH), scFv.

[0081] An antigen-binding function of an antibody can be performed by fragments of a full-length antibody. The methods for creating and manufacturing these antibody fragments are well known in the art (see for example Verma R et al., 1998, J. Immunol. Methods, 216, 165-181).

[0082] Methods for screening antibodies of the invention that do not share 100% amino acid sequence identity with one of the antibodies disclosed herein, that possess the desired specificity, affinity and functional activity include the methods described herein, e.g. enzyme linked immunosorbent assays, biacore, focus reduction neutralisation assay (FRNT), and other techniques known within the art.

[0083] With regards to function, an antibody of the invention may be able to neutralise at least one biological activity of SAR-CoV-2 (a neutralising antibody), particularly to neutralise virus infectivity.

[0084] Neutralisation may also be determined using IC50 or IC90 values. For example, the antibody may have an IC50 value of <lpg / ml, <0.5pg / ml , <0.1pg / ml, <0.05pg / ml, <0.01pg / ml <0.005pg / ml or <0.002pg / ml for one or more variants of SARS-CoV-2. In some instances an antibody of the invention may have an IC50 value of between 0.0001 pg / ml and 0.1 pg / ml, sometimes between 0.0001 pg / ml and 0.05 pg / ml or even between 0.0001 pg / ml and 0.001 pg / ml for one or more variants of SARS-CoV-2.

[0085] Variants of SARS-CoV-2 which may be neutralized by the antibodies of the present invention include Victoria, Alpha, Beta, Gamma, Delta, BA.1, BA.1.1, BA.2, BA.2.12.1, BA.4 / 5, BA.2.75, BA.2.75.2, BA.2.75.5, BA.2.3.20, BA.2.10.4, BA.4.6, BA.5 ,BQ. l, BQ.1.1, DS. l, CK. l, EG.l, FK. l, BN. l, BN.1.2.1, BS.l, BJ.l, BF.7, CH.1.1, CA.3.1, XBB, XBB.l, XBB.1.5, XBB.2.3 XBB.1.5.10, XBB.1.16, XBB.1.16.1, XBF, XBB.1.5.70 and any other variant of concern (VoC).

[0086] An antibody of the invention may have an IC50 value of <0.1 pg / ml for at least 1, at least 5, at least 10, at least 20, at least 30, or all of these strains. Alternatively, antibody of the invention may have an IC50 value of <0.05 pg / ml for at least 1, at least 5, at least 10, at least 20, at least 30, or all of these variants.

[0087] In some instances, an antibody of the invention may have an IC50 value of between 0.0001 pg / ml and 0.1 pg / ml for at least 1, at least 5, at least 10, at least 20, at least 30, or all of these variants. Alternatively, an antibody of the invention may have an IC50 value of between 0.0001 pg / ml and 0.05 pg / ml or even between 0.0001 pg / ml and 0.001 pg / ml for at least 1, at least 5, at least 10, at least 20, at least 30, or all of these variants.

[0088] An antibody of the invention may maybe differentially active against different variants within the given ranges. In preferred embodiments, the antibodies of the invention will have an IC50 value within the given range against at least 5, at least 10, at least 15 or at least 20 different variants.

[0089] Preferably, the variants are selected from Victoria, Alpha, Beta, Gamma, Delta, BA. l, BA.1.1, BA.2, BA.2.12.1, BA.4 / 5, BA.2.75, BA.2.75.2, BA.2.75.5, BA.2.3.20, BA.2.10.4, BA.4.6, BA.5, BQ. l, BQ.1.1, DS. l, CK. l, EG. l, FK.l, BN. l, BN.1.2.1, BS. l, BJ.l, BF.7, CH.1.1, CA.3.1, XBB, XBB.l, XBB.1.5, XBB.2.3, XBB.1.5.10, XBB.1.16, XBB.1.16.1, XBF, and XBB.1.5.70. For example, the IC50 values of antibody SD1-2 are provided in Table 4 and Table 5. The IC50 values of antibody SD1-6 are provided in Table 6 and Table 7.

[0090] The ability of an antibody to neutralise virus infectivity may be measured using an appropriate assay, particularly using a cell-based neutralisation assay, as is known in the art. For example, the neutralisation ability may be measured in a focus reduction neutralisation assay (FRNT) where the reduction in the number of cells (e.g. human cells) infected with the virus (e.g. for 2 hours at 37 °C) in the presence of the antibody is compared to a negative control in which no antibodies were added.

[0091] An antibody of the invention may inhibit the interaction between the spike protein of SAR-CoV-2 with the cell surface receptor, angiotensin-converting enzyme 2 (ACE2), of the target cell, e.g. by direct blocking or by disrupting the pre-fusion conformation of the spike protein. Inhibition of the interaction between the spike protein of SAR-CoV-2 and ACE2 can be total or partial. For example, an antibody of the invention may reduce spike- ACE2 formation by >50%, >60%, >70%, >80%, >90%, >95%, >99% or 100%. Inhibition of spike-ACE2 formation can be measured by any suitable means known in the art, for example, by ELISA.

[0092] In terms of binding kinetics, an antibody of the invention may have an affinity constant (KD) value for the spike protein of SARS-CoV-2 of <10nM, <5nM, <4nM, <3nM, <2nM, <lnM, <0.5nM, <0.4nM, <0.3nM, <0.2nM or <0.1nM.

[0093] The KD value can be measured by any suitable means known in the art, for example, by ELISA or Surface Plasmon Resonance (Biacore) at 25 °C.

[0094] Binding affinity (KD) may be quantified by determining the dissociation constant (Kd) and association constant (Ka) for an antibody and its target. For example, the antibody may have an association constant (Ka) of > 10000 M^s'1, > 50000 M^s’1, > 100000 M^s’1, > 200000 M^s’1, > 500000 M^s’1, > 5000000 M^s^or and / or a dissociation constant (Kd) of < 0.001 s’1, < 0.0005 s’1, < 0.004 s’1, < 0.003 s’1, < 0.002 s’1or, < 0.0001 s’1, < 0.00001 s'1or < 0.000001 s’1.

[0095] An antibody of the invention is preferably able to provide in vivo protection in coronavirus (e.g. SARS-CoV-2) infected animals. For example, administration of an antibody of the invention to coronavirus (e.g. SARS-CoV-2) infected animals may result in a survival rate of >30%, >40%, >50%, >60%, >70%, >80%, >90%, >95% or 100%. Survival rates may be determined using routine methods.

[0096] Antibodies of the invention may have any combination of one or more of the above properties.

[0097] Antibodies of the invention may bind to the same epitope as, or compete for binding to SARS-CoV-2 spike protein with, any one of the antibodies described herein (i.e. in particular with antibodies with the heavy and light chain variable regions described above). Methods for identifying antibodies binding to the same epitope, or crosscompeting with one another, are used in the Examples and discussed further below.

[0098] Fc regions

[0099] An antibody of the invention may or may not comprise an Fc domain.

[0100] The antibodies of the invention may be modified in the Fc region in order to improve their stability. Such modifications are known in the art. Modifications may improve the stability of the antibody during storage of the antibody. The in vivo half-life of the antibody may be improved by modifications of the Fc-region.

[0101] For example, cysteine residue(s) can be introduced into the Fc region, thereby allowing interchain disulphide bond formation in this region. The homodimeric antibody thus generated can have improved internalization capability and / or increased complement- mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC). (See Caron et al., J. Exp Med., 176: 1191-1195 (1992) and Shopes, J. Immunol., 148: 2918-2922 (1992)). Alternatively, an antibody can be engineered that has dual Fc regions and can thereby have enhanced complement lysis and ADCC capabilities. (See Stevenson et al., Anti-Cancer Drug Design, 3: 219-230 (1989)).

[0102] For example, an antibody of the invention may be modified to promote the interaction of the Fc domain with FcRn. The Fc domain may be modified to improve the stability of the antibody by affecting Fc and FcRn interaction at low pH, such as in the endosome. The M252Y / S254T / T256E (YTE) mutation may be used to improve the halflife of an IgGl antibody.

[0103] The antibody may be modified to affect the interaction of the antibody with other receptors, such as FcyRI, FcyRIIA, FcyRIIB, FcyRIII, and FcaR. Such modifications may be used to affect the effector functions of the antibody.

[0104] In one embodiment, an antibody of the invention comprises an altered Fc domain as described herein below. In another preferred embodiment an antibody of the invention comprises an Fc domain, but the sequence of the Fc domain has been altered to modify one or more Fc effector functions.

[0105] In one embodiment, an antibody of the invention comprises a “silenced” Fc region. For example, in one embodiment an antibody of the invention does not display the effector function or functions associated with a normal Fc region. An Fc region of an antibody of the invention does not bind to one or more Fc receptors.

[0106] In one embodiment, an antibody of the invention does not comprise a CH2 domain. In one embodiment, an antibody of the invention does not comprise a CH3 domain. In one embodiment, an antibody of the invention comprises additional CH2 and / or CH3 domains.

[0107] In one embodiment, an antibody of the invention does not bind Fc receptors. In one embodiment, an antibody of the invention does not bind complement. In an alternative embodiment, an antibody of the invention does not bind FcyR, but does bind complement.

[0108] In one embodiment, an antibody of the invention in general may comprise modifications that alter serum half-life of the antibody. Hence, in another embodiment, an antibody of the invention has Fc region modification(s) that alter the half-life of the antibody. Such modifications may be present as well as those that alter Fc functions. In one preferred embodiment, an antibody of the invention has modification(s) that alter the serum half-life of the antibody.

[0109] In one embodiment, an antibody of the invention may comprise a human constant region, for instance IgA, IgD, IgE, IgG or IgM domains. In particular, human IgG constant region domains may be used, especially of the IgGl and IgG3 isotypes when the antibody molecule is intended for therapeutic uses where antibody effector functions are required. Alternatively, IgG2 and IgG4 isotypes may be used when the antibody molecule is intended for therapeutic purposes and antibody effector functions are not required.

[0110] In one embodiment, the antibody heavy chain comprises a CHi domain and the antibody light chain comprises a CL domain, either kappa or lambda. In one embodiment, the antibody heavy chain comprises a CHi domain, a CEE domain and a CH3 domain and the antibody light chain comprises a CL domain, either kappa or lambda.

[0111] The four human IgG isotypes bind the activating Fey receptors (FcyRI, FcyRIIa, FcyRIIc, FcyRIIIa), the inhibitory FcyRIIb receptor, and the first component of complement (Clq) with different affinities, yielding very different effector functions (Bruhns P. et al., 2009. Specificity and affinity of human Fey receptors and their polymorphic variants for human IgG subclasses. Blood. 113(16): 3716-25), see also Jeffrey B. Stavenhagen, et al. Cancer Research 2007 Sep 15; 67(18):8882-90. In one embodiment, an antibody of the invention does not bind to Fc receptors. In another embodiment of the invention, the antibody does bind to one or more type of Fc receptors.

[0112] In one embodiment the Fc region employed is mutated, in particular a mutation described herein. In one embodiment the Fc mutation is selected from the group comprising a mutation to remove or enhance binding of the Fc region to an Fc receptor, a mutation to increase or remove an effector function, a mutation to increase or decrease half-life of the antibody and a combination of the same. In one embodiment, where reference is made to the impact of a modification it may be demonstrated by comparison to the equivalent antibody but lacking the modification.

[0113] Some antibodies that selectively bind FcRn at pH 6.0, but not pH 7.4, exhibit a higher half-life in a variety of animal models. Several mutations located at the interface between the CH2 and CH3 domains, such as T250Q / M428L (Hinton PR. et al., 2004. Engineered human IgG antibodies with longer serum half-lives in primates. J Biol Chem. 279(8):6213-6) and M252Y / S254T / T256E + H433K / N434F (Vaccaro C. et al., 2005. Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels. Nat Biotechnol. 23(10): 1283-8), have been shown to increase the binding affinity to FcRn and the half-life of IgGl in vivo. Hence, modifications may be present at M252 / S254 / T256 + H44 / N434 that alter serum half-life and in particular M252Y / S254T / T256E + H433K / N434F may be present. In one embodiment, it is desired to increase half-life. In another embodiment, it may be actually desired to decrease serum half-life of the antibody and so modifications may be present that decrease serum half-life.

[0114] Numerous mutations have been made in the CH2 domain of human IgGl and their effect on ADCC and CDC tested in vitro (Idusogie EE. etal., 2001. Engineered antibodies with increased activity to recruit complement. J Immunol. 166(4):2571-5). Notably, alanine substitution at position 333 was reported to increase both ADCC and CDC. Hence, in one embodiment a modification at position 333 may be present, and in particular one that alters ability to recruit complement. Lazar et al. described a triple mutant (S239D / I332E / A330L) with a higher affinity for FcyRIIIa and a lower affinity for FcyRIIb resulting in enhanced ADCC (Lazar GA. et al., 2006). Hence, modifications at S239 / I332 / A330 may be present, particularly those that alter affinity for Fc receptors and in particular S239D / I332E / A330L . Engineered antibody Fc variants with enhanced effector function. PNAS 103(11): 4005-4010). The same mutations were used to generate an antibody with increased ADCC (Ryan MC. etal., 2007. Antibody targeting of B-cell maturation antigen on malignant plasma cells. Mol. Cancer Ther., 6: 3009 - 3018). Richards et al. studied a slightly different triple mutant (S239D / I332E / G236A) with improved FcyRIIIa affinity and FcyRIIa / FcyRIIb ratio that mediates enhanced phagocytosis of target cells by macrophages (Richards JO et al 2008. Optimization of antibody binding to Fcgamma Rlla enhances macrophage phagocytosis of tumor cells. Mol Cancer Ther. 7(8):2517-27). In one embodiment, S239D / I332E / G236A modifications may be therefore present.

[0115] In another embodiment, an antibody of the invention may have a modified hinge region and / or CHI region. Alternatively, the isotype employed may be chosen as it has a particular hinge regions.

[0116] Major public V regions

[0117] Public V-regions, also described as public V-genes herein, are the V regions of the germline heavy chain and light chain regions that are found in a large proportion of the antibody responses to SARS-CoV-2 found within the population. In this application, the V regions are specific responses to the original BA.4 / 5 SARS-CoV-2 variant. That is to say, many individuals utilise the same v-regions from their germline v-region repertoire when generating an immune response to SARS-CoV-2 variants.

[0118] As used herein, an antibody “derived” from a specific v-region refers to antibodies that were generated by V(D)J recombination using that germline v-region sequence. For example, the germline IGHV1-69 v-region sequence may undergo somatic recombination and somatic mutation to arrive at an antibody that specifically binds to the spike protein of SARS-CoV-2. The nucleotide sequence encoding the antibody does not comprise a sequence identical to the IGHV1-69 germline sequence, nevertheless, the antibody is still derived from this v-region. An antibody of the invention typically comprises no more than 20 non-silent mutations in the v-region, when compared to the germline sequence, such as no more than 17 non-silent mutations. An antibody of the invention typically comprises between 5-20 non-silent mutations in the v-region, when compared to the germline sequence, such as between 6-18, 7-17 and 8-15 non-silent mutations. An antibody of the invention typically comprises between 5-15 amino acid changes in the v-region, when compared to the amino acid sequence encoded by the germline sequence, such as between 6-14 and 7-12 amino acid changes. Germline v-region sequences are well known in the art, and methods of identifying whether a certain region of an antibody is derived from a particular germline v-region sequence are also well known in the art.

[0119] In one embodiment, an antibody of the invention derives from the v-region IGHV5- 51, IGHV3-23, or IGHV1-46.

[0120] A silent mutation is defined herein is a change in the nucleotide sequence without a change in the amino acid sequence for which the nucleotide sequence encodes. A non- silent mutation is therefore a mutation that leads to a change in the amino acid sequence encoded by the nucleotide sequence.

[0121] The inventors have surprisingly found that the light chain variable region of two antibodies having the same heavy chain v-region may be exchanged to produce a mixed- chain antibody comprising the heavy chain variable region of a first antibody and the light chain variable region of a second antibody (Dejnirattisai et al. 2021, PMID: 33852911). Preferably, both antibodies also comprise a light chain variable region derived from the same light chain v-region, although this is not essential.

[0122] In one embodiment, the invention provides a method of generating an antibody that binds specifically to the spike protein of SARS-CoV-2 (e.g. a SARS-CoV-2 strain of the Victoria, Alpha, Beta, Gamma, Delta, BA.l, BA.1.1, BA.2, BA.10.4, BA.2.12.1, BA.2.30.2, BA.2.75, BA.2.75.2, BA.4 / 5, BA.4.6, BQ. l, BQ.1.1, BJ.l, BS.l, BF.7, BN. l, XBB, XBB.l, XBB.1.16, XBB.1.16.1, XBB.2.3, XBB.1.5 and / or XBB.1.5.70), the method comprising identifying two or more antibodies derived from the same light chain and / or heavy chain v-regions, replacing the light chain of a first antibody with the light chain of a second antibody, to thereby generate a mixed-chain antibody comprising the heavy chain of the first antibody and the light chain of the second antibody. In one embodiment, the method further comprises determining the affinity for and / or neutralisation of SARS-CoV- 2 of the mixed-chain antibody. The method may further comprise comparing the affinity of the mixed-chain antibody with that of the first and / or second antibodies. The method may further comprise selecting a mixed chain antibody that has the same or greater affinity than the first and / or second antibodies.

[0123] Antibody conjugates

[0124] The invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate). Conjugates of the antibody and cytotoxic agent may be made using a variety of bifunctional protein-coupling agents known in the art.

[0125] An antibody, of the invention may be conjugated to a molecule that modulates or alters serum half-life. An antibody, of the invention may bind to albumin, for example in order to modulate the serum half-life. In one embodiment, an antibody of the invention will also include a binding region specific for albumin. In another embodiment, an antibody of the invention may include a peptide linker which is an albumin binding peptide. Examples of albumin binding peptides are included in WO2015 / 197772 and W02007 / 106120 the entirety of which are incorporated by reference.

[0126] Polynucleotides, vectors and host cells

[0127] The invention also provides one or more isolated polynucleotides (e.g. DNA) encoding the antibody of the invention. In one embodiment, the polynucleotide sequence is collectively present on more than one polynucleotide, but collectively together they are able to encode an antibody of the invention. For example, the polynucleotides may encode the heavy and / or light chain variable regions(s) of an antibody of the invention. The polynucleotides may encode the full heavy and / or light chain of an antibody of the invention. Typically, one polynucleotide would encode each of the heavy and light chains. Polynucleotides which encode an antibody of the invention can be obtained by methods well known to those skilled in the art. For example, DNA sequences coding for part or all of the antibody heavy and light chains may be synthesised as desired from the corresponding amino acid sequences.

[0128] General methods by which the vectors may be constructed, transfection methods and culture methods are well known to those skilled in the art. In this respect, reference is made to “Current Protocols in Molecular Biology”, 1999, F. M. Ausubel (ed), Wiley Interscience, New York and the Maniatis Manual produced by Cold Spring Harbor Publishing.

[0129] A polynucleotide of the invention may be provided in the form of an expression cassette, which includes control sequences operably linked to the inserted sequence, thus allowing for expression of the antibody of the invention in vivo. Hence, the invention also provides one or more expression cassettes encoding the one or more polynucleotides that encoding an antibody of the invention. These expression cassettes, in turn, are typically provided within vectors (e.g. plasmids or recombinant viral vectors). Hence, in one embodiment, the invention provides a vector encoding an antibody of the invention. In another embodiment, the invention provides vectors which collectively encode an antibody of the invention. The vectors may be cloning vectors or expression vectors. A suitable vector may be any vector which is capable of carrying a sufficient amount of genetic information, and allowing expression of a polypeptide of the invention.

[0130] The polynucleotides, expression cassettes or vectors of the invention are introduced into a host cell, e.g. by transfection. Hence, the invention also provides a host cell comprising the one or more polynucleotides, expression cassettes or vectors of the invention. The polynucleotides, expression cassettes or vectors of the invention may be introduced transiently or permanently into the host cell, allowing expression of an antibody from the one or more polynucleotides, expression cassettes or vectors. Such host cells include transient, or preferably stable higher eukaryotic cell lines, such as mammalian cells or insect cells, lower eukaryotic cells, such as yeast, or prokaryotic cells, such as bacteria cells. Particular examples of cells include mammalian HEK293, such as HEK293F, HEK293T, HEK293S or HEK Expi293F, CHO, HeLa, NSO and COS cells, or any other cell line used herein, such as the ones used in the Examples. Preferably the cell line selected will be one which is not only stable, but also allows for mature glycosylation.

[0131] The invention also provides a process for the production of an antibody of the invention, comprising culturing a host cell containing one or more vectors of the invention under conditions suitable for the expression of the antibody from the one or more polynucleotides of the invention, and isolating the antibody from said culture.

[0132] Combination of antibodies

[0133] Certain Table 1 antibodies may be particularly effective when used in combination, e.g. to minimise loss of activity due to SARS-CoV-2 variants, maximise therapeutic effects and / or increase diagnostic power. Useful combinations include antibodies that do not cross-compete with one another and / or bind to non-overlapping epitopes.

[0134] Thus, the invention provides a combination of the antibodies of the invention, wherein each antibody is capable of binding to the spike protein of coronavirus SARS- CoV-2, wherein at least one antibody comprises all six CDRs of an antibody in Table 1.

[0135] The invention also provides a combination of antibodies, comprising a first antibody which is an antibody according to the invention, in combination with at least one further antibody that does not compete with the first antibody for binding to the spike protein of coronavirus SARS-CoV-2. The first and the at least one further antibodies may bind to different epitopes in the same domain, or may bind to epitopes in different domains in the spike protein. For example, the first antibody may bind to the SD1 domain and the at least one further antibody may bind to the NTD, RBD and / or SD2 domain of the spike protein.

[0136] For example, the first antibody may comprise all six CDRs of SD1-2 (which binds to the SD1 domain), and the at least one further antibody may bind to a different domain of the spike protein, such as the NTD, RBD and / or SD2 domain of the spike protein.

[0137] A combination of the antibodies of the invention may be useful as a therapeutic cocktail. Hence, the invention also provides a pharmaceutical composition comprising a combination of the antibodies of the invention. This is because a new SARS-CoV-2 variant may circulate that is not neutralised by a first of the antibodies in the cocktail but is neutralised by a second antibody in the cocktail, whilst the converse may be true for a further SARS-CoV-2 variant that circulates. Thus, a cocktail of antibodies of the invention may provide a more robust treatment for SARS-CoV-2 than a single antibody of the invention alone.

[0138] A combination of the antibodies of the invention may be useful for diagnosis. Hence, the invention also provides a diagnostic kit comprising a combination of the antibodies of the invention. Also provided herein are methods of diagnosing a disease or complication associated with coronavirus infections in a subject, as explained further below.

[0139] A fully cross-neutralising antibody may be used as a reference to confirm the presence and / or amount of any variants of concern (VoC) SARS-CoV-2 in the sample. An antibody that binds to a limited number of VoCs may be used to confirm the presence and / or amount of that VoC in the sample This may be determined by any method known to the skilled person, such as via an immunoassay, e.g. an ELISA or an immunochromatographic assay. Reduced binding may be determined by comparison and / or normalisation to the reference, and / or by comparison to positive / negative control samples or data.

[0140] Pharmaceutical composition

[0141] The invention provides a pharmaceutical composition comprising an antibody of the invention. The composition may comprise a combination (such as two, three or four) of the antibodies of the invention. The pharmaceutical composition may also comprise a pharmaceutically acceptable carrier.

[0142] The composition of the invention may include one or more pharmaceutically acceptable salts. A "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects. Examples of such salts include acid addition salts and base addition salts.

[0143] Suitable pharmaceutically acceptable carriers comprise aqueous carriers or diluents. Examples of suitable aqueous carriers include water, buffered water and saline.

[0144] Other suitable pharmaceutically acceptable carriers include ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. In many cases, it will be desirable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.

[0145] Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration.

[0146] Pharmaceutical compositions of the invention may comprise additional therapeutic agents, for example an anti-viral agent. The anti-viral agent may bind to coronavirus and inhibit viral activity. Alternatively, the anti-viral agent may not bind directly to coronavirus but still affect viral activity / infectivity. The anti-viral agent could be a further anti-coronavirus antibody, which binds somewhere on SARS-CoV-2 other than the spike protein. Examples of an anti-viral agent useful with the invention include Remdesivir, Lopinavir, ritonavir, APN01, and Favilavir.

[0147] The additional therapeutic agent may be an anti-inflammatory agent, such as a corticosteroid (e.g. Dexamethasone) or a non-steroidal anti-inflammatory drug (e.g. Tocilizumab).

[0148] The additional therapeutic agent may be an anti-coronavirus vaccine.

[0149] The pharmaceutical composition may be administered subcutaneously, intravenously, intradermally, intramuscularly, intranasally or orally.

[0150] Also within the scope of the invention are kits comprising antibodies or other compositions of the invention and instructions for use. The kit may further contain one or more additional reagents, such as an additional therapeutic or prophylactic agent as discussed herein.

[0151] Methods and uses of the invention

[0152] The invention further relates to the use of the antibodies and the pharmaceutical compositions, described herein, e.g. in a method for treatment of the human or animal body by therapy, or in a diagnostic method. The method of treatment may be therapeutic or prophylactic.

[0153] For example, the invention relates to methods of treating coronavirus (e.g. SARS- CoV-2) infections, a disease or complication associated therewith, e.g. COVID-19. The method may comprise administering a therapeutically effective amount of an antibody, a combination of antibodies, or a pharmaceutical composition of the invention. The method may further comprise identifying the presence of coronavirus, or fragments thereof, in a sample, e.g. SARS-CoV-2, from the subject. The invention also relates to an antibody, a combination of antibodies, or a pharmaceutical composition according to the invention for use in a method of treating coronavirus (e.g. SARS-CoV-2) infections, a disease or complication associated therewith, e.g. COVID-19.

[0154] The invention also relates to a method of formulating a composition for treating coronavirus (e.g. SARS-CoV-2) infections, a disease or complication associated therewith, e.g. COVID-19, wherein said method comprises mixing an antibody, a combination of antibodies, or a pharmaceutical composition according to the invention with an acceptable carrier to prepare said composition. The invention also relates to the use of an antibody, a combination of antibodies, or a pharmaceutical composition according to the invention for treating coronavirus (e.g. SARS-CoV-2) infections or a disease or complication associated therewith, e.g. COVID- 19.

[0155] The invention also relates to the use of an antibody, a combination of antibodies, or a pharmaceutical composition according to the invention for the manufacture of a medicament for treating or preventing coronavirus (e.g. SARS-CoV-2) infections or a disease or complication associated therewith, e.g. COVID-19.

[0156] The invention also relates to preventing, treating or diagnosing coronavirus infection caused by any SARS-CoV-2 strain. The coronavirus infection may be caused by any SARS-CoV-2 strain.

[0157] The SARS-CoV-2 strain may be the earliest identified Wuhan strain (hCoV- 19 / Wuhan / WIV04 / 2019 (WIV04); GISAID accession no. EPI_ISL_402124), and variants thereof. For example, the SARS-CoV-2 strain may be a member of lineage Victoria, Alpha, Beta, Gamma, Delta, BA. l, BA.1.1, BA.2, BA.2.10.4, BA.2.12.1, BA.2.3.20, BA.2.75, BA.2.75.2, BA.4 / 5, BA.4.6, BA.5, BQ. l, BQ.1.1, BJ.l, BS.l, BF.7, BN. l, XBB, XBB.l, XBB 1.5, or XBB.1.5.70. The strain may be an as-yet-unidentified strain of SARS-CoV-2 comprising mutations already identified in the existing strains.

[0158] The BA.4 and BA.5 variants have identical Spike sequences. “BA.4 / 5” therefore refers to the common spike sequence of the BAA and BA.5 variants.

[0159] The SARS-CoV-2 strain may comprise one or more mutations, e.g. in the spike protein, relative to the hCoV-19 / Wuhan / WIV04 / 2019 (WIV04) (GISAID accession no. EPI ISL 402124). In other words, the SARS-CoV-2 strain may be a modified hCoV- 19 / Wuhan / WIV04 / 2019 (WIV04) strain comprising one or more modifications, e.g. in the spike protein.

[0160] The mutation may be the mutations (e.g. substitutions) observed in the BA.4 / 5 strain of SARS-CoV-2. The mutation may be the mutations (e.g. substitutions) observed in the Victoria, Alpha, Beta, Gamma, Delta, BA.l, BA.1.1, BA.2, BA.2.10.4, BA.2.12.1, BA.2.3.20, BA.2.75, BA.2.75.2, BA.4 / 5, BA.4.6, BQ. l, BQ.1.1, BJ. l, BS. l, BF.7, BN.l, XBB, XBB. l, XBB 1.5, or XBB.1.5.70 strains of SARS-CoV-2.

[0161] Antibodies SD1-2 and SD1-6 are effective in neutralising the BA.4 / 5 SARS-Cov-2 strain (see Figure 1 A). Hence, the invention may relate to SD1-2 and / or SD1-6 antibodies for use in treating, prevent, treating or diagnosing coronavirus infection caused by a SARS-Cov-2 strain. The methods and uses of the invention may comprise inhibiting the disease state (such as COVID-19), e.g. arresting its development; and / or relieving the disease state (such as CO VID-19), e.g. causing regression of the disease state until a desired endpoint is reached.

[0162] The methods and uses of the invention may comprise the amelioration or the reduction of the severity, duration or frequency of a symptom of the disease state (such as COVID-19) (e.g. lessen the pain or discomfort), and such amelioration may or may not be directly affecting the disease. The symptoms or complications may be fever, headache, fatigue, loss of appetite, myalgia, diarrhoea, vomiting, abdominal pain, dehydration, respiratory tract infections, cytokine storm, acute respiratory distress syndrome (ARDS) sepsis, and / or organ failure (e.g. heart, kidneys, liver, GI, lungs).

[0163] The methods and uses of the invention may lead to a decrease in the viral load of coronavirus (e.g. SARS-CoV-2), e.g. by >10%, >20%, >30%, >40%, >50%, >60%, >70%, >80%, >90%, or 100% compared to pre-treatment. Methods of determining viral load are well known in the art, e.g. infection assays.

[0164] The methods and uses of the invention may comprise preventing the coronavirus infection from occurring in a subject (e.g. humans), in particular, when such subject is predisposed to complications associated with coronavirus infection.

[0165] The invention also relates to identifying subjects that have a coronavirus infection, such as by SARS-CoV-2. For example, the methods and uses of the invention may involve identifying the presence of coronavirus (e.g. SARS-CoV-2), or a protein or a fragment thereof, in a sample. The detection may be carried out in vitro or in vivo. In certain embodiments, the invention relates to population screening.

[0166] The invention relates to identifying any SARS-CoV-2 strain, as described herein.

[0167] The invention may also relate to a method of identifying escape mutants of SARS- CoV-2, comprising contacting a sample with a combination of antibodies of the invention and identifying if each antibody binds to the virus. The term “escape mutants” refers to variants of SARS-CoV-2 comprising non-silent mutations that may affect the efficacy of existing treatments of SARS-CoV-2 infection. Typically, the non-silent mutations is on an epitope recognised by a prior art antibody and / or antibodies described herein that specifically binds to an epitope of SARS-CoV-2, e.g. on the spike protein of SARS-CoV-2. If the antibody does not bind to the target, it may indicate that the target comprises a mutation that may alter the efficacy of existing SARS-CoV-2 treatments. The methods and uses of the invention may include contacting a sample with an antibody or a combination of the antibodies of the invention, and detecting the presence or absence of an antibody-antigen complex, wherein the presence of the antibody-antigen complex indicates that the subject is infected with SARS-CoV-2.

[0168] Methods of determining the presence of an antibody-antigen complex are known in the art. For example, in vitro detection techniques include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. In vivo techniques include introducing into a subject a labelled anti-analyte protein antibody. For example, the antibody can be labelled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques. The detection techniques may provide a qualitative or a quantitative readout depending on the assay employed.

[0169] Typically, the invention relates to methods and uses for a human subject in need thereof. However, non-human animals such as rats, rabbits, sheep, pigs, cows, cats, or dogs is also contemplated.

[0170] The subject may be at risk of exposure to coronavirus infection, such as a healthcare worker or a person who has come into contact with an infected individual. A subject may have visited or be planning to visit a country known or suspected of having a coronavirus outbreak. A subject may also be at greater risk, such as an immunocompromised individual, for example an individual receiving immunosuppressive therapy or an individual suffering from human immunodeficiency syndrome (HIV) or acquired immune deficiency syndrome (AIDS).

[0171] The subject may be asymptomatic or pre-symptomatic.

[0172] The subject may be early, middle or late phase of the disease.

[0173] The subject may be in hospital or in the community at first presentation, and / or later times in hospital.

[0174] The subject may be male or female. In certain embodiments, the subject is typically male.

[0175] The subject may not have been infected with coronavirus, such as SARS-CoV-2.

[0176] The subject may have a predisposition to the more severe symptoms or complications associated with coronavirus infections. The method or use of the invention may comprise a step of identifying whether or not a patient is at risk of developing the more severe symptoms or complications associated with coronavirus. In embodiments of the invention relating to prevention or treatment, the subject may or may not have been diagnosed to be infected with coronavirus, such as SARS-CoV- 2.

[0177] The invention relates to analysing samples from subjects. The sample may be tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. The sample may be blood and a fraction or component of blood including blood serum, blood plasma, or lymph. Typically, the sample is from a throat swab, nasal swab, or saliva.

[0178] The antibody-antigen complex detection assays may be performed in situ, in which case the sample is a tissue section (fixed and / or frozen) of the tissue obtained from biopsies or resections from a subject.

[0179] In the embodiments of the invention where the antibodies pharmaceutical compositions and combinations are administered, they may be administered subcutaneously, intravenously, intradermally, orally, intranasally, intramuscularly or intracranially. Typically, the antibodies pharmaceutical compositions and combinations are administered intravenously or subcutaneously.

[0180] The dose of an antibody may vary depending on the age and size of a subject, as well as on the disease, conditions and route of administration. Antibodies may be administered at a dose of about 0.1 mg / kg body weight to a dose of about 100 mg / kg body weight, such as at a dose of about 5 mg / kg to about 10 mg / kg. Antibodies may also be administered at a dose of about 50 mg / kg, 10 mg / kg or about 5 mg / kg body weight.

[0181] A combination of the invention may for example be administered at a dose of about 5 mg / kg to about 10 mg / kg for each antibody, or at a dose of about 10 mg / kg or about 5 mg / kg for each antibody. Alternatively, a combination may be administered at a dose of about 5 mg / kg total (e.g. a dose of 1.67 mg / kg of each antibody in a three antibody combination).

[0182] The antibody or combination of antibodies of the invention may be administered in a multiple dosage regimen. For example, the initial dose may be followed by administration of a second or plurality of subsequent doses. The second and subsequent doses may be separated by an appropriate time.

[0183] As discussed above, the antibodies of the invention are typically used in a single pharmaceutical composition / combination (co-formulated). However, the invention also generally includes the combined use of antibodies of the invention in separate preparations / compositions. The invention also includes combined use of the antibodies with additional therapeutic agents, as described above.

[0184] Combined administration of the two or more agents and / or antibodies may be achieved in a number of different ways. In one embodiment, all the components may be administered together in a single composition. In another embodiment, each component may be administered separately as part of a combined therapy.

[0185] For example, the antibody of the invention may be administered before, after or concurrently with another antibody, or binding fragment thereof, of the invention. The particularly useful combinations are described above for example.

[0186] For example, the antibody of the invention may be administered before, after or concurrently with an anti-viral agent or an anti-inflammatory agent.

[0187] In embodiments where the invention relates to detecting the presence of coronavirus, e.g. SARS-CoV-2, or a protein or a fragment thereof, in a sample, the antibody contains a detectable label. Methods of attaching a label to an antibody are known in the art, e.g. by direct labelling of the antibody by coupling (i.e., physically linking) a detectable substance to the antibody. Alternatively, the antibody may be indirect labelled, e.g. by reactivity with another reagent that is directly labelled. Examples of indirect labelling include detection of a primary antibody using a fluorescently-labelled secondary antibody and end-labelling of a DNA probe with biotin such that it can be detected with fluorescently-labelled streptavidin.

[0188] The detection may further comprise: (i) an agent known to be useful for detecting the presence of coronavirus, , e.g. SARS-CoV-2, or a protein or a fragment thereof, e.g. an antibody against other epitopes of the spike protein, or other proteins of the coronavirus, such as an anti-nucleocapsid antibody; and / or (ii) an agent known to not be capable of detecting the presence of coronavirus, , e.g. SARS-CoV-2, or a fragment thereof, i.e. providing a negative control.

[0189] In certain embodiments, the antibody is modified to have increased stability. Suitable modifications are explained above.

[0190] The invention also encompasses kits for detecting the presence of coronavirus, e.g. SARS-CoV-2, in a sample. For example, the kit may comprise: a labelled antibody or a combination of labelled antibodies of the invention; means for determining the amount of coronavirus, e.g. SARS-CoV-2, in a sample; and means for comparing the amount of coronavirus, e.g. SARS-CoV-2, in the sample with a standard. The labelled antibody or the combination of labelled antibodies can be packaged in a suitable container. The kit can further comprise instructions for using the kit to detect coronavirus, e.g. SARS-CoV-2, in a sample. The kit may further comprise other agents known to be useful for detecting the presence of coronavirus, as discussed above.

[0191] For example, the antibodies or combinations of antibodies of the invention are used in a lateral flow test. Typically, the lateral flow test kit is a hand-held device with an absorbent pad, which based on a series of capillary beds, such as pieces of porous paper, microstructured polymer, or sintered polymer. The test runs the liquid sample along the surface of the pad with reactive molecules that show a visual positive or negative result. The test may further comprise using other agents known to be useful for detecting the presence of coronavirus, e.g. SARS-CoV-2, or a fragment thereof, as discussed above, such as anti- an anti-nucleocapsid antibody.

[0192] Other

[0193] It is to be understood that different applications of the disclosed antibodies combinations, or pharmaceutical compositions of the invention may be tailored to the specific needs in the art. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only, and is not intended to be limiting.

[0194] In addition as used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural references unless the content clearly dictates otherwise. Thus, for example, reference to “an antibody” includes two or more “antibodies”.

[0195] Furthermore, when referring to “>x” herein, this means equal to or greater than x. When referred to “<x” herein, this means less than or equal to x.

[0196] For the purpose of this invention, in order to determine the percent identity of two sequences (such as two polynucleotide or two polypeptide sequences), the sequences are aligned for optimal comparison purposes (e.g. gaps can be introduced in a first sequence for optimal alignment with a second sequence). The nucleotide or amino acid residues at each position are then compared. When a position in the first sequence is occupied by the same nucleotide or amino acid as the corresponding position in the second sequence, then the nucleotides or amino acids are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity = number of identical positions / total number of positions in the reference sequence x 100). Typically the sequence comparison is carried out over the length of the reference sequence. For example, if the user wished to determine whether a given (“test”) sequence is 95% identical to SEQ ID NO: 3, SEQ ID NO: 3 would be the reference sequence. To assess whether a sequence is at least 95% identical to SEQ ID NO: 3 (an example of a reference sequence), the skilled person would carry out an alignment over the length of SEQ ID NO: 3, and identify how many positions in the test sequence were identical to those of SEQ ID NO: 3. If at least 95% of the positions are identical, the test sequence is at least 95% identical to SEQ ID NO: 3. If the sequence is shorter than SEQ ID NO: 3, the gaps or missing positions should be considered to be non-identical positions.

[0197] The skilled person is aware of different computer programs that are available to determine the homology or identity between two sequences. For instance, a comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In an embodiment, the percent identity between two amino acid or nucleic acid sequences is determined using the Needleman and Wunsch (1970) algorithm which has been incorporated into the GAP program in the Accelrys GCG software package (available at http: / / www.accelrys.com / products / gcg / ), using either a Blosum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.

[0198] The CDRs of the heavy chain (CDRH) and light chain variable domain (CDRL) are located at residues 27-38 (CDR1), residues 56-65 (CDR2) and residues 105-117 (CDR3) of each chain according to the IMGT numbering system (http: / / www.imgt.org; Lefranc MP, 1997, J, Immunol. Today, 18, 509). This numbering system is used in the present specification except where otherwise indicated.

[0199] All publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.

[0200] The following examples illustrate the invention. EXAMPLES

[0201] Example 1.

[0202] Potently neutralising mAb isolated following BA.4 / 5 infection

[0203] Following ethical approval and informed consent, a blood sample was taken from a volunteer 30 days after PCR confirmed positive BA.4 infection following 3 doses of SARS-CoV-2 vaccine. PBMC were isolated and single cell sorting was performed to acquire SD1 -specific IgG+ memory B cells. Heavy chains (HC) and light chains (LC) were recovered by reversetranscript PCR (RT-PCR) followed by Nested-PCR. PCR products were ligated into HC and LC expression plasmids, respectively, by Gibson assembly. Gibson products were transfected into HEK-293T cells in 24-well plates, and the supernatant was harvested and tested against Pseudovirus BA.4+all (mutations G339H, R346T, L368I, K444R, V445P, G446S, N450D, L452M, N460K, V483 A, E484R, F486S, F490V and S494P were added to BA.4 / 5 spike protein) and XBB.1.5. Neutralising antibodies were selected, including SD1- 2, which was selected for its potent neutralising ability. The antibodies were expressed by polyethylenimine (PEI) transfection of HEK-293T cells and purified by protein A / G column for further analysis.

[0204] Heavy chain and light chain usage of SD1-2

[0205] The heavy chain and light chain expression plasmids were sequenced by Sanger sequencing. The heavy chain of SD1-2 is IGVH3-23 and light chain is IGLV3-1 (Table 2). The number of amino acid changes in heavy chain sequence is 5, but it has 11 amino acid changes in its light chain sequence.

[0206] Cross reactivity of SD1-2 and SD1-6

[0207] Due to the lack of mutations in the SD1 region of the SARS-CoV-2 Spike protein, similar levels of reactivity towards different SARS-CoV-2 variants was expected.

[0208] SD1-2 was tested against a set of pseudovirus variants (Figure 1A and IB, and Table 4). It neutralized all variants with ICso< 0.1 pg / mL (except for Beta, BA.2.10.4, BA.2.3.20 and EG1), with less than 10-fold difference between the lowest IC50 (BA.2, IC50=0.016 pg / mL) and the highest (XBB.1.16, IC50 =0.098 pg / mL). The IC50 against Beta, BA.2.10.4, BA.2.3.20, and EG1 were relatively higher but were still all lower than 0.4 pg / mL, at 0.311 pg / mL, 0.244 pg / mL, 0.102 pg / mL, and 0.131 pg / mL respectively. Antibody SD1-2 was then tested against authentic viruses by using Focus Reduction Neutralization Test (FRNT) (Figure 1C and Table 5). The IC50 shown on authentic virus neutralisation were higher than the IC50 on the pseudovirus neutralization assay observed previously. SD1-2 potently neutralizes the early pandemic strain, Victoria, along with two early variants, Alpha and Gamma, with IC50 at 0.052 pg / mL, 0.051 pg / mL, and 0.012 pg / mL, respectively. For the other variants, the IC50 fall between 0.1 pg / mL to 0.8 pg / mL.

[0209] SD1-6 was also tested against a set of pseudovirus variants (Figure 2A). It neutralized all variants with ICso< 0.1 pg / mL, with less than 3-fold difference between the lowest IC50 (XBB.1.16, ICso= 0.026 pg / mL) and the highest (Victoria, IC50 =0.060 pg / mL).

[0210] Antibody SD1-6 was then tested against authentic viruses by using Focus Reduction Neutralization Test (FRNT) (Figure 2B). The IC50 shown on authentic virus neutralisation were also higher than the IC50 on the pseudovirus neutralization assay, with the IC50 falling between 0.038 pg / mL to 0.439 pg / mL.

[0211] Expression and purification of XBB.1.5 SD1

[0212] PCR was performed to amplify the gene encoding recombinant SD1 protein, with the plasmid containing DNA of XBB.1.5 spike as the template. The mammalian expression vector pHLsec was cut with restriction enzymes Agel and Kpnl and the amplified gene was ligated into the vector. This plasmid encodes a recombinant SD1 protein, which comprises 320V to 33 IN of the XBB.1.5 spike, a GGSGGS linker, 528K to 591 S of the XBB.1.5 spike, a 3c protease cleavage site and ends with a C-terminal twin-strep tag. To express the recombinant SD1 protein, the plasmid was transiently transfected into Gibco Expi293F Cells cultured in Expi293 Expression Medium. The supernatant was harvested and SD1 protein was purified using Strep-Tactin XT 4Flow high capacity resin from IB A Lifesciences.

[0213] Isolation of SD1 single B cells by FACS

[0214] PBMC were isolated and SD1 -specific memory B cells were isolated by staining PBMC with LIVE / DEAD Fixable Aqua dye (Invitrogen) followed by recombinant SD1 -twin-Strep of SARS-CoV-2. Antibodies CD3-FITC, CD14-FITC, CD16-FITC, CD56-FITC, IgM- FITC, IgA-FITC, IgD-FITC, IgG-BV786, and CD19-BUV395 were then added into cells along with Strep-MAB-DY549 to stain the twin strep tag of the SD1 protein. IgG+ memory B cells were gated as CD19+, IgG+, CD3-, CD14-, CD56-, CD16-, IgM-, IgA- and IgD-, and SD1+ was further selected and single cells were sorted into 96-well PCR plates with 10 mL of catching buffer (Tris, Nuclease-free-H2O and RNase inhibitor). Plates were briefly centrifuged at 2000*g for 1 min and left on dry ice before being stored at -80°C.

[0215] Cloning and expression of SD1 mAbs (SD1-1, SD1-2, SD1-3 and SD1-6) Gene for Ig IGHV, Ig VK and Ig VX were recovered from positive wells by RT-PCR. Genes encoding Ig IGHV, Ig VK and Ig VX were then amplified using Nested-PCR by a cocktail of primers specific to human IgG. PCR products of HCs and LCs were ligated into the expression vectors of human IgGl or immunoglobulin k-chain or k-chain by Gibson assembly. For mAb expression, plasmids encoding heavy chains and light chains were co-transfected by PEI- transfection into a HEK293T cell line, and supernatants containing mAbs were collected and filtered 4-5 days after transfection. The supernatants were further characterised by ELISA or purified by Protein A / G beads.

[0216] Focus reduction neutralisation assay (FRNT)

[0217] The neutralisation potential of Ab was measured using a Focus Reduction Neutralisation Test (FRNT), where the reduction in the number of the infected foci is compared to a negative control well without antibody. Briefly, serially diluted Ab or plasma was mixed with SARS-CoV-2 strains and incubated for 1 h at 37°C. The mixtures were then transferred to 96-well, cell culture-treated, flat-bottom microplates containing confluent Vero cell monolayers in duplicate and incubated for a further 2 hours, followed by the addition of 1.5% semi-solid carboxymethyl cellulose (CMC) overlay medium to each well to limit virus diffusion. A focus forming assay was then performed by staining Vero cells with human anti-NP mAb (mAb206) followed by peroxidase-conjugated goat anti -human IgG (AO 170; Sigma). Finally, the foci (infected cells) reached approximately 100 per well in the absence of antibodies, and were visualized by adding TrueBlue Peroxidase Substrate. Virus-infected cell foci were counted on the classic AID Eli Spot reader using AID ELISpot software. The percentage of focus reduction was calculated and IC50 was determined using the probit program from the SPSS package.

[0218] Pseudoviral neutralisation test

[0219] The neutralising activity of monoclonal antibody SD1-2 was tested against pseudovirus Victoria (an early pandemic strain), Alpha, Beta, Gamma, Delta, BA.l, BA.2, BA.4 / 5, BA.2.75, BA.2.75.2, BA.2.3.20, BA.2.10.4, BA.4.6, BQ. l, BQ.1.1, DS.l, CK. l, BN. l, BN.1.2.1, BS.l, BJ.l, BF.7, CH.1.1, CA.3.1, XBB, XBB.l, XBB.1.5, XBB.1.5.10, XBB.1.16, XBF and XBB.1.5.70. A four-fold serial dilution of each mAb was incubated with pseudoviral particles at 37°C, 5% CO2 for 1 hour. The stable HEK293T / 17 cells expressing human ACE2 were then added to the mixture at 1.5 x 104cells / well. At 48 h post transduction, culture supernatants were removed and 50 mL of 1 :2 Bright-GloTM Luciferase assay system (Promega, USA) in lx PBS was added to each well. The reaction was incubated at room temperature for 5 min and the firefly luciferase activity was measured using CLARIOstar (BMG Labtech, Ortenberg, Germany). The percentage of neutralisation was calculated relative to the control. Probit analysis was used to estimate the value of dilution that inhibits half of the maximum pseudotyped lentivirus infection (PVNT50).

[0220] The neutralising activity of monoclonal antibody SD1-6 was tested using the same method against pseudoviruses Victoria (an early pandemic strain) , Alpha, XBB.1.5, XBB.1.5.10, XBB.1.16, XBB.1.16.1, XBB.2.3 and XBB.1.5.70.

[0221] Tables

[0222] Table 1 - Antibodies

[0223] Table 2 - Heavy chain and light chain usage of SD1 antibodies

[0224] Table 3 - Examples of the mixed chain antibodies Table 4 - Pseudovirus (PV) Neutralisation IC50 for mAb SD1-2 Table 5 - Live Virus (LV) Neutralisation IC50 for mAb SD1-2 Table 6 - Pseudovirus (PV) Neutralisation IC50 for mAb SD1-6

[0225] Table 7 Live Virus (LV) Neutralisation IC50 for mAb SD1-6 Sequence Listing

[0226] Amino acid and nucleotide sequences of heavy chain and light chain variable regions of selected antibodies

[0227] CDR sequences of selected antibodies

Claims

Claims1. An antibody capable of binding to the spike protein of coronavirus SARS-CoV-2, wherein the antibody comprises:(a) CDRs of SEQ ID NOs: 20, 21, 22, 29, 30 and 31;(b) CDRs of SEQ ID NOs: 17, 18, 19, 26, 27 and 28; or(c) CDRs of SEQ ID NOs: 23, 24, 25, 32, 33 and 34.

2. The antibody according to claim 1, comprising a heavy chain having at least 80% identity to the heavy chain variable domain of any one of SEQ ID Nos: 9, 11, 13 and 15. and / or a light chain variable domain having at least 80% identity to the light chain variable domain of any one of SEQ ID Nos: 10, 12, 14 and 16.

3. The antibody according to claim 2 wherein:(a) the heavy chain consists of the amino acid sequence of SEQ ID NO: 9 and / or the light chain variable domain consists of the amino acid sequence of 10;(b) the heavy chain consists of the amino acid sequence of SEQ ID NO: 11 and / or the light chain variable domain consists of the amino acid sequence of 12;(c) the heavy chain consists of the amino acid sequence of SEQ ID NO: 13 and / or the light chain variable domain consists of the amino acid sequence of 14; or(d) the heavy chain consists of the amino acid sequence of SEQ ID NO: 15 and / or the light chain variable domain consists of the amino acid sequence of 16.

4. The antibody of any one of claims 1 to 3, wherein the antibody is selected from the group consisting of SD1-1, SD1-2, SD1-3 and SD1-6.

5. An antibody capable of binding to the spike protein of coronavirus SARS-CoV-2, wherein the antibody comprises CDRH1, CDRH2 and CDRH3 from a first antibody in Table 1 and CDRL1, CDRL2 and CDRL3 from a second antibody in Table 1, with the proviso that the first antibody and the second antibody are different.

6. The antibody according to claim 5, comprising a heavy chain variable domain amino acid sequence having at least 80% sequence identity to the heavy chain variabledomain from a first antibody in Table 1, and a light chain variable domain amino acid sequence having at least 80% sequence identity to the light chain variable domain from a second antibody in Table 1.

7. The antibody according to claim 5 or claim 6, wherein the first and second antibodies derive from the same germline heavy chain v-region.

8. The antibody according to any one of the preceding claims, wherein the antibody is a full-length antibody.

9. The antibody according to any one of the preceding claims, wherein the antibody comprises an IgGl constant region.

10. The antibody according to any one of the preceding claims, wherein the antibody comprises an Fc region comprising at least one modification such that serum half-life is extended.

11. The antibody according to claim 10, wherein the Fc region comprises the modifications M252Y / S254T / T256E.

12. A polynucleotide encoding one or both of the heavy chain and / or light chain of an antibody according to any one of the preceding claims.

13. A vector comprising one or more polynucleotides according to claim 11.

14. A host cell comprising one or more polynucleotides according to claim 12 or one or more vectors according to claim 13.

15. A method for producing an antibody that is capable of binding to the spike protein of coronavirus SARS-CoV-2, the method comprising culturing the host cell of claim 14 and isolating the antibody from said culture.

16. A pharmaceutical composition comprising one or more of: (a) the antibody according to any one of claims 1 to 11, and (b) at least one pharmaceutically acceptable diluent or carrier.

17. The antibody according to any one of claims 1 to 11, or the pharmaceutical composition according to claim 16, for use in a method for treatment of a human or animal by therapy.

18. The antibody according to any one of claims 1 to 11, or the pharmaceutical composition according to claim 16, for use in a method of treating or preventing coronavirus infection, or a disease or complication associated with coronavirus infection.

19. A method of treating or preventing coronavirus infection, or a disease or complication associated with coronavirus infection in a subject, comprising administering a therapeutically effective amount of the antibody according to any one of claims 1 to 11, or the pharmaceutical composition according to claim 16, to said subject.

20. The method according to claim 19, wherein the method is for treating SARS-CoV- 2 infection, or a disease or complication associated therewith, such as COVID-19.

21. A method of identifying the presence of coronavirus, or a protein fragment thereof, in a sample, comprising:(i) contacting the sample with the antibody according to any one of claims 1 to 11, and(ii) detecting the presence or absence of an antibody-antigen complex, wherein the presence of the antibody-antigen complex indicates the presence of coronavirus, or a fragment thereof, in the sample.

22. A method of treating or preventing coronavirus infection, or a disease or complication associated therewith, in a subject, the method comprising identifying the presence of coronavirus according to the method of claim 16 in a sample, and treating the subject with the antibody according to any one of claims 1 to 11 with an anti-viral drug or an anti-inflammatory agent.

23. Use of the antibody according to any one of claims 1 to 11, or the pharmaceutical composition according to claim 16, for preventing, treating and / or diagnosing coronavirus infection, or a disease or complication associated therewith.

24. Use of the antibody according to any one of claims 1 to 11, or the pharmaceutical composition according to claim 16 for the manufacture of a medicament for treating or preventing coronavirus infection, or a disease or complication associated therewith.

25. The antibody for use according to claim 17 or 18, the method according to any one of claims 19 to 22, or the use according to claim 23 or 24, wherein the coronavirus infection is caused by a SARS-CoV-2 strain of the lineage Victoria, Alpha, Beta, Gamma, Delta, BA. l, BA.1.1, BA.2, BA.2.12.1, BA.4 / 5, BA.2.75, BA.2.75.2, BA.2.75.5,BA.2.3.20, BA.2.10.4, BA.4.6, BQ. l, BQ.1.1, DS.l, CK.l, EG.l, FK. l BN. l, BN.1.2.1, BS. l, BJ. l, BF.7, CH.1.1, CA.3.1, XBB, XBB.l, XBB.1.5, XBB.2.3 XBB.1.5.10, XBB.1.16, XBB.1.16.1, XBF and XBB.1.5.70.

Images