Composition

Abstract

The present invention relates to antibodies capable of binding to the spike protein of the coronavirus SARS-CoV-2 and methods and uses thereof in the prevention, treatment and / or diagnosis of coronavirus infections, including COVID-19, and diseases and / or complications associated with coronavirus infections.

Description

[Technical field]

[0001] The present invention relates to antigen-binding molecules, in particular antibodies, fragments and variants thereof, that bind to SARS-CoV-2 and the use of said antigen-binding molecules in the prevention, treatment and / or diagnosis of coronavirus infections, including COVID-19. [Background technology]

[0002] SARS-CoV-2 is a novel betacoronavirus that was first identified as the cause of an outbreak of severe viral respiratory disease in Wuhan, China, in January 2020. The disease, subsequently named COVID-19, was declared a global pandemic.

[0003] Several variants of SARS-CoV-2 have emerged and are currently circulating. These include alpha (also known as B.1.1.7, first demonstrated in the UK in September 2020), beta (also known as 501Y.V2 or B.1.351, first demonstrated in South Africa in May 2020), gamma (also known as P.1 or 501Y.V2, first demonstrated in Brazil in November 2020), delta (also known as B.1.617.2, first demonstrated in India in October 2020), and omicron (B.1.1.529, first demonstrated in multiple countries in November 2021).

[0004] Coronaviruses such as SARS-CoV-2 have four structural proteins, nucleocapsid, envelope, membrane and spike (S) proteins. The SARS-CoV-2 spike protein forms a homotrimeric structure containing three spike monomers. Each spike monomer contains an S1 subunit and an S2 subunit. The S1 subunit further contains an N-terminal domain (NTD) and a receptor binding domain (RBD). The trimeric spike protein is responsible for engaging target cells and triggering fusion with the target cell membrane via engagement with the angiotensin-converting enzyme 2 (ACE2) cell surface receptor.

[0005] Currently approved SARS-CoV-2 vaccines are designed to induce an immune response against the S protein of the original Wuhan variant (hCoV-19 / Wuhan / WIV04 / 2019). However, many of the SARS-CoV-2 variants contain mutations within the S protein. Thus, antibodies generated in response to vaccination or previous infection with hCoV-19 / Wuhan / WIV04 / 2019 may be less effective at recognizing these and currently unidentified strains, leading to a greater risk of vaccine failure and increased susceptibility to breakthrough infection or repeat infection in previously infected individuals. Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention aims to provide improved antibodies for preventing, treating and / or diagnosing coronavirus infections, including COVID-19 and Long COVID, and diseases and / or complications associated with coronavirus infections. In particular, the present invention aims to provide antibodies with broad activity against multiple known variants of SARS-CoV-2 and currently unidentified variants with additional mutations in the spike protein. [Means for solving the problem]

[0007] The present invention relates to human monoclonal antibodies (mAbs) that specifically bind to the spike protein of SARS-CoV-2 and are effective in neutralizing SARS-CoV-2.

[0008] In some embodiments, the antibodies of the invention specifically bind to an epitope on the S1 subunit of the spike protein. In some embodiments, the antibodies of the invention specifically bind to an epitope on the receptor binding domain (RBD) of the S1 subunit. In alternative embodiments, the antibodies of the invention bind to a quaternary epitope that arises through binding to the conformation that constitutes the trimeric spike protein.

[0009] Preferably, the antibodies of the invention are broadly effective against multiple variants of SARS-CoV-2. For example, the antibodies of the invention may be effective in neutralizing some or all of the hCoV-19 / Wuhan / WIV04 / 2019, SARS-CoV-2 / human / AUS / VIC01 / 2020 (hCoV-19 / Wuhan / WIV04 / 2019-related variant, also known as the "Victoria" variant because it was isolated in Australia early in the pandemic), alpha (B.1.1.7), beta (B.1.351), gamma (P1), delta (B1.617.2) and / or omicron (B.1.1.529) variants and / or other variants, variants of interest (VOI) and other variants of particular concern (VOC).

[0010] "Variants of concern" means variants of SARS-CoV-2 currently designated as such by the World Health Organization (WHO) in accordance with their current working definition or any other relevant criteria. Variants currently designated as "variants of concern" are known to those of skill in the art and are listed, for example, at https: / / www.who.int / en / activities / tracking-SARS-CoV-2-variants / . As of October 2021, the designated "variants of concern" are the alpha (B.1.1.7), beta (B.1.351), gamma (P1), and delta (B1.617.2) variants.

[0011] "Variants of interest" means variants of SARS-CoV-2 currently designated as such by the World Health Organization (WHO) in accordance with their current working definition or any other relevant criteria. Variants currently designated as "variants of interest" are also known to those of skill in the art and are listed, for example, at https: / / www.who.int / en / activities / tracking-SARS-CoV-2-variants / . As of October 2021, the designated "variants of interest" are the lambda (C.37) and mu (B1.621) variants.

[0012] In some embodiments, the antibodies of the invention may be effective in neutralizing variants containing specific mutations within the RBD of the spike protein of SARS-CoV-2, such as 501Y, 484K, 417N / T, L452R or T478K.

[0013] Preferably, the antibodies of the invention provide potent neutralization of at least two, at least three, at least four, at least five or more than five different variants of SARS-CoV-2. In some embodiments, the antibodies of the invention may be effective in neutralizing multiple variants, including at least two, at least three, at least four or more than four "variants of concern", in particular multiple "variants of concern" or at least two, at least three, at least four or at least all of the hCoV-19 / Wuhan / WIV04 / 2019, SARS-CoV-2 / human / AUS / VIC01 / 2020, alpha, beta, gamma and delta variants.

[0014] In some embodiments, the antibody of the present invention may be a mixed chain antibody generated by swapping light and heavy chains from two different antibody clones. Preferably, the two different antibody clones are derived from the same published V gene. For example, the antibody of the present invention may comprise a heavy chain derived from RQCov-01 and a light chain derived from RQCov-02, RQCov-03 or RQCov-04.

[0015] Alternatively, an antibody of the invention may comprise heavy and light chains derived from the same antibody clone, hi some embodiments, an antibody of the invention may comprise heavy and light chains derived from RQCov-01.

[0016] Preferably, the heavy and / or light chains of the antibodies of the invention comprise one or more further modifications, e.g., to improve the stability or efficacy of the antibody. In particular, the Fc region of the antibodies of the invention preferably comprises one or more further modifications, e.g., to improve the stability or efficacy of the antibody.

[0017] In one aspect, the invention provides an antibody capable of binding to the spike protein of coronavirus SARS-CoV-2, the antibody comprising a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2 and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 3, 31 or 34, and / or (a) VLCDR1 comprising the amino acid sequence of SEQ ID NO:6, VLCDR2 comprising the amino acid sequence of SEQ ID NO:7, and VLCDR3 comprising the amino acid sequence of SEQ ID NO:8; (b) VLCDR1 comprising the amino acid sequence of SEQ ID NO: 11, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 12, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 13; (c) VLCDR1 comprising the amino acid sequence of SEQ ID NO: 16, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 17, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 18, or (d) VLCDR1 comprising the amino acid sequence of SEQ ID NO: 21, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 23 The light chain variable region comprises:

[0018] In some embodiments, the antibody comprises: (a) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 3, and a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 6, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 8; (b) a heavy chain variable region comprising a VHCDR1 having the amino acid sequence of SEQ ID NO: 1, a VHCDR2 having the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 31, and a light chain variable region comprising a VLCDR1 having the amino acid sequence of SEQ ID NO: 6, a VLCDR2 having the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 having the amino acid sequence of SEQ ID NO: 8; (c) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 34, and a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 6, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 8; (d) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 3, and a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 11, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 12, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 13; (e) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 31, and a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 11, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 12, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 13; (f) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 34, and a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 11, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 12, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 13; (g) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 3, and a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 16, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 17, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 18; (h) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 31, and a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 16, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 17, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 18; (i) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 34, and a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 16, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 17, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 18; (j) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 3, and a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 21, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 23; (k) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 31, and a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 21, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 23, or (l) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 34, and a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 21, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 23 Includes.

[0019] In one embodiment, the invention provides an antibody capable of binding to the spike protein of coronavirus SARS-CoV-2, the antibody comprising (a) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO:1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO:2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO:3, SEQ ID NO:31, or SEQ ID NO:34, and (b) a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO:6, a VLCDR2 comprising the amino acid sequence of SEQ ID NO:7, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO:8.

[0020] In one embodiment, the invention provides an antibody capable of binding to the spike protein of coronavirus SARS-CoV-2, the antibody comprising (a) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO:1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO:2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO:3, SEQ ID NO:31, or SEQ ID NO:34, and (b) a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO:11, a VLCDR2 comprising the amino acid sequence of SEQ ID NO:12, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO:13.

[0021] In one embodiment, the invention provides an antibody capable of binding to the spike protein of coronavirus SARS-CoV-2, the antibody comprising (a) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO:1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO:2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO:3, SEQ ID NO:31, or SEQ ID NO:34, and (b) a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO:16, a VLCDR2 comprising the amino acid sequence of SEQ ID NO:17, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO:18.

[0022] In one embodiment, the invention provides an antibody capable of binding to the spike protein of coronavirus SARS-CoV-2, the antibody comprising (a) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO:1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO:2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO:3, SEQ ID NO:31, or SEQ ID NO:34, and (b) a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO:21, a VLCDR2 comprising the amino acid sequence of SEQ ID NO:22, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO:23.

[0023] In some embodiments, the antibody comprises (a) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO:4, SEQ ID NO:32, or SEQ ID NO:35, and / or a light chain variable domain having at least 80% sequence identity to SEQ ID NO:9, 14, 19, or 24.

[0024] In some embodiments, the antibody comprises (a) a heavy chain variable domain having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more than 99% sequence identity to SEQ ID NO:4, SEQ ID NO:32, or SEQ ID NO:35, and / or (b) a light chain variable domain having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more than 99% sequence identity to SEQ ID NO:9, 14, 19, or 24.

[0025] In some embodiments, the antibody comprises (a) a heavy chain variable domain having the sequence of SEQ ID NO:4, SEQ ID NO:32, or SEQ ID NO:35, and (b) a light chain variable domain having the sequence of SEQ ID NO:9, 14, 19, or 24.

[0026] For example, the antibody may comprise a heavy chain comprising a heavy chain variable domain having the sequence of SEQ ID NO:4, SEQ ID NO:32 or SEQ ID NO:35 and a light chain comprising a light chain variable domain having the sequence of SEQ ID NO:9, 14, 19 or 24.

[0027] In some embodiments, the antibody comprises: (a) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO: 4 and a light chain variable domain having at least 80% sequence identity to SEQ ID NO: 9; (b) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO: 32 and a light chain variable domain having at least 80% sequence identity to SEQ ID NO: 9; (c) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO: 35 and a light chain variable domain having at least 80% sequence identity to SEQ ID NO: 9; (d) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO:4 and a light chain variable domain having at least 80% sequence identity to SEQ ID NO:14; (e) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO: 32 and a light chain variable domain having at least 80% sequence identity to SEQ ID NO: 14; (f) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO: 35 and a light chain variable domain having at least 80% sequence identity to SEQ ID NO: 14; (g) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO:4 and a light chain variable domain having at least 80% sequence identity to SEQ ID NO:19; (h) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO: 32 and a light chain variable domain having at least 80% sequence identity to SEQ ID NO: 19; (i) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO: 35 and a light chain variable domain having at least 80% sequence identity to SEQ ID NO: 19; (j) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO: 4 and a light chain variable domain having at least 80% sequence identity to SEQ ID NO: 24; (k) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO: 32 and a light chain variable domain having at least 80% sequence identity to SEQ ID NO: 24; or (l) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO: 35 and a light chain variable domain having at least 80% sequence identity to SEQ ID NO: 24 Includes.

[0028] In some embodiments, the antibody comprises (a) a heavy chain variable domain having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or more than 99% sequence identity to SEQ ID NO:4, SEQ ID NO:32 or SEQ ID NO:35, and (b) a light chain variable domain having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or more than 99% sequence identity to SEQ ID NO:9.

[0029] In some embodiments, the antibody comprises (a) a heavy chain variable domain having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more than 99% sequence identity to SEQ ID NO:4, SEQ ID NO:32, or SEQ ID NO:35, and (b) a light chain variable domain having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more than 99% sequence identity to SEQ ID NO:14.

[0030] In some embodiments, the antibody comprises (a) a heavy chain variable domain having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more than 99% sequence identity to SEQ ID NO:4, SEQ ID NO:32, or SEQ ID NO:35, and (b) a light chain variable domain having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more than 99% sequence identity to SEQ ID NO:19.

[0031] In some embodiments, the antibody comprises (a) a heavy chain variable domain having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or more than 99% sequence identity to SEQ ID NO:4, SEQ ID NO:32 or SEQ ID NO:35, and (b) a light chain variable domain having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or more than 99% sequence identity to SEQ ID NO:24.

[0032] In a further aspect, the invention provides a bispecific antibody comprising (a) a first heavy chain comprising a heavy chain variable domain having the sequence of SEQ ID NO: 4, SEQ ID NO: 32 or SEQ ID NO: 35, (b) a first light chain comprising a light chain variable domain having the sequence of SEQ ID NO: 9, 14, 19 or 24, (c) a second heavy chain, and (d) a second light chain.

[0033] Preferably, the first heavy chain associates with the first light chain to form a first binding domain that specifically binds to an epitope on the spike protein of SARS-CoV-2, and the second heavy chain associates with the second light chain to form a second binding domain.

[0034] Preferably, the second heavy chain is derived from a different antibody clone to the first heavy chain.

[0035] In some embodiments, the first light chain has the same sequence as the second light chain, e.g., both the first and second light chains are light chains that include a light chain variable domain having the sequence of SEQ ID NO: 9, 14, 19 or 24.

[0036] In alternative embodiments, the first light chain does not have the same sequence as the second light chain, for example, the first light chain comprises a light chain variable domain having a sequence selected from SEQ ID NO: 9, 14, 19 or 24, and the second light chain comprises a light chain variable domain having a different sequence selected from SEQ ID NO: 9, 14, 19 or 24.

[0037] In some embodiments, the second light chain is derived from a different antibody clone to the first light chain. For example, the second light chain can be derived from the same antibody clone as the second heavy chain.

[0038] Thus, in some embodiments, the first light chain comprises a light chain variable domain having a sequence selected from SEQ ID NO: 9, 14, 19, or 24, and the second light chain comprises a light chain variable domain that does not have a sequence selected from SEQ ID NO: 9, 14, 19, or 24.

[0039] In some embodiments, a bispecific antibody of the invention comprises (a) a first heavy chain comprising a heavy chain variable domain having the sequence of SEQ ID NO:4, SEQ ID NO:32 or SEQ ID NO:35, (b) a second heavy chain derived from a different antibody clone relative to the first heavy chain, and (c) first and second light chains comprising light chain variable domains having the sequence of SEQ ID NO:9.

[0040] In some embodiments, a bispecific antibody of the invention comprises (a) a first heavy chain comprising a heavy chain variable domain having the sequence of SEQ ID NO:4, SEQ ID NO:32 or SEQ ID NO:35, (b) a second heavy chain derived from a different antibody clone relative to the first heavy chain, and (c) first and second light chains comprising light chain variable domains having the sequence of SEQ ID NO:14.

[0041] In some embodiments, a bispecific antibody of the invention comprises (a) a first heavy chain comprising a heavy chain variable domain having the sequence of SEQ ID NO:4, SEQ ID NO:32 or SEQ ID NO:35, (b) a second heavy chain derived from a different antibody clone relative to the first heavy chain, and (c) first and second light chains comprising light chain variable domains having the sequence of SEQ ID NO:19.

[0042] In some embodiments, a bispecific antibody of the invention comprises (a) a first heavy chain comprising a heavy chain variable domain having the sequence of SEQ ID NO:4, SEQ ID NO:32 or SEQ ID NO:35, (b) a second heavy chain derived from a different antibody clone relative to the first heavy chain, and (c) first and second light chains comprising light chain variable domains having the sequence of SEQ ID NO:24.

[0043] In some embodiments, the second binding domain may bind to the same epitope on the spike protein of SARS-CoV-2 as the first binding domain. In other embodiments, the second binding domain may bind to a different epitope on the spike protein of SARS-CoV-2. In certain embodiments, the second binding domain may bind to a secondary or quaternary epitope on the trimeric spike of SARS-CoV-2. In other embodiments, the second binding domain may bind to a protein other than the spike protein of SARS-CoV-2. The different protein may be another SARS-CoV-2 protein or a non-SARS-CoV2 protein.

[0044] In some embodiments, the antibody comprises (a) a heavy chain having at least 80% sequence identity to SEQ ID NO:5, SEQ ID NO:33, or SEQ ID NO:36, and / or (b) a light chain having at least 80% sequence identity to SEQ ID NO:10, 15, 20, or 25.

[0045] In some embodiments, the antibody comprises (a) a heavy chain having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more than 99% sequence identity to SEQ ID NO:5, SEQ ID NO:33, or SEQ ID NO:36, and / or (b) a light chain having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more than 99% sequence identity to SEQ ID NO:10, 15, 20, or 25.

[0046] In some embodiments, the antibody comprises (a) a heavy chain having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more than 99% sequence identity to SEQ ID NO:5, SEQ ID NO:33, or SEQ ID NO:36, and (b) a light chain having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more than 99% sequence identity to SEQ ID NO:10.

[0047] In some embodiments, the antibody comprises (a) a heavy chain having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more than 99% sequence identity to SEQ ID NO:5, SEQ ID NO:33, or SEQ ID NO:36, and (b) a light chain having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more than 99% sequence identity to SEQ ID NO:15.

[0048] In some embodiments, the antibody comprises (a) a heavy chain having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or greater than 99% sequence identity to SEQ ID NO:5, SEQ ID NO:33, or SEQ ID NO:36, and (b) a light chain having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or greater than 99% sequence identity to SEQ ID NO:20.

[0049] In some embodiments, the antibody comprises (a) a heavy chain having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more than 99% sequence identity to SEQ ID NO:5, SEQ ID NO:33, or SEQ ID NO:36, and (b) a light chain having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more than 99% sequence identity to SEQ ID NO:25.

[0050] In some embodiments, the antibody comprises (a) a heavy chain having the sequence of SEQ ID NO:5, SEQ ID NO:33, or SEQ ID NO:36, optionally containing one or more amino acid substitutions in the heavy chain constant region, and (b) a light chain having the sequence of SEQ ID NO:10, 15, 20, or 25, optionally containing one or more amino acid substitutions in the light chain constant region.

[0051] In some embodiments, the antibody comprises (a) a heavy chain having the sequence of SEQ ID NO:5, SEQ ID NO:33, or SEQ ID NO:36, optionally comprising one or more amino acid substitutions within the heavy chain constant region, and (b) a light chain derived from a different antibody clone relative to the heavy chain.

[0052] In some embodiments, the antibody comprises (a) a light chain having the sequence of SEQ ID NO: 10, 15, 20 or 25, optionally comprising one or more amino acid substitutions within the light chain constant region, and (b) a heavy chain derived from a different antibody clone relative to the light chain.

[0053] In a further aspect, the invention provides a bispecific antibody comprising: (a) a first heavy chain having the sequence of SEQ ID NO: 5, SEQ ID NO: 33 or SEQ ID NO: 36, optionally comprising one or more amino acid substitutions in the heavy chain constant region; (b) a first light chain having the sequence of SEQ ID NO: 10, 15, 20 or 25, optionally comprising one or more amino acid substitutions in the light chain constant region; (c) a second heavy chain; and (d) a second light chain.

[0054] Preferably, the first heavy chain associates with the first light chain to form a first binding domain that specifically binds to an epitope on the spike protein of SARS-CoV-2, and the second heavy chain associates with the second light chain to form a second binding domain.

[0055] In some embodiments, the antibody comprises (a) a first heavy chain having the sequence of SEQ ID NO:5, SEQ ID NO:33, or SEQ ID NO:36, optionally comprising one or more amino acid substitutions in the heavy chain constant region, (b) a first light chain having the sequence of SEQ ID NO:10, 15, 20, or 25, optionally comprising one or more amino acid substitutions in the light chain constant region, (c) a second heavy chain derived from a different antibody clone relative to the first heavy chain, and (d) a second light chain.

[0056] In some embodiments, the first light chain has the same sequence as the second light chain, for example, both the first and second light chains have the sequence of SEQ ID NO: 10, 15, 20, or 25, optionally containing one or more amino acid substitutions within the light chain constant region.

[0057] In an alternative embodiment, the first light chain has a sequence selected from SEQ ID NO: 10, 15, 20 or 25, optionally containing one or more amino acid substitutions in the light chain constant region, and the second light chain has a different sequence selected from SEQ ID NO: 10, 15, 20 or 25, optionally containing one or more amino acid substitutions in the light chain constant region.

[0058] In some embodiments, the second light chain is derived from a different antibody clone to the first light chain. For example, the second light chain can be derived from the same antibody clone as the second heavy chain.

[0059] In some embodiments, the bispecific antibody comprises (a) a first heavy chain having the sequence of SEQ ID NO:5, SEQ ID NO:33 or SEQ ID NO:36, optionally comprising one or more amino acid substitutions in the heavy chain constant region, (b) a second heavy chain derived from a different antibody clone relative to the first heavy chain, and (c) first and second light chains having the sequence of SEQ ID NO:10, optionally comprising one or more amino acid substitutions in the light chain constant region.

[0060] In some embodiments, the bispecific antibody comprises (a) a first heavy chain having the sequence of SEQ ID NO:5, SEQ ID NO:33 or SEQ ID NO:36, optionally comprising one or more amino acid substitutions in the heavy chain constant region, (b) a second heavy chain derived from a different antibody clone relative to the first heavy chain, and (c) first and second light chains having the sequence of SEQ ID NO:15, optionally comprising one or more amino acid substitutions in the light chain constant region.

[0061] In some embodiments, the bispecific antibody comprises (a) a first heavy chain having the sequence of SEQ ID NO:5, SEQ ID NO:33 or SEQ ID NO:36, optionally comprising one or more amino acid substitutions in the heavy chain constant region, (b) a second heavy chain derived from a different antibody clone relative to the first heavy chain, and first and second light chains having the sequence of SEQ ID NO:20, optionally comprising one or more amino acid substitutions in the light chain constant region.

[0062] In some embodiments, the bispecific antibody comprises (a) a first heavy chain having the sequence of SEQ ID NO:5, SEQ ID NO:33 or SEQ ID NO:36, optionally comprising one or more amino acid substitutions in the heavy chain constant region, (b) a second heavy chain derived from a different antibody clone relative to the first heavy chain, and (c) first and second light chains having the sequence of SEQ ID NO:25, optionally comprising one or more amino acid substitutions in the light chain constant region.

[0063] The antibody of the present invention may further comprise a constant region. Preferably, the constant region is of human origin. In some embodiments, the heavy chain constant region may be an IgA, IgD, IgE, IgG or IgM constant region. Preferably, the constant region is an IgG constant region, such as an IgG1, IgG2, IgG3 or IgG4. In a preferred embodiment, the constant region is an IgG1 constant region. The light chain constant region may be a lambda or kappa constant region. Preferably, the light chain constant region is a kappa constant region.

[0064] In preferred embodiments, the heavy chain constant region comprises one or more or all of a CH1, CH2 and / or CH3 domain, and the light chain constant region comprises a CL domain.

[0065] In some embodiments, the antibody comprises (a) a heavy chain of SEQ ID NO:5, SEQ ID NO:33, or SEQ ID NO:36, and (b) a light chain of SEQ ID NO:10, 15, 20, or 25, where the heavy chain constant domain and / or the light chain constant domain further comprise one or more amino acid substitutions. For example, the constant domain can comprise amino acid substitutions that enhance binding of the Fc region to one or more Fc receptors, increase or decrease one or more Fc effector functions, extend or decrease the half-life of the antibody, improve the manufacturability of the antibody, promote heterodimerization of the antibody heavy and / or light chain, or any combination thereof.

[0066] Alternatively, or in addition, the variable domains may contain amino acid substitutions that improve the binding affinity of the antibody to one or more variants of SARS-CoV-2.

[0067] In a preferred embodiment, the antibody further comprises an Fc region. Preferably, the Fc region is an IgG1 Fc region. In some embodiments, the Fc region may be a modified IgG1 Fc region comprising one or more amino acid substitutions compared to a wild-type IgG1 Fc region. In a preferred embodiment, the amino acid substitutions extend the half-life of the antibody compared to a wild-type IgG1 Fc region.

[0068] In certain embodiments, the amino acid substitutions used to improve the half-life of an IgG1 antibody are selected from M252Y / S254T / T256E ("YTE"), M428L / N434S ("LS"), S239D / I332E ("DE"), M252Y / T256D ("YD"), T256D / T307Q ("DQ") and / or T256D / T307W ("DW") or any combination thereof (numbered according to EU numbering). In a preferred embodiment, the amino acid substitutions M252Y / S254T / T256E ("YTE") may be used to extend the half-life of an IgG1 antibody.

[0069] In other embodiments, the one or more substitutions may eliminate or enhance binding of the Fc region to an Fc receptor, may increase or eliminate an effector function such as antibody-dependent cellular cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC), may enhance immune complex formation, or any combination thereof. The one or more substitutions may be any suitable substitution known in the art.

[0070] In other embodiments, one or more substitutions may promote heterodimerization of the antibody heavy and / or light chains. For example, when the antibody of the invention is a bispecific antibody, the Fc region of the first heavy chain and the Fc region of the second heavy chain may each contain one or more substitutions that promote selective association of the first heavy chain and the second heavy chain.

[0071] Alternatively or in addition, the CH1 region of the first heavy chain and the CL region of the first light chain may each comprise one or more substitutions that promote selective association of the first heavy chain with the first light chain, and / or the CH1 region of the second heavy chain and the CL region of the second light chain may each comprise one or more substitutions that promote selective association of the first heavy chain with the first light chain.

[0072] In a further aspect, the present invention provides a polynucleotide encoding an antibody according to the invention, a vector comprising said polynucleotide or a host cell comprising said vector.

[0073] In a further aspect, the present invention provides a pharmaceutical composition comprising an antibody according to the invention and at least one pharma- ceutically acceptable diluent or carrier. Optionally, the pharmaceutical composition may also contain one or more further antibodies capable of binding to SARS-CoV-2. Alternatively or in addition, the pharmaceutical composition may also contain one or more additional therapeutic agents, such as anti-inflammatory or antiviral agents.

[0074] In some embodiments, the invention provides pharmaceutical compositions comprising one or more antibodies according to the invention. For example, the composition may comprise one, two, three or all four of the antibodies in Table 2.

[0075] The antibodies of the invention can provide in vivo protection from a coronavirus (e.g., SARS-CoV-2) in an infected subject. For example, administration of an antibody of the invention to a subject infected with a coronavirus (e.g., SARS-CoV-2) can result in prevention of infection, improved chances of survival, shortened disease duration and / or reduced severity of symptoms.

[0076] In some embodiments, the antibodies of the invention may be used to prevent infection before exposure to SARS-CoV-2 (pre-exposure prophylaxis). In some embodiments, the antibodies of the invention may be used to prevent infection after recent exposure to SARS-CoV-2 (post-exposure prophylaxis). In some embodiments, the antibodies of the invention may be used to treat acute SARS-CoV-2 infection (COVID-19). In some embodiments, the antibodies of the invention may be used to treat long-term effects of SARS-CoV-2 infection (Long COVID).

[0077] Thus, in a further aspect, the invention provides an antibody or pharmaceutical composition for use in a method for treating, preventing or diagnosing a disease or complication associated with a coronavirus (e.g., SARS-CoV-2) infection.

[0078] In one embodiment, the antibodies or pharmaceutical compositions of the invention are used in a method for treating, preventing or diagnosing a coronavirus infection caused by a SARS-CoV2 variant. Examples of SARS-CoV-2 variants that can be treated with one or more antibodies of the invention include, but are not limited to, hCoV-19 / Wuhan / WIV04 / 2019, SARS-CoV-2 / human / AUS / VIC01 / 2020, A.23.1, B.1.1.7 (alpha), B.1.351 (beta), B.1.258, B.1.526.2, B.1.616, B.1.617.1, B.1.617.2 (delta), C36.3, C.37 or P.1 (gamma).

[0079] In a preferred embodiment, the antibody or pharmaceutical composition of the invention is used in a method for treating, preventing or diagnosing a COVID-19 infection caused by the hCoV-19 / Wuhan / WIV04 / 2019 variant, the SARS-CoV-2 / human / AUS / VIC01 / 2020 variant, the alpha (B.1.1.7) variant, the beta (B.1.351) variant, the gamma (P1) variant, the delta (B1.617.2) variant, another variant comprising a mutation at one or more of positions 501, 484, 452, 478 and / or 417 in the RBD of the spike protein of SARS-CoV-2 and / or any other variant of concern.

[0080] The skilled artisan will recognize that the above list is not exhaustive and that the antibodies or pharmaceutical compositions of the invention may be suitable for use in methods of treating, preventing or diagnosing coronavirus infections caused by any other known or as yet unidentified SARS-CoV-2 variants, including any variant whose viral genotype is listed in the SARS-CoV-2 database, any variant known to exist in nature, any variant generated in laboratory experiments or any variant generated by infection of susceptible animals. Examples of variants that can be treated, prevented or diagnosed by the antibodies according to the invention are listed in the SARS-CoV-2 Genome and Spike Database.

[0081] For example, the antibodies according to the invention may be used in a method of treating, preventing or diagnosing a coronavirus infection caused by a SARS-CoV2 variant having genetic mutations in the spike gene compared to the hCoV-19 / Wuhan / WIV04 / 2019 variant. In some embodiments, the spike protein of the variant may be more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98% or more than 99% identical to that of hCoV-19 / Wuhan / WIV04 / 2019. For example, the spike protein of the variant may differ from the spike protein of hCoV-19 / Wuhan / WIV04 / 2019 by 1, 2, 3, 4, 5, more than 5 or up to 10 amino acids. In some embodiments, the mutations are mutations observed in naturally occurring variants of SARS-CoV-2. In other embodiments, the mutation is not found in naturally occurring variants of SARS-CoV-2, but is a mutation engineered in a laboratory. In a preferred embodiment, the mutation is at one or more of positions 501, 484, 452, 478 and / or 417 in the RBD of the spike protein of SARS-CoV-2.

[0082] In a further aspect, the invention provides a method of treating a subject comprising administering to said subject a therapeutically effective amount of an antibody according to the invention or a pharmaceutical composition according to the invention. Further provided is an antibody according to the invention for use in the manufacture of a medicament for treating a subject.

[0083] In a further aspect, the present invention provides a method for producing an antibody capable of binding to the spike protein of SARS-CoV-2, comprising culturing a host cell of the invention under conditions optimal for the production of an antibody according to the invention and isolating the antibody from said culture.

[0084] In a further aspect, the invention provides a method for identifying the presence of a coronavirus (e.g., SARS-CoV-2) or a component or fragment thereof in a sample, comprising contacting the sample with an antibody according to the invention and determining whether the antibody forms an antibody-antigen complex, wherein formation of the antibody-antigen complex indicates that the sample is positive for a coronavirus (e.g., SARS-CoV-2).

[0085] In some embodiments, the antibodies of the invention do not contain an N-glycosylation site in the heavy and / or light chain variable region. In one embodiment, the antibodies of the invention do not contain an N-glycosylation site in the heavy chain variable region. Preferably, the antibodies of the invention do not contain an N-glycosylation site in VHCDR3.

[0086] The binding affinity of the antibodies according to the invention to the spike protein of SARS-CoV-2 is determined by the equilibrium dissociation constant (K D In some embodiments, the antibodies of the invention have a K of less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, less than 1 nM, less than 0.5 nM, less than 0.4 nM, less than 0.3 nM, less than 0.2 nM, or less than 0.1 nM to the spike protein of a SARS-CoV-2 variant. D Combine by value. K D The value can be measured by any suitable means known in the art, such as ELISA or surface plasmon resonance (Biacore). In a preferred embodiment, the SARS-CoV-2 variant tested is SARS-CoV-2 / human / AUS / VIC01 / 2020 or 19 / Wuhan / WIV04 / 2019.

[0087] In further embodiments, the variant tested is an alpha (B.1.1.7) variant, a beta (B.1.351) variant, a gamma (P1) variant, a delta (B1.617.2) variant, another variant comprising a mutation at one or more of positions 501, 484, 452, 478 and / or 417 within the RBD of the spike protein of SARS-CoV-2, and / or another variant of concern.

[0088] In one embodiment, the antibodies of the invention block, in whole or in part, the interaction between the spike protein of SARS-CoV-2 and ACE2 (a cell surface receptor that mediates target cell fusion). For example, the antibodies of the invention may directly block the interaction or indirectly interfere with fusion by disrupting the conformation of the spike protein. In some embodiments, the antibodies of the invention may reduce spike-ACE2 interaction by more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 95%, more than 99% or 100%. Blocking of spike-ACE2 formation can be measured by any suitable means known in the art, for example, ELISA.

[0089] In one embodiment, the antibody of the present invention can neutralize at least one biological activity of SAR-CoV-2. For example, the antibody of the present invention can neutralize viral infectivity. Suitable methods for measuring viral infectivity are known in the art. For example, the ability of an antibody to neutralize viral infectivity can be measured by focus reduction neutralization assay (FRNT) or any other suitable method.

[0090] Neutralization of SARS-CoV-2 was achieved by measuring the half maximal inhibitory concentration (IC 50 In some embodiments, the antibodies according to the invention have an IC value of less than 0.1 μg / ml, less than 0.05 μg / ml, less than 0.01 μg / ml, less than 0.005 μg / ml, less than 0.002 μg / ml, or less than 0.001 μg / ml. 50 Optionally, the antibodies of the invention may have an IC value of 0.0001 μg / ml to 0.1 μg / ml, 0.0001 μg / ml to 0.05 μg / ml, or 0.0001 μg / ml to 0.001 μg / ml against one or more SAR-CoV-2 variants. 50 It may have a value.

[0091] In a preferred embodiment, the antibody according to the invention has an IC of less than 0.1 μg / ml, less than 0.05 μg / ml, less than 0.01 μg / ml, less than 0.005 μg / ml, less than 0.002 μg / ml or less than 0.001 μg / ml against the hCoV-19 / Wuhan / WIV04 / 2019 variant, the SARS-CoV-2 / human / AUS / VIC01 / 2020 variant, the alpha (B.1.1.7) variant, the beta (B.1.351) variant, the gamma (P1) variant, the delta (B1.617.2) variant, another variant comprising a mutation at one or more of positions 501, 484, 452, 478 and / or 417 in the RBD of the spike protein of SARS-CoV-2, and / or another variant of concern. 50 It may have a value.

[0092] In a particularly preferred embodiment, the IC 50 The values ​​are less than 0.01 μg / ml or less than 0.02 μg / ml for the hCoV-19 / Wuhan / WIV04 / 2019 variant, the SARS-CoV-2 / human / AUS / VIC01 / 2020 variant, the alpha (B.1.1.7) variant, the beta (B.1.351) variant, the gamma (P1) variant, the delta (B1.617.2) variant, another variant containing a mutation at one or more of positions 501, 484, 452, 478 and / or 417 within the RBD of the spike protein of SARS-CoV-2, and / or another variant of concern.

[0093] Optionally, the antibody of the invention has an IC of 0.0001 μg / ml to 0.1 μg / ml, 0.0001 μg / ml to 0.05 μg / ml, or 0.0001 μg / ml to 0.001 μg / ml against the hCoV-19 / Wuhan / WIV04 / 2019 variant, the SARS-CoV-2 / human / AUS / VIC01 / 2020 variant, the alpha (B.1.1.7) variant, the beta (B.1.351) variant, the gamma (P1) variant, the delta (B1.617.2) variant, another variant comprising a mutation at one or more of positions 501, 484, 452, 478, and / or 417 within the RBD of the spike protein of SARS-CoV-2, and / or any other variant of concern. 50 It may have a value.

[0094] Neutralization of SARS-CoV-2 was achieved by measuring the 80% maximum inhibitory concentration (IC 80 In some embodiments, the antibodies according to the invention have an IC value of less than 0.1 μg / ml, less than 0.05 μg / ml, less than 0.01 μg / ml, less than 0.005 μg / ml, less than 0.002 μg / ml, or less than 0.001 μg / ml. 80 Optionally, the antibodies of the invention may have an IC value of 0.0001 μg / ml to 0.1 μg / ml, 0.0001 μg / ml to 0.05 μg / ml, or 0.0001 μg / ml to 0.001 μg / ml against one or more SAR-CoV-2 variants. 50 It may have a value.

[0095] In a preferred embodiment, the antibody according to the invention has an IC of less than 0.1 μg / ml, less than 0.05 μg / ml, less than 0.01 μg / ml, less than 0.005 μg / ml, less than 0.002 μg / ml or less than 0.001 μg / ml against the hCoV-19 / Wuhan / WIV04 / 2019 variant, the SARS-CoV-2 / human / AUS / VIC01 / 2020 variant, the alpha (B.1.1.7) variant, the beta (B.1.351) variant, the gamma (P1) variant, the delta (B1.617.2) variant, another variant comprising a mutation at one or more of positions 501, 484, 452, 478 and / or 417 in the RBD of the spike protein of SARS-CoV-2, and / or another variant of concern. 80 It may have a value.

[0096] In a particularly preferred embodiment, the IC 80 The values ​​are less than 0.03 μg / ml or less than 0.06 μg / ml for the hCoV-19 / Wuhan / WIV04 / 2019 variant, the SARS-CoV-2 / human / AUS / VIC01 / 2020 variant, the alpha (B.1.1.7) variant, the beta (B.1.351) variant, the gamma (P1) variant, the delta (B1.617.2) variant, another variant containing a mutation at one or more of positions 501, 484, 452, 478 and / or 417 within the RBD of the spike protein of SARS-CoV-2, and / or another variant of concern.

[0097] Optionally, the antibody of the invention has an IC of 0.0001 μg / ml to 0.1 μg / ml, 0.0001 μg / ml to 0.05 μg / ml, or 0.0001 μg / ml to 0.001 μg / ml against the hCoV-19 / Wuhan / WIV04 / 2019 variant, the SARS-CoV-2 / human / AUS / VIC01 / 2020 variant, the alpha (B.1.1.7) variant, the beta (B.1.351) variant, the gamma (P1) variant, the delta (B1.617.2) variant, another variant comprising a mutation at one or more of positions 501, 484, 452, 478, and / or 417 within the RBD of the spike protein of SARS-CoV-2, and / or any other variant of concern. 80 It may have a value. [Brief description of the drawings]

[0098] [Figure 1] Neutralization plots for RQCov-05 / 02, RQCov-05 / 03, RQCov-05 / 04 and RQCov-05 / 05 monoclonal antibodies against SARS-CoV-2 Victoria, alpha, beta, gamma and delta variants. Data is shown as log antibody concentration (μg / ml) plotted on the X-axis against % neutralization plotted on the Y-axis. [Diagram 2] Neutralization plots for RQCov-06 / 03 monoclonal antibodies against SARS-CoV-2 Victoria, alpha, beta, gamma and delta variants. Data is shown as log antibody concentration (μg / ml) plotted on the X-axis against % neutralization plotted on the Y-axis. [Diagram 3] Neutralization plots for RQCov-07 / 02, RQCov-07 / 03 and RQCov-07 / 07 monoclonal antibodies against SARS-CoV-2 Victoria, alpha, beta, gamma and delta variants. Data is shown as log antibody concentration (μg / ml) plotted on the X-axis against % neutralization plotted on the Y-axis. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0099] The antibodies of the present invention specifically bind to the spike protein of SARS-CoV-2. Preferably, the antibodies of the present invention bind to the receptor binding domain (RBD) of the S1 subunit of the spike protein of SARS-CoV-2. Alternatively, the antibodies of the present invention may bind to a quaternary epitope that arises through binding to the higher-order structure that constitutes the trimeric spike protein.

[0100] An antibody of the invention may comprise at least three, four, five or six CDRs of Table 1. For example, an antibody may comprise at least one, at least two or all three heavy chain CDRs (VH CDRs) and / or at least one, at least two or all three light chain CDRs (VL CDRs) from an antibody of Table 1. Preferably, the antibody comprises six CDRs of Table 1 (i.e. all three heavy chain CDRs and all three light chain CDRs).

[0101] In one embodiment, an antibody of the present invention may comprise VHCDR1, VHCDR2 and VHCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively, and VLCDR1, VLCDR2 and VLCDR3 having (a) the amino acid sequences of SEQ ID NOs: 6, 7 and 8, respectively, (b) the amino acid sequences of SEQ ID NOs: 11, 12 and 13, respectively, (c) the amino acid sequences of SEQ ID NOs: 16, 17 and 18, respectively, or (d) the amino acid sequences of SEQ ID NOs: 21, 22 and 23, respectively.

[0102] In one embodiment, an antibody of the present invention may comprise VHCDR1, VHCDR2 and VHCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2 and 31, respectively, and VLCDR1, VLCDR2 and VLCDR3 having (a) the amino acid sequences of SEQ ID NOs: 6, 7 and 8, respectively, (b) the amino acid sequences of SEQ ID NOs: 11, 12 and 13, respectively, (c) the amino acid sequences of SEQ ID NOs: 16, 17 and 18, respectively, or (d) the amino acid sequences of SEQ ID NOs: 21, 22 and 23, respectively.

[0103] In one embodiment, an antibody of the present invention may comprise VHCDR1, VHCDR2 and VHCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2 and 34, respectively, and VLCDR1, VLCDR2 and VLCDR3 having (a) the amino acid sequences of SEQ ID NOs: 6, 7 and 8, respectively, (b) the amino acid sequences of SEQ ID NOs: 11, 12 and 13, respectively, (c) the amino acid sequences of SEQ ID NOs: 16, 17 and 18, respectively, or (d) the amino acid sequences of SEQ ID NOs: 21, 22 and 23, respectively.

[0104] In one embodiment, an antibody of the invention may comprise (a) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 3, 31 or 34, and / or (b) a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 6, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 8.

[0105] In one embodiment, an antibody of the invention may comprise (a) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 3, 31 or 34, and / or (b) a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 11, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 12, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 13.

[0106] In one embodiment, an antibody of the invention may comprise (a) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 3, 31 or 34, and / or (b) a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 16, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 17, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 18.

[0107] In one embodiment, an antibody of the invention may comprise (a) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 3, 31 or 34, and / or (b) a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 21, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 23.

[0108] In a further embodiment, an antibody of the invention may comprise a heavy chain variable domain comprising, or consisting of, an amino acid sequence having at least 80% sequence identity to the heavy chain variable domain of an antibody in Table 1. Alternatively or in addition, an antibody of the invention may comprise a light chain variable domain comprising, or consisting of, an amino acid sequence having at least 80% sequence identity to the light chain variable domain of an antibody in Table 1.

[0109] In one embodiment, an antibody of the invention may comprise a heavy chain variable domain comprising or consisting of an amino acid sequence having greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99% or 100% sequence identity to SEQ ID NO: 4, SEQ ID NO: 32 or SEQ ID NO: 35. In one embodiment, an antibody of the invention may comprise a light chain variable domain comprising or consisting of an amino acid sequence having greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99% or 100% sequence identity to SEQ ID NO: 9, 14, 19 or 24.

[0110] In one embodiment, an antibody of the invention may comprise a heavy chain comprising or consisting of an amino acid sequence having greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99% or 100% sequence identity to SEQ ID NO: 5, SEQ ID NO: 33 or SEQ ID NO: 36. In one embodiment, an antibody of the invention may comprise a light chain comprising or consisting of an amino acid sequence having greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99% or 100% sequence identity to SEQ ID NO: 10, 15, 20 or 25.

[0111] The antibodies of the invention may be derived from antibodies identified from recovered SARS-CoV-2 COVID-19 patients (see, e.g., Dejnirattisai et al. "The antigenic anatomy of SARS-CoV-2 receptor binding domain." Cell 184.8(2021):2183-2200 and Dejnirattisai et al. "Antibody evasion by the P.1 variant of SARS-CoV-2." Cell 184.11(2021):2939-2954).

[0112] Preferably, the antibodies from which the antibodies of the invention are derived retain potent neutralizing capacity against multiple SARS-CoV-2 variants, i.e. are effective against two or more SARS-CoV-2 variants.

[0113] For example, these antibodies may have an IC of less than 0.1 μg / ml, less than 0.05 μg / ml, less than 0.01 μg / ml, less than 0.005 μg / ml, less than 0.002 μg / ml, or less than 0.001 μg / ml. 50 Optionally, the antibodies of the invention may have an IC value of 0.0001 μg / ml to 0.1 μg / ml, 0.0001 μg / ml to 0.05 μg / ml, or 0.0001 μg / ml to 0.001 μg / ml against at least two, at least three, at least four, or at least five or more different SARS-CoV-2 variants. 50 It may have a value.

[0114] The antibody of the invention may be a mixed chain antibody. In one embodiment, the antibody of the invention may comprise a heavy chain variable domain derived from antibody RQCov-01. In one embodiment, the antibody of the invention may comprise a light chain variable domain derived from antibody RQCov-02, RQCov-03 or RQCov-04. In one embodiment, the antibody of the invention may comprise a heavy chain derived from RQCov-01 and a light chain derived from RQCov-02. In one embodiment, the antibody of the invention may comprise a heavy chain derived from RQCov-01 and a light chain derived from RQCov-03. In one embodiment, the antibody of the invention may comprise a heavy chain derived from RQCov-01 and a light chain derived from RQCov-04. In one embodiment, the antibody of the invention may comprise a heavy chain derived from RQCov-01 and a light chain derived from RQCov-04.

[0115] In some embodiments, the heavy chain variable domain from antibody RQCov-01 is the heavy chain variable domain of RQCov-05. In some embodiments, the heavy chain variable domain from antibody RQCov-01 is the heavy chain variable domain of RQCov-06. In some embodiments, the heavy chain variable domain from antibody RQCov-01 is the heavy chain variable domain of RQCov-07. The heavy chains of RQCov-05, RQCov-06 and RQCov-07 are modified to not contain N-glycosylation sites in the heavy chain variable region within VHCDR3.

[0116] The heavy chain domain of each of RQCov-01, RQCov-02, RQCov-03, RQCov-04, RQCov-05, RQCov-06 and RQCov-07 is derived from the IGHV1-58 v-region. It has been found that heavy and light chain switching between different monoclonal antibodies with heavy chain variable domains derived from the same v-region results in antibodies that are particularly useful for neutralizing SARS-CoV-2.

[0117] In a preferred embodiment, the antibody of the invention has one of the heavy and light chain combinations provided in Table 2.

[0118] [Table 1]

[0119] [Table 2]

[0120] [Table 3]

[0121] [Table 4]

[0122] [Table 5]

[0123] The antibodies of the invention may be engineered antibodies that have been modified to not contain an N-glycosylation site in the heavy and / or light chain variable regions. Preferably, the antibodies of the invention do not contain an N-glycosylation site in the heavy chain variable region in VHCDR3. The inventors have surprisingly found that the antibodies of the invention retain potency against SARS-CoV2 when the glycosylation motif "NRT" in VHCRD3 is removed by replacing the amino acid residue asparagine (N) with a specific alternative amino acid residue.

[0124] In a preferred embodiment, the asparagine (N) in the glycosylation motif "NRT" is replaced with aspartic acid (D) to form the motif "DRT". Thus, in a preferred embodiment, an antibody of the invention comprises a substitution of asparagine (N) at position 6 of VHCDR3 of antibody RQCov-01 (SEQ ID NO:29) with aspartic acid (D) such that the N-glycosylation motif "NRT" is replaced with the motif "DRT" (SEQ ID NO:3).

[0125] In a further preferred embodiment, the asparagine (N) in the glycosylation motif "NRT" is replaced with a serine (S) to form the motif "SRT". Thus, in a preferred embodiment, an antibody of the invention comprises a substitution of an asparagine (N) at position 6 of the VHCDR3 of the antibody RQCov-01 (SEQ ID NO: 29) with a serine (S) such that the N-glycosylation motif "NRT" is replaced with the motif "SRT" (SEQ ID NO: 31).

[0126] In a further preferred embodiment, the asparagine (N) in the glycosylation motif "NRT" is replaced with a glutamine (Q) to form the motif "QRT". Thus, in a preferred embodiment, an antibody of the invention comprises a substitution of an asparagine (N) at position 6 of the VHCDR3 of the antibody RQCov-01 (SEQ ID NO: 29) with a glutamine (Q) such that the N-glycosylation motif "NRT" is replaced with the motif "QRT" (SEQ ID NO: 34).

[0127] Surprisingly, these antibodies were found to bind strongly to SARS-CoV-2 and retain the ability to neutralize multiple SARS-CoV-2 variants without loss of potency (see Figures 1-3 and Example 1).

[0128] The term "antibody" as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that specifically binds to an antigen, whether natural or partially or wholly synthetically produced. The term also encompasses any polypeptide or protein having a binding domain that is, or is homologous to, an antibody binding domain. Antibodies can be polyclonal or monoclonal. Antibodies can be derived from natural sources or partially or wholly synthetically produced. As used herein, "specifically binds" means that the antibody binds to the desired antigen with high affinity and does not significantly bind to or cross-react with other antigens.

[0129] An antibody is a polypeptide that typically contains two identical heavy chains and two identical light chains. In mammals, there are two types of light chains called lambda (λ) and kappa (κ). Each heavy chain and each light chain is composed of a variable region and a constant region. The heavy chain variable region is called the VH region and the light chain variable region is called the VL region. For a kappa light chain, the VL region may also be called the VK region. Preferably, the antibody according to the invention comprises a kappa light chain.

[0130] The variable region of each of the heavy and light chains contains three complementarity determining regions (CDRs), namely CDR1, CDR2 and CDR3, which are designated VHCDR1, VHCDR2 and VHCDR3 and VLCDR1, VLCDR2 and VLCDR3, respectively. Antibodies of any immunoglobulin isotype (e.g., IgG, IgE, IgM, IgD and IgA) and their isotype subclasses, fragments comprising the antigen-binding domain, such as Fab, F(ab')2, Fv, scFv, dAb, Fd and diabodies, are also contemplated by the present invention. Preferably, the antibody according to the present invention is an IgG antibody.

[0131] In a preferred embodiment, the antibody of the present invention is a full-length antibody, i.e. an antibody consisting of two full-length heavy chains, each comprising a variable domain (VH) and a constant domain (CH1, CH2 and CH3), and two full-length light chains, each comprising a variable domain (VL) and a constant domain (CL). Preferably, the heavy chains are IgG1 heavy chains and the light chains are kappa light chains.

[0132] Unless explicitly stated otherwise, any reference in this application to antibody numbering of the variable domains refers to the numbering according to the IMGT numbering system (http: / / www.imgt.org; Lefranc MP, 1997, J, Immunol. Today, 18, 509) and any reference in this application to antibody numbering of the constant domains refers to the numbering according to the EU index (e.g. Kabat, EA. et al., 1991, Sequences of proteins of immunological interest. 5th Edition).

[0133] In another embodiment, the antibody of the present invention may be a fragment of a whole antibody, in particular an antigen-binding fragment that comprises one or more antigen-binding regions. It has been shown that fragments of a whole antibody can perform antigen-binding functions. Examples of binding fragments include Fab fragments consisting of VL, VH, CL and CH1 domains, Fd fragments consisting of VH and CH1 domains, Fv fragments consisting of the VL and VH domains of a single antibody, dAb fragments consisting of the VH domain, isolated CDR regions, F(ab')2 fragments, which are bivalent fragments containing two linked Fab fragments, single chain Fv molecules (scFv) in which the VH and VL domains are linked by a peptide linker that allows the two domains to associate to form an antigen-binding site, bispecific single chain Fv dimers, and "diabodies", which are multivalent or multispecific fragments constructed by gene fusion.

[0134] Preferably, the antibodies of the present invention are monoclonal antibodies. The monoclonal antibodies (mAbs) of the present invention may be generated by a variety of techniques, including conventional monoclonal antibody methodology.

[0135] The antibodies of the invention may also be multispecific (e.g., bispecific) antibodies. Bispecific antibodies are antibodies that can simultaneously bind to two targets, such as two antigens or two epitopes on the same antigen. For example, one binding domain of the antibody may bind to an epitope on the spike protein of SARS-CoV-2, and the other binding domain may bind to a different antigen or a different epitope on the same antigen. In one embodiment, the bispecific antibodies of the invention may bind to two separate epitopes on the spike protein of SARS-CoV-2. In another embodiment, the bispecific antibodies of the invention may bind to the spike protein of SARS-CoV-2 and a different protein. The different protein may be another SARS-CoV-2 protein or a non-SARS-CoV-2 protein.

[0136] The bispecific antibodies of the present invention can be in any suitable format. Examples of bispecific antibody formats include, but are not limited to, (mAb)2, Fcab, F(mAb')2, quadroma, scFv (single chain variable fragment), bsDb (bispecific diabody), scBsDb (single chain bispecific diabody), BiTE (bispecific T cell engager), DART (dual affinity retargeting antibody), charge pair, tandem antibody, tandem scFv-Fc, Fab-scFv-Fc, Fab-scFv, minibody, zybodies, DNL-F(ab)3 (dock-and-lock trivalent Fab) and bssdAb (bispecific single domain antibody).

[0137] Alternatively, the antigen-binding molecule of the present invention may be monovalent for the spike protein of SAR-CoV-2, e.g., a monovalent antibody fragment. A monovalent antigen-binding molecule is an antigen-binding molecule that has only one binding site for an epitope or antigen.

[0138] In further embodiments, the antibodies or antigen-binding molecules of the invention may also be conjugated to other molecules, such as drugs, prodrugs or toxic moieties.

[0139] In some embodiments, the antibodies of the invention comprise an Fc region. In one embodiment, the antibodies of the invention may comprise a human Fc region, such as an IgA, IgD, IgE, IgG, or IgM Fc region. Preferably, the antibodies of the invention comprise an IgG Fc region, such as an IgG1, IgG2, IgG3, or IgG4. More preferably, the antibodies of the invention comprise an IgG1 Fc region.

[0140] In some embodiments, the Fc region is a hybrid Fc. A hybrid Fc comprises Fc portions derived from two or more different classes or subclasses of antibodies. In some embodiments, the Fc is an IgG1 / 3 hybrid Fc. In other embodiments, the Fc is an IgG2 / 4 hybrid Fc.

[0141] The antibodies of the invention may contain modifications in the Fc region. For example, the Fc region of an antibody of the invention may be modified to improve its stability, extend its half-life, and / or modify its effector functions. Suitable modifications are known in the art.

[0142] In one embodiment, the Fc region may be modified to contain one or more amino acid substitutions compared to a wild-type Fc region of the same isotype. For example, the substitutions may eliminate or enhance binding of the Fc region to an Fc receptor, increase or eliminate effector function, such as antibody-dependent cellular cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC), extend or shorten the half-life of the antibody, enhance immune complex formation, or any combination thereof.

[0143] In one embodiment, the antibodies of the invention may include Fc region modifications that modify the half-life of the antibody. In some embodiments, the antibodies of the invention may be modified to promote the interaction of the Fc domain with FcRn. In some embodiments, the Fc domain modifications are selected from the combinations M252Y / S254T / T256E ("YTE"), M428L / N434S ("LS"), S239D / I332E ("DE"), M252Y / T256D ("YD"), T256D / T307Q ("DQ"), T256D / T307W ("DW") and / or G236A / A330L / I332E (GAALIE) (numbered according to EU numbering). In a preferred embodiment, the antibodies of the invention have one or more modifications that modify the serum half-life of the antibody. In particularly preferred embodiments, M252Y / S254T / T256E (YTE) mutations may be used to improve antibody stability and serum half-life. Such modifications may be in addition to modifications that alter Fc effector function.

[0144] In some embodiments, antibodies may also be modified to alter the interaction of the antibody with other receptors, such as FcγRI, FcγRIIa, FcγRIIc, FcγRIIIa, FcγRIIB, FcγRIII, and FcαR. Such modifications may increase or decrease the effector functions of the antibody.

[0145] 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 antibody-dependent cellular cytotoxicity (ADCC) and / or complement dependent cytotoxicity (CDC) or other functions associated with a standard Fc region, and / or does not bind to one or more activating Fcγ receptors.

[0146] In another embodiment, an antibody of the invention comprises an Fc region with enhanced effector function, for example, in one embodiment, an antibody of the invention exhibits increased ADCC and / or CDC function compared to ADCC and / or CDC function associated with a standard Fc region.

[0147] In one embodiment, the antibody of the present invention does not bind to an Fc receptor. For example, the antibody does not bind to one or more Fc receptors. In one embodiment, the antibody of the present invention does not bind to an FcγR receptor. In one embodiment, the antibody of the present invention does not bind to one or more or all of the activating Fc receptors FcγRI, FcγRIIa, FcγRIIc, FcγRIIIa. In one embodiment, the antibody of the present invention does not bind to the inhibitory Fc receptor FcγRIIb receptor. In one embodiment, the antibody of the present invention does not bind to complement. In an alternative embodiment, the antibody of the present invention does not bind to FcγR but does bind to complement.

[0148] In one embodiment, an antibody of the invention binds with enhanced affinity to an Fc receptor. In one embodiment, an antibody of the invention binds with enhanced affinity to an Fcγ receptor. In one embodiment, an antibody of the invention binds with enhanced affinity to one or more of the activating Fc receptors FcγRI, FcγRIIa, FcγRIIc, FcγRIIIa. In one embodiment, an antibody of the invention binds with enhanced affinity to the inhibitory Fc receptor FcγRIIb receptor. In one embodiment, an antibody of the invention binds with enhanced affinity to complement. In one embodiment, an antibody of the invention binds with enhanced affinity to FcRn.

[0149] In one embodiment, the Fc region of an antibody of the invention does not comprise a CH2 domain. In one embodiment, the Fc does not comprise a CH3 domain. In one embodiment, the Fc comprises additional CH2 and / or CH3 domains.

[0150] In some embodiments, cysteine ​​residues are introduced in the Fc region, thereby allowing interchain disulfide bond formation in this region.

[0151] In other embodiments, one or more substitutions may promote heterodimerization of the antibody heavy and / or light chains. For example, when the antibody of the present invention is a bispecific antibody, the Fc region of the first heavy chain and the Fc region of the second heavy chain may each contain one or more substitutions that promote the selective association of the first heavy chain and the second heavy chain. Strategies suitable for promoting Fc heterodimerization are known in the art and include steric complementarity (e.g., knob-in-hole technology), electrostatic complementarity (e.g., DD-KK substitution), isotype chain exchange (e.g., SEED) or combinations thereof. Those skilled in the art will recognize that any suitable heterodimerization strategy may be applied to the bispecific antibody of the present invention.

[0152] Alternatively or additionally, the CH1 region of the first heavy chain and the CL region of the first light chain may each contain one or more substitutions that promote the selective association of the first heavy chain with the first light chain, and / or the CH1 region of the second heavy chain and the CL region of the second light chain may each contain one or more substitutions that promote the selective association of the second heavy chain with the second light chain. Suitable strategies for promoting heavy chain-light chain heterodimerization are known in the art. The skilled artisan will recognize that any suitable heterodimerization strategy may be applied to the bispecific antibodies of the present invention.

[0153] "Identity," as known in the art, is a relationship between two or more polypeptide sequences or two or more polynucleotide sequences, as determined by comparing the sequences. As used herein, identity may be used interchangeably with "homology" and "similarity."

[0154] A specific reference to % identity applies equally to % homology and % similarity. The percent identity of two amino acid sequences or two nucleic acid sequences is determined by aligning the sequences for optimal comparison purposes (e.g., gaps can be introduced in the first sequence for best alignment with the sequence) and comparing the amino acid residues or nucleotides at corresponding positions. The "best alignment" is the alignment of two sequences that results in the highest percent identity. The percent identity is determined by the number of identical amino acid residues or nucleotides in the sequences being compared (i.e., % identity = number of identical positions / total number of positions x 100). Usually, reference to % identity herein refers to the % identity along the entire length of the molecule, unless the context specifies or implies otherwise. The determination of the percent identity between two sequences can be achieved using mathematical algorithms known to those skilled in the art. Suitable algorithms include FASTA, BLAST and Gapped BLAST. Software for performing these analyses is publicly available.

[0155] In preferred embodiments, the amino acid sequences of the VH, VL, CH1, CH2 and CH3 regions of an antibody of the invention have at least 70% identity to an amino acid sequence in Table 1. More typically, the VH and VL regions have at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or at least 99% identity at the amino acid level to an amino acid sequence in Table 1.

[0156] Thus, in one embodiment, a heavy chain variable region comprising a VHCDR1 that comprises at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 1, a VHCDR2 that comprises at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 2, a VHCDR3 that comprises at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 3, 31 or 34, and / or and a VLCDR3 that comprises at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO:6, a VLCDR2 that comprises at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO:7, and a VLCDR3 that comprises at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO:8, or a fragment or variant thereof. In a preferred embodiment, the VHCDR3 is 100% identical to the amino acid sequence of SEQ ID NO:3, SEQ ID NO:31 or SEQ ID NO:34.

[0157] In one embodiment, the invention provides an antibody that binds to SARS-CoV-2 comprising a heavy chain variable region having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:32 or SEQ ID NO:35 and / or a light chain variable region having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO:9, 14, 19 or 24.

[0158] The antibody of the present invention is typically a monoclonal antibody. In a preferred embodiment, the antibody is a fully human monoclonal antibody in which a human constant region is used. Preferably, the antibody is a fully human antibody derived from a recovered SARS-CoV-2 COVID-19 patient.

[0159] The antibodies of the present invention can be produced using any suitable expression system known in the art. For example, Chinese Hamster Ovary (CHO) cells are suitable for expressing the antibodies of the present invention. RQCov-05 / 03 shows excellent expression and is therefore particularly suitable for use in certain embodiments of the present invention.

[0160] It is possible to use monoclonal and other antibodies and to generate other antibodies or chimeric molecules using recombinant DNA technology. Such techniques may involve combining DNA encoding the immunoglobulin variable region or the complementarity determining regions (CDRs) of one antibody with DNA encoding the constant regions or the constant regions and framework regions of a different antibody. The hybridoma or other cells that produce the antibodies may be subject to genetic mutations or other changes that may or may not alter the binding specificity of the antibody produced. In a preferred embodiment, the antibody is a chimeric antibody comprising a light chain variable domain derived from a first antibody clone and a heavy chain variable domain derived from a second antibody clone.

[0161] The present invention also extends to variants of the sequences in Table 1, including the addition, deletion, substitution, etc. of one or more amino acids. For example, amino acid substitutions can be made which improve the stability, manufacturability, or functional properties of the molecule.

[0162] Those skilled in the art know that various amino acids have similar properties. One or more such amino acids can be substituted by one or more other such amino acids, often without eliminating the desired activity of the substance. Alternatively, amino acids that have no substantial effect on the activity of the polypeptide or at least do not eliminate such activity can be deleted. Substitutions of this nature are often referred to as "conservative" or "semi-conservative" amino acid substitutions.

[0163] In one embodiment, the antibody of the present invention comprises one or more amino acid substitutions. In some embodiments, the antibody of the present invention contains one or more "conservative" or "semi-conservative" amino acid substitutions. In some embodiments, the one or more amino acid substitutions are in the CDR regions. In other embodiments, the one or more amino acid substitutions are in the framework regions, i.e., the variable heavy and light chains, but not in the CDR regions. In other embodiments, the one or more amino acid substitutions can be at any position in the variable heavy and / or variable light regions. In some embodiments, the amino acid substitutions do not adversely affect the binding specificity and / or affinity of the antibody. Thus, the variant antibody can have a functional profile that is the same as or better than the antibody from which it is derived.

[0164] Amino acid substitutions or insertions within the scope of the present invention can be made using naturally occurring or non-naturally occurring amino acids, although naturally occurring amino acids may be preferred. For example, amino acid substitutions can include labeled or non-naturally occurring amino acids, provided that the function of the antibody is not significantly adversely affected.

[0165] In some embodiments, all of the amino acid substitutions are in the CDRs of the variable regions. In some embodiments, all of the amino acid substitutions are in the framework regions of the variable regions.

[0166] Such antibodies may be used to inhibit the functional activity (e.g., EC 50 ,I C 50 ,I C 80 and / or K D ) may be held.

[0167] The antibodies of the invention can be modified to identify possible substitutions within the antibody that would, for example, compensate for changes in epitope characteristics, to improve potency or to accommodate new SARS-CoV-2 variants or to broaden the ability to neutralize multiple SARS-CoV-2 variants.

[0168] The modifications of the antibodies of the invention described above can be prepared by modification during or after synthesis of the antibody or when the antibody is in recombinant form. Suitable techniques, such as site-directed mutagenesis, random mutagenesis, enzymatic cleavage and / or ligation of nucleic acids, are known in the art.

[0169] In a further aspect, the invention provides pharmaceutical compositions comprising one or more antibodies of the invention. For example, the pharmaceutical composition may comprise one, two, three or all of the antibodies provided in Table 2.

[0170] In one embodiment, a pharmaceutical composition of the invention comprises an antibody according to the invention and one or more pharma- ceutically acceptable carriers, buffers, excipients, adjuvants, vehicles, diluents, or stabilizers, or any combination thereof.

[0171] Examples of carriers suitable for use in the present invention include water, saline, buffered saline, dextrose, ethanol, liposomes, glycerol, polyethylene glycol, and combinations thereof.

[0172] The pharmaceutical composition may be in any suitable form or may be formulated for use by any suitable method of administration, for example, it may be formulated for oral, buccal, sublingual, rectal, nasal, transdermal, vaginal, parenteral, subcutaneous, intramuscular, intravenous or intradermal routes.

[0173] The pharmaceutical compositions of the invention may also contain one or more additional therapeutically active agents in addition to the molecules of the invention. For example, the pharmaceutical compositions of the invention may contain one or more additional antibodies that specifically bind to SARS-CoV-2. Alternatively or in addition, the pharmaceutical compositions of the invention may contain one or more antiviral agents, anti-inflammatory agents, or another therapeutically active agent.

[0174] Examples of suitable antiviral agents include remdesivir, lopinavir, ritonavir, APN01 and Favilavir. Examples of suitable anti-inflammatory agents include corticosteroids (e.g., dexamethasone) or non-steroidal anti-inflammatory drugs.

[0175] In some embodiments, the active drug concentrate formulation may include a pharma- ceutically acceptable tonicity agent, a buffering agent, and a pharma- ceutically acceptable surfactant.

[0176] It will be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art for the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0177] Also provided are kits comprising an antibody or other composition of the invention and instructions for use. The kits may further contain one or more additional active agents, such as an additional therapeutic or prophylactic agent.

[0178] The present invention further relates to the use of an antibody according to the invention for a method of treatment or diagnosis.

[0179] In one aspect, the invention relates to a method of treating a coronavirus (e.g., SARS-CoV-2) infection or a disease or complication associated with a coronavirus infection (e.g., COVID-19 or Long COVID).

[0180] In one embodiment, the method comprises administering to a subject suffering from a disease or complication associated with a coronavirus (e.g., COVID-19 or long COVID), a therapeutically effective amount of an antibody or pharmaceutical composition of the invention.

[0181] The antibody or pharmaceutical composition of the invention may be administered by any suitable method, for example, subcutaneously, intravenously, intradermally, orally, intranasally, intramuscularly or intracranially. In a preferred embodiment, the antibody or pharmaceutical composition of the invention is administered intravenously or subcutaneously.

[0182] In some embodiments, the invention provides methods of reducing the severity of or preventing the onset or progression of symptoms or complications associated with a coronavirus infection (e.g., COVID-19 or long COVID). In other embodiments, the invention provides methods of preventing a coronavirus infection from occurring in a subject, such as a subject who has been exposed to or is at high risk of being exposed to a coronavirus or a subject who is at high risk of experiencing severe symptoms or complications associated with a coronavirus infection (e.g., COVID-19 or long COVID).

[0183] The invention also relates to an antibody or pharmaceutical composition according to the invention for use in a method for treating a coronavirus (e.g., SARS-CoV-2) infection or a disease or complication associated therewith (e.g., COVID-19 or long COVID).

[0184] In another aspect, the invention relates to a method of formulating a composition for treating a coronavirus (e.g., SARS-CoV-2) infection or a disease or complication associated therewith (e.g., COVID-19), said method comprising mixing an antibody according to the invention with a pharma- ceutically acceptable carrier to prepare said composition.

[0185] In another aspect, the invention relates to the use of an antibody or pharmaceutical composition according to the invention for the manufacture of a medicament for the treatment of a coronavirus (e.g., SARS-CoV-2) infection or a disease or complication associated therewith (e.g., COVID-19).

[0186] The present invention also relates to preventing, treating or diagnosing a coronavirus infection caused by any of the SARS-CoV-2 variants as described herein. COVID-19 can be caused by any of the SARS-CoV-2 variants.

[0187] In a preferred embodiment, the invention relates to preventing, treating or diagnosing an infection caused by a SARS-CoV-2 variant from lineages hCoV-19 / Wuhan / WIV04 / 2019, SARS-CoV-2 / human / AUS / VIC01 / 2020, alpha (B.1.1.7), beta (B.1.351), gamma (P1), delta (B1.617.2) or omicron (B.1.1.529). In some embodiments, the invention relates to preventing, treating or diagnosing an infection caused by a SARS-CoV-2 variant comprising a mutation at one or more of positions 501, 484, 452, 478 and / or 417 in the RBD of the spike protein of SARS-CoV-2 compared to hCoV-19 / Wuhan / WIV04 / 2019. In some embodiments, the invention relates to an infection caused by a SARS-CoV-2 variant of concern.

[0188] For example, an antibody of the invention can be administered before, after, or simultaneously with another antibody or binding fragment thereof of the invention, and / or before, after, or simultaneously with an antiviral or anti-inflammatory agent. In one embodiment, all therapeutic agents can be administered together in a single composition. In another embodiment, each component can be administered separately as part of a combination therapy regimen.

[0189] In some embodiments, the methods of the invention may result in a reduction in coronavirus (e.g., SARS-CoV-2) viral load, e.g., by more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or 100% compared to before treatment. Methods for determining viral load are well known in the art and include, for example, infection assays.

[0190] Also provided are methods of identifying a subject having a coronavirus infection (e.g., SARS-CoV-2 infection). For example, the methods and uses of the invention can include identifying the presence of a coronavirus (e.g., SARS-CoV-2) or a component or fragment thereof in a sample.

[0191] Thus, in another aspect, the method includes identifying the presence of a coronavirus (e.g., SARS-CoV-2) or a component or fragment thereof in a sample from a subject. The sample can be any suitable sample, such as a tissue biopsy, a throat swab, a nasal swab, or a saliva sample.

[0192] In a further aspect, the invention provides a method for identifying the presence of a coronavirus (e.g., SARS-CoV-2) or a component or fragment thereof in a sample, the method comprising contacting the sample with an antibody of the invention and determining whether the antibody forms an antibody-antigen complex, wherein formation of the antibody-antigen complex indicates that the sample is positive for a coronavirus (e.g., SARS-CoV-2).

[0193] In embodiments in which the invention is directed to detecting the presence of coronavirus in a sample, the antibody preferably contains a detectable label, such as a fluorophore, a small molecule, a nanoparticle, a radioisotope or an enzyme.

[0194] Detection may be performed in vitro, in vivo or in situ. Any suitable method for determining the presence of an antibody-antigen complex may be used. Suitable methods are known in the art. For example, in vitro detection techniques include ELISA, Western blot, immunoprecipitation and immunofluorescence. In vivo techniques include labeled antibodies. Detection techniques may provide a qualitative or quantitative readout.

[0195] In a preferred embodiment, the subject is a human subject in need thereof. However, the subject can also be a non-human animal, such as a rat, mouse, rabbit, sheep, pig, cow, cat or dog. The subject can have symptomatic disease. Alternatively, the subject can be asymptomatic or pre-symptomatic.

[0196] The present invention also encompasses kits for detecting the presence of a coronavirus (e.g., SARS-CoV-2) in a sample. For example, the kit may include a labeled antibody according to the present invention, a means for determining the presence or amount of a coronavirus (e.g., SARS-CoV-2) in a sample, and a means for comparing the amount of coronavirus (e.g., SARS-CoV-2) in the sample to a standard or control. In some embodiments, the kit is a lateral flow test kit.

[0197] The method of the invention can be used to identify any SARS-CoV-2 variant. In a preferred embodiment, the invention relates to identifying a SARS-CoV-2 variant selected from alpha (B.1.1.7), beta (B.1.351), gamma (P1) or delta (B1.617.2).

[0198] The present invention also provides a method for detecting SARS-CoV-1 in a sample using an antibody or a pharmaceutical composition according to the invention, e.g. for the diagnosis of SARS-CoV-1 infection or a disease or complication associated with SARS-CoV-1.

[0199] The antibodies of the invention may be effective in neutralizing multiple SARS-CoV-2 variants.

[0200] A SARS-CoV-2 variant is a version of SARS-CoV-2 that contains changes in the genetic sequence of the virus when compared to the reference sequence of hCoV-19 / Wuhan / WIV04 / 2019 (GenBank: MN908947).

[0201] In particular, the antibodies of the invention may be effective in neutralizing SARS-CoV-2 variants designated as "Variants of Concern" (VOC) and / or "Variants of Interest" (VOI).

[0202] "Variants of concern" and "variants of interest" mean variants of SARS-CoV-2 currently designated as such by the World Health Organization (WHO) according to their current working definition or any other relevant criteria. Variants currently designated as "variants of concern" and "variants of interest" are known to those of skill in the art and are listed, for example, at https: / / www.who.int / en / activities / tracking-SARS-CoV-2-variants / . Databases describing the range of SARS-CoV-2 genetic variation can be found at Nextstrain (https: / / nextstrain.org / ), GISAID (https: / / www.gisaid.org / ) and COG-UK (https: / / www.cogconsortium.uk / ).

[0203] The designated "variants of concern" as of October 2021 are the alpha (B.1.1.7), beta (B.1.351), gamma (P1), and delta (B1.617.2) variants. The designated "variants of interest" (VOI) as of October 2021 are the lambda (C.37) and mu (B.1.621) variants.

[0204] It will be recognized by those skilled in the art that due to the continuing evolution of the SARS-CoV-2 virus and ongoing research into the impact of its variants, these designations are not fixed and variants may be added to, removed from, or moved between these designations that are considered essential, e.g. if further changes to the viral genome cause the emergence of new variants or new developments in the understanding of the impact of existing variants necessitate a reassessment of the risk posed.

[0205] As such, previously designated "Variants of Interest" (VOI) or "Variants of Concern" (VOC) that have been conclusively demonstrated to no longer pose a major additional risk to global public health compared to other circulating SARS-CoV-2 variants may be reclassified. Conversely, a variant not previously designated as a variant of interest (VOI) or of concern (VOC) may be so designated if it is determined by WHO or the relevant public health body to meet the relevant criteria, as outlined in the working definition, or is otherwise determined to pose a sufficient additional risk to justify such a designation.

[0206] It will also be recognized that the working definitions provided by the World Health Organization (WHO) for "Variants of Interest" (VOI) or "Variants of Concern" (VOC) are periodically adjusted to account for, for example, the changing public health situation, the emergence of new variants, or further developments in the understanding of the relative public health risks posed by different variants.

[0207] As of October 2021, the term "variants of interest" (VOI) is understood to refer to SARS-CoV-2 variants with genetic changes that are predicted or known to affect virus characteristics, such as transmissibility, severity, immune escape, diagnostic or therapeutic escape, and that have been identified as causing significant community transmission or multiple COVID-19 clusters in multiple countries with increased relative prevalence parallel to an increase in the number of cases over time or other apparent epidemiological impacts suggesting an emerging risk to global public health.

[0208] As of October 2021, the term "variants of concern" (VOC) is understood to refer to SARS-CoV-2 variants that meet the definition of a VOI (see above) and that have been demonstrated, through comparative assessment, to be associated with one or more of the following changes in degree of global public health importance: - Increased transmissibility or adverse changes in COVID-19 epidemiology, or - Increased virulence or change in clinical signs, or - A decline in the effectiveness of public health and social measures or available diagnostics, vaccines and therapeutic agents.

[0209] The WHO's current working definitions of "Variants of Interest" (VOI) and "Variants of Concern" (VOC) for SARS-CoV2 are known to the skilled artisan and are listed, for example, at https: / / www.who.int / en / activities / tracking-SARS-CoV-2-variants / .

[0210] It is to be understood that the various uses of the disclosed antibodies or pharmaceutical compositions of the present invention can be tailored to the specific needs of 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.

[0211] Additionally, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to an "antibody" includes two or more "antibodies."

[0212] All publications, patents, and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety. EXAMPLES

[0213] Example 1: Neutralization of SARS-CoV-2 Serially diluted RQCov-05 / 02, RQCov-05 / 03, RQCov-05 / 04, RQCov-05 / 05, RQCov-06 / 03, RQCov-07 / 02, RQCov-07 / 03 or RQCov-07 / 07 monoclonal antibodies (mAbs) were mixed with SARS-CoV-2 virus and incubated for 1 h at 37 °C. The mixtures were then transferred in duplicate to Vero cell monolayers and incubated for an additional 2 h before adding 1.5% semi-solid carboxymethylcellulose (CMC) overlay medium to each well to limit virus spread. Focus (infected cell) formation assays were then performed by staining Vero cells with human anti-NP mAb (mAb206) followed by peroxidase-conjugated goat anti-human IgG (A0170; Sigma). Finally, foci (approximately 100 per well in the absence of antibody) were visualized by adding TrueBlue peroxidase substrate. Virus-infected cell foci were counted on a classic AID EliSpot reader using AID ELISpot software. The percentage of focus reduction was calculated to give IC 50 and IC 80 was calculated using the probit program in the SPSS package.

[0214] For further details, please see Dejnirattisai et.al.(2021).Antibody evasion by the P.1 strain of SARS-CoV-2 Cell 184(11)2939-2954 https: / / doi.org / 10.1016 / j.cell.2021.03.055.

[0215] As shown in Figures 1-3 and Tables 3-8, antibodies RQCov-05 / 02, RQCov-05 / 03, RQCov-05 / 04, RQCov-05 / 05, RQCov-06 / 03, RQCov-07 / 02, RQCov-07 / 03 and RQCov-07 / 07 were all highly effective at neutralizing all COVID variants tested.

[0216] Figure 1 and Tables 3 and 4 show neutralization of COVID variants by antibodies RQCov-05 / 02, RQCov-05 / 03, RQCov-05 / 04 and RQCov-05 / 05.

[0217] Figure 2 and Tables 5 and 6 show neutralization of COVID variants by antibody RQCov-06 / 03.

[0218] Figure 3 and Tables 7 and 8 show neutralization of COVID variants by antibodies RQCov-07 / 02, RQCov-07 / 03 and RQCov-07 / 07.

[0219] [Table 6]

[0220] [Table 7]

[0221] [Table 8]

[0222]

Table 9

[0223]

Table 10

[0224]

Table 11

Claims

1. an antibody capable of binding to the spike protein of SARS-CoV-2 coronavirus, the antibody comprising a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 3, 31, or 34; and / or (a) a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 6, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 8; (b) a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 11, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 12, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 13; (c) a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 16, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 17, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 18; or (d) a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 21, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 23; An antibody comprising:

2. (a) an epitope on the S1 subunit of the spike protein, optionally an epitope on the receptor binding domain (RBD) of the S1 subunit; or (b) Quaternary epitopes arising through binding to the higher-order structure that constitutes the trimeric spike protein. The antibody of claim 1 , which specifically binds to

3. (a) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO: 4, 32, or 35; and (b) a light chain variable domain having at least 80% sequence identity to SEQ ID NO: 9, 14, 19, or 24. The antibody of claim 1, comprising:

4. The antibody of claim 1 further comprising an IgG1 Fc region.

5. The antibody of claim 4, wherein the Fc region further comprises one or more amino acid substitutions compared to the wild-type IgG1 Fc sequence (SEQ ID NO: 26).

6. 6. The antibody of claim 5, wherein the Fc region comprises a combination of amino acid substitutions selected from M252Y / S254T / T256E ("YTE"), M428L / N434S ("LS"), S239D / I332E ("DE"), M252Y / T256D ("YD"), T256D / T307Q ("DQ") and / or T256D / T307W ("DW"), or any combination thereof.

7. (a) two full-length IgG1 heavy chains, each having at least 80% sequence identity to SEQ ID NO: 5, 33, or 36; and (b) two full-length kappa light chains, each having at least 80% sequence identity to SEQ ID NO: 10, 15, 20, or 25. The antibody of claim 1, comprising:

8. K of less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, less than 1 nM, less than 0.5 nM, less than 0.4 nM, less than 0.3 nM, less than 0.2 nM, or less than 0.1 nM for at least two different variants of SARS-CoV-2 Ｄ The antibody of claim 1 , which binds at a value of 0.

05.

9. an IC of less than 0.02 g / ml against two or more SARS-CoV-2 variants selected from the hCoV-19 / Wuhan / WIV04 / 2019 variant, the SARS-CoV-2 / human / AUS / VIC01 / 2020 variant, the alpha (B.1.1.7) variant, the beta (B.1.351) variant, the gamma (P1) variant, the delta (B1.617.2) variant, the omicron (B.1.1.529) variant, another variant comprising a mutation at one or more of positions 501, 484, 452, 478, and / or 417 in the RBD of the spike protein of SARS-CoV-2, and / or another variant of concern; ５０ The antibody of claim 1 having a value.

10. An IC of less than 0.06 μg / ml against two or more SARS-CoV-2 variants selected from the hCoV-19 / Wuhan / WIV04 / 2019 variant, the SARS-CoV-2 / human / AUS / VIC01 / 2020 variant, the alpha (B.1.1.7) variant, the beta (B.1.351) variant, the gamma (P1) variant, the delta (B1.617.2) variant, another variant comprising a mutation at one or more of positions 501, 484, 452, 478, and / or 417 in the RBD of the spike protein of SARS-CoV-2, and / or another variant of concern ８０ The antibody of claim 1 having a value.

11. (a) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 3; and a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 6, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 8; (b) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 31; and a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 6, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 8; (c) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 34; and a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 6, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 8; (d) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 3; and a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 11, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 12, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 13; (e) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 31; and a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 11, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 12, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 13; (f) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 34; and a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 11, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 12, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 13; (g) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 3; and a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 16, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 17, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 18; (h) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 31; and a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 16, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 17, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 18; (i) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 34; and a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 16, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 17, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 18; (j) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 3; and a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 21, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 23; (k) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 31, and a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 21, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 23; or (l) a heavy chain variable region comprising VHCDR1 comprising the amino acid sequence of SEQ ID NO: 1, VHCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and VHCDR3 comprising the amino acid sequence of SEQ ID NO: 34; and a light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 21, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 23 The antibody of claim 1, comprising:

12. (a) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO: 4 and a light chain variable domain having at least 80% sequence identity to SEQ ID NO: 9; (b) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO: 32 and a light chain variable domain having at least 80% sequence identity to SEQ ID NO: 9; (c) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO: 35 and a light chain variable domain having at least 80% sequence identity to SEQ ID NO: 9; (d) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO:4 and a light chain variable domain having at least 80% sequence identity to SEQ ID NO:14; (e) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO: 32 and a light chain variable domain having at least 80% sequence identity to SEQ ID NO: 14; (f) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO: 35 and a light chain variable domain having at least 80% sequence identity to SEQ ID NO: 14; (g) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO:4 and a light chain variable domain having at least 80% sequence identity to SEQ ID NO:19; (h) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO: 32 and a light chain variable domain having at least 80% sequence identity to SEQ ID NO: 19; (i) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO: 35 and a light chain variable domain having at least 80% sequence identity to SEQ ID NO: 19; (j) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO:4 and a light chain variable domain having at least 80% sequence identity to SEQ ID NO:24; (k) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO: 32 and a light chain variable domain having at least 80% sequence identity to SEQ ID NO: 24; or (l) a heavy chain variable domain having at least 80% sequence identity to SEQ ID NO: 35 and a light chain variable domain having at least 80% sequence identity to SEQ ID NO:

24. The antibody of claim 1, comprising:

13. (a) a first heavy chain comprising a heavy chain variable domain having the sequence of SEQ ID NO: 4, 32, or 35; (b) a first light chain comprising a light chain variable domain having the sequence of SEQ ID NO: 9, 14, 19, or 24; (c) a second heavy chain derived from a different antibody clone to the first heavy chain; and (d) a second light chain wherein the first heavy chain associates with the first light chain to form a first binding domain that specifically binds to an epitope on the spike protein of SARS-CoV-2 or a quaternary epitope that arises through binding to the higher-order structure that constitutes the trimeric spike protein, and the second heavy chain associates with the second light chain to form a second binding domain.

14. (a) the second light chain is the same as the first light chain; or (b) the second light chain is derived from the same antibody clone as the second heavy chain.

15. A polynucleotide encoding the antibody or bispecific antibody of any one of claims 1 to 14.

16. A vector comprising the polynucleotide of claim 15.

17. A host cell comprising the polynucleotide of claim 15.

18. The antibody or bispecific antibody according to any one of claims 1 to 14, a polynucleotide encoding said antibody or bispecific antibody, or a vector comprising said polynucleotide, and at least one pharmaceutically acceptable diluent or carrier A pharmaceutical composition comprising:

19. Two or more antibodies according to any one of claims 1 to 14, two or more polynucleotides encoding said antibodies, or two or more vectors comprising said polynucleotides, and at least one pharmaceutically acceptable diluent or carrier A pharmaceutical composition comprising:

20. 19. The pharmaceutical composition of claim 18, further comprising one or more additional antibodies capable of binding to SARS-CoV-2.

21. For use as a medicine, An antibody or bispecific antibody according to any one of claims 1 to 14. a polynucleotide encoding the antibody or bispecific antibody; a vector comprising the polynucleotide; a host cell containing the polynucleotide; or A pharmaceutical composition comprising said antibody or bispecific antibody, said polynucleotide or said vector, and at least one pharmaceutically acceptable diluent or carrier.

22. For use in a method for treating or preventing a disease or complication associated with a coronavirus infection, optionally wherein the coronavirus is SARS-CoV-2; An antibody or bispecific antibody according to any one of claims 1 to 14. a polynucleotide encoding the antibody or bispecific antibody; a vector comprising the polynucleotide; a host cell containing the polynucleotide; or A pharmaceutical composition comprising said antibody or bispecific antibody, said polynucleotide or said vector, and at least one pharmaceutically acceptable diluent or carrier.

23. For use in the manufacture of a medicament for treating or preventing a disease or complication associated with a coronavirus infection, optionally wherein the disease is COVID-19 or long COVID. An antibody or bispecific antibody according to any one of claims 1 to 14. a polynucleotide encoding the antibody or bispecific antibody; a vector comprising the polynucleotide; a host cell containing the polynucleotide; or A pharmaceutical composition comprising said antibody or bispecific antibody, said polynucleotide or said vector, and at least one pharmaceutically acceptable diluent or carrier.

24. 20. A method for producing an antibody capable of binding to the spike protein of coronavirus SARS-CoV-2, comprising culturing the host cell of claim 17 and isolating the antibody from the culture.

25. 1. A method for identifying the presence of coronavirus or a component or fragment thereof in a sample, comprising: (a) contacting the sample with an antibody according to any one of claims 1 to 12; (b) determining whether the antibody forms an antibody-antigen complex; wherein said formation of said antibody-antigen complex indicates that said sample is positive for coronavirus, and optionally said coronavirus is SARS-CoV-2.

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