SARS-CoV-2 spike binding molecules

Abstract

A SARS-CoV-2 spike protein binding molecule is disclosed. Also disclosed are nucleic acids and expression vectors encoding the SARS-CoV-2 spike protein binding molecules, compositions comprising the SARS-CoV-2 spike protein binding molecules, and methods of using the SARS-CoV-2 spike protein binding molecules.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to patent application No. SG 10202260528T filed on December 21, 2022, all contents and elements of which are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to the field of molecular biology, more specifically to the field of antibody technology. The present disclosure also relates to medical treatment and prevention methods. Background Art

[0004] COVID-19, the human pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and its ongoing spread have caused significant economic and human losses worldwide. The emergence of SARS-CoV-2 variants has posed a serious challenge to the broad-spectrum treatment and prevention of COVID-19.

[0005] WO2022 / 245288A1 and Westendorf et al. in Cell Reports, Vol. 39, No. 7, 2022, p. 110812, describe antibodies that inhibit the binding of the spike protein of SARS-CoV-2 and SARS-CoV-2 variants to the spike protein receptor ACE2, thereby inhibiting infection of ACE2-expressing cells by these viruses. However, there remains an unmet need for antibodies that can neutralize infection by a broader range of betacoronaviruses, including emerging and future SARS-CoV-2 variants and other betacoronaviruses with epidemic potential. Summary of the Invention

[0006] In a first aspect of the present disclosure, an optionally isolated antigen-binding molecule that binds to a beta coronavirus spike protein is provided, the antigen-binding molecule comprising: (I) a VH region comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in column A of Table A; (II) a VL region comprising LC-CDR1, LC-CDR2, and LC-CDR3 as shown in column B of Table A, wherein the sequences in columns A and B are selected from the same row of Table A.

[0007] In some embodiments, the antigen binding molecule comprises:

[0008] (i) a heavy chain variable region (VH), comprising the following CDRs:

[0009] HC-CDR1 containing the amino acid sequence of SEQ ID NO: 37

[0010] HC-CDR2 containing the amino acid sequence of SEQ ID NO: 53

[0011] HC-CDR3 containing the amino acid sequence of SEQ ID NO: 54

[0012] (ii) a light chain variable region (VL), comprising the following CDRs:

[0013] LC-CDR1 containing the amino acid sequence of SEQ ID NO: 60

[0014] LC-CDR2 containing the amino acid sequence of SEQ ID NO: 61

[0015] LC-CDR3 comprising the amino acid sequence of SEQ ID NO:62.

[0016] In other embodiments, the antigen-binding molecule comprises: (i) a VH region comprising the amino acid sequence shown in column A of Table C; (ii) a VL region comprising the amino acid sequence shown in column B of Table C, wherein the sequences in columns A and B are selected from the same row of Table C.

[0017] In some embodiments, the antigen binding molecule comprises:

[0018] a VH region having an amino acid sequence that is at least 70% identical to SEQ ID NO: 52; and

[0019] A VL region having an amino acid sequence that is at least 70% identical to SEQ ID NO:59.

[0020] In some embodiments, the antigen binding molecule is a multispecific antigen binding molecule, which further comprises an antigen binding domain that binds to an antigen other than the betacoronavirus spike protein.

[0021] The present disclosure also provides a chimeric antigen receptor (CAR), which comprises the antigen binding molecule described in the present disclosure.

[0022] The present disclosure also provides one or more optionally isolated nucleic acids encoding the antigen binding molecules as described herein, or the CAR as described herein.

[0023] The present disclosure also provides one or more expression vectors comprising one or more nucleic acids as described herein.

[0024] The present disclosure also provides a cell comprising the antigen binding molecule, CAR, one or more nucleic acids, or one or more expression vectors as described in the present disclosure.

[0025] The present disclosure also provides a method of culturing a cell as described herein under conditions suitable for the cell to express an antigen binding molecule or a CAR.

[0026] The present disclosure also provides a composition comprising an antigen binding molecule, a CAR, a nucleic acid or plurality of nucleic acids, an expression vector or plurality of expression vectors, a cell as described herein; and a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

[0027] In some embodiments, the composition further comprises:

[0028] (a) an antigen binding molecule that binds to a spike protein of a coronavirus, comprising a VH region having an amino acid sequence at least 70% identical to SEQ ID NO: 824, and a VL region having an amino acid sequence at least 70% identical to SEQ ID NO: 830; or

[0029] (b) an antigen binding molecule that binds to a spike protein of a coronavirus, comprising a VH region having an amino acid sequence at least 70% identical to SEQ ID NO: 839, and a VL region having an amino acid sequence at least 70% identical to SEQ ID NO: 846.

[0030] The present disclosure also provides a combination comprising: (i) an antigen binding molecule as described herein, and (ii) (a) an antigen binding molecule that binds to a spike protein of a coronavirus, comprising a VH region having an amino acid sequence at least 70% identical to SEQ ID NO: 824, and a VL region having an amino acid sequence at least 70% identical to SEQ ID NO: 830; or (b) an antigen binding molecule that binds to a spike protein of a coronavirus, comprising a VH region having an amino acid sequence at least 70% identical to SEQ ID NO: 839, and a VL region having an amino acid sequence at least 70% identical to SEQ ID NO: 846.

[0031] The present disclosure also provides an antigen binding molecule, a CAR, a nucleic acid or plurality of nucleic acids, an expression vector or plurality of expression vectors, a cell, a composition or combination as described herein for use in a method of medical treatment and prevention.

[0032] The present disclosure also provides an antigen binding molecule, a CAR, a nucleic acid or plurality of nucleic acids, an expression vector or plurality of expression vectors, a cell, a composition or combination as described herein for use in the treatment or prevention of a disease or condition characterised by a coronavirus infection, optionally the coronavirus infection disease or condition is COVID-19.

[0033] The present disclosure also provides a use of an antigen binding molecule, CAR, one or more nucleic acids, one or more expression vectors, cells, compositions and combinations as described herein in the preparation of a medicament for treating or preventing a disease or condition characterized by betacoronavirus infection, optionally, the betacoronavirus infection disease or condition is COVID-19.

[0034] The present disclosure also provides a method for treating or preventing a disease or condition characterized by betacoronavirus infection in a subject, comprising administering to the subject a therapeutically or prophylactically effective amount of an antigen binding molecule, CAR, one or more nucleic acids, one or more expression vectors, cells, compositions and combinations as described herein to prepare a drug for treating or preventing a disease or condition characterized by betacoronavirus infection, optionally, the betacoronavirus infection disease or condition is COVID-19.

[0035] The present disclosure also provides an optionally isolated in vitro complex comprising an antigen binding molecule as described herein bound to a betacoronavirus or a betacoronavirus spike protein.

[0036] The present disclosure also provides a method for detecting betacoronavirus and betacoronavirus spike protein in a sample, which comprises contacting a sample containing or suspected of containing betacoronavirus or betacoronavirus spike protein with an antigen-binding molecule as described in the present disclosure, and detecting the formation of a complex between the antigen-binding molecule and betacoronavirus or betacoronavirus spike protein.

[0037] The present disclosure also provides a method for selecting and stratifying subjects for treatment with a betacoronavirus targeted drug, the method comprising contacting a sample from a subject in vitro with an antigen-binding molecule as described in the present disclosure, and detecting the formation of a complex between the antigen-binding molecule and betacoronavirus or betacoronavirus spike protein.

[0038] The present disclosure also provides use of the antigen-binding molecules described herein as in vitro or in vivo diagnostic or prognostic reagents. DETAILED DESCRIPTION

[0039] The present disclosure provides antigen-binding molecules that bind to a betacoronavirus spike protein (e.g., a SARS-CoV-2 spike protein and / or a SARS-CoV-2 variant spike protein) and have novel biophysical and / or functional properties compared to antigen-binding molecules disclosed in the art.

[0040] In particular, the present disclosure provides antigen binding molecules that bind to the spike protein of betacoronavirus and inhibit the binding of the spike protein of betacoronavirus to ACE2. Such antigen binding molecules can be used to inhibit the infection of ACE2 expressing cells by betacoronavirus containing such spike proteins.

[0041] The antigen binding molecules of the present disclosure can (inhibit) the interaction between ACE2 and a range of betacoronavirus spike proteins, including a broad range of SARS-CoV-2 variant spike proteins. The antigen binding molecules of the present disclosure can thus be used to treat and prevent diseases caused by a broad range of betacoronavirus, including a broad range of SARS-CoV-2 variants. It has also been demonstrated that antigen binding molecules as described in the present disclosure can more efficiently inhibit the binding of ACE2 to betacoronavirus spike proteins compared to known antibodies binding to betacoronavirus spike proteins.

[0042] The present disclosure also provides compositions comprising novel combinations of antigen binding molecules and methods of therapeutic / prophylactic intervention using compositions comprising novel combinations of antigen binding molecules that can more efficiently inhibit the infection of ACE2 expressing cells by betacoronavirus and / or inhibit the infection of ACE2 expressing cells by a broader range of betacoronavirus compared to known compositions / intervention methods.

[0043] Betacoronaviruses, SARSr-CoV, SARSr-CoV-2, and SARSr-CoV-2 variants

[0044] The present disclosure relates to betacoronavirus, which is a member of the Betacoronavirus subgenus of the Betacoronavirus genus and can infect humans, bats and other specific mammals. It is an enveloped, positive-sense, single-stranded RNA virus.

[0045] According to evolutionary relationships, betacoronavirus can be divided into three major clades: clade 1, clade 2 and clade 3; see Xiang et al. in Cell Rep 2022 39(13) 111004 and Tortorici et al. in Nature 2021 597 103-108.

[0046] Coronavirus group 1 can be further divided into subgroups la, lb, and lc. Coronavirus group 1a includes SARS-CoV (also known as SARS-CoV-1), WIV-1, LYRa11, Rs4231, BtSY1, RsSHC014, and Rs9401. Coronavirus group 1b includes SARS-CoV-2, SARS-CoV-2 variants, RaTG13, BANAL-20-15, BANAL-20-52, BANAL-20-236, BANAL-20-103, Rc-o319, RsSTT182, BtSY2, GX-P5L, and GD-1. Coronavirus group 1c includes RaTG15 and RpYN04. Coronavirus group 2 includes RmYN02, RacCS203, SL-ZX45, SL-ZXC21, BANAL-20-116, BANAL-20-247, PrC31, RpYN06, Rml, Rfl, Rp3, HKU3-1, JTMC15, SX2013, HeB2013, Rs4237, 16BO133, and Anlong-103. Coronavirus group 3 includes BtKY72, BM48-31, and Khosta-2.

[0047] In certain embodiments, the betacoronavirus as described herein refers to a betacoronavirus group 1, 2, or 3. In certain embodiments, the betacoronavirus refers to a betacoronavirus group 1 or 3. In certain embodiments, the betacoronavirus is a betacoronavirus group 1b or 3. In certain embodiments, the betacoronavirus is not a betacoronavirus group 2. In certain embodiments, the betacoronavirus refers to a betacoronavirus group 1. In certain embodiments, the betacoronavirus refers to a betacoronavirus group la or lb.

[0048] In certain embodiments, the betacoronavirus as described herein refers to a betacoronavirus having a nucleotide sequence that is at least 60% (≥ 60%, ≥ 65%, ≥ 70%, ≥ 75%, ≥ 80%, ≥ 85%, ≥ 86%, ≥ 87%, ≥ 88%, ≥ 89%, ≥ 90%, ≥ 91%, ≥ 92%, ≥ 93%, ≥ 94%, ≥ 95%, ≥ 96%, ≥ 97%, ≥ 98%, ≥ 99%, or ≥ 100%) sequence identical to the nucleotide sequence of GenBank: MN908947.3.

[0049] In certain embodiments, the betacoronavirus as described herein is a severe acute respiratory syndrome-related coronavirus (SARSr-CoV). Viral characteristics of SARSr-CoV and epidemiological studies of disease associated with SARSr-CoV infection can be found in Cheng et al., Clin Microbiol Rev 2007 20:660-694 and de Wit et al., Nat Rev Microbial 2016 14:523-534, both of which are incorporated by reference herein in their entirety.

[0050] Two strains of SARSr-CoV have caused major outbreaks of severe respiratory illness in humans: SARS-CoV caused the severe acute respiratory syndrome (SARS) outbreak between 2002 and 2003, and SARS-CoV-2 caused the coronavirus disease 2019 (COVID-19) pandemic. Hundreds of strains of SARSr-CoV are known that infect only non-human species; bats are the primary intermediate host for multiple SARS-related coronaviruses.

[0051] In certain embodiments, the betacoronavirus as described herein refers to SARS-CoV-2 or a SARS-CoV-2 variant.

[0052] “SARS-CoV-2” as used herein refers to SARS-CoV having the GenBank: MN908947.3 (“Severe acute respiratory syndrome coronavirus 2 Wuhan-Hu-1 isolate complete genome”) nucleotide sequence as described in Wu et al., Nature 2020 579:265-269.

[0053] A large number of SARS-CoV-2 variants have been observed and described, as described in Planas et al., Nat. Commun. 2023 14:824, Habib et al., Microbial Resour Announc. 2023 12 3:e00001-23, Katzmarzyk et al., Front Immunol. 2023 14:1288794, Lasrado et al., Vaccine 2023 41 47:6904-6909, and Rahman et al., Microbial Resour Announc. 2023 12 10:e00562-23.

[0054] As used herein, "SARSr-CoV" refers to a betacoronavirus having a nucleotide sequence that is at least 70% (one of ≥70%, ≥75%, ≥80%, ≥85%, ≥86%, ≥87%, ≥88%, ≥89%, ≥90%, ≥91%, ≥92%, ≥93%, ≥94%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99% or ≥100%) identical to the nucleotide sequence of GenBank: MN908947.3.

[0055] The "SARS-CoV-2 variant" described herein is a betacoronavirus having a nucleotide sequence that is at least 70% (one of ≥70%, ≥75%, ≥80%, ≥85%, ≥86%, ≥87%, ≥88%, ≥89%, ≥90%, ≥91%, ≥92%, ≥93%, ≥94%, ≥95%, ≥96%, ≥97%, ≥98% or ≥99%) identical to the nucleotide sequence of GenBank: MN908947.3, and its nucleotide sequence is not the same as the nucleotide sequence of GenBank: MN908947.3.

[0056] SARS-CoV-2 variants of particular interest to the present disclosure include: BA.1 (also known as Omicron; B.1.1.529; as represented by GISAID number EPI_ISL_7358094.2). Omicron subvariants such as BA.2 (such as GISAID number EPI_ISL_6795834.2). BA.5 (GISAID number EPI_ISL_12268495.2). BA.2.75 (such as represented by GISAID number EPI_ISL_13692860). BA.2.75.2 (such as represented by GISAID number EPI_ISL_15731524). BA.4.6.1 (such as represented by GISAID number EPI_ISL_13925521). BF.7 (such as represented by GISAID number EPI_ISL_13692860). BQ.1.1 (such as represented by GISAID number EPI_ISL_15731523). XBB (such as represented by GISAID number EPI_ISL_15503511). XBB.1 (such as represented by GISAID number EPI_ISL_15503005). XBB.1.16 (such as represented by GISAID number EPI_ISL_17646715). XBB.2.3 (such as represented by GISAID number EPI_ISL_17719186). EG.5 (such as represented by GISAID number EPI_ISL_17976635). EG.5.1 (such as represented by GISAID number EPI_ISL_18125149). B.1.1.7 (also known as Alpha; GISAID EPI_ISL_674612). B.1.351 (also known as Beta and 501Y.V2; GISAID EPI_ISL_940877). B.1.617.2 (also known as Delta; GISAID EPI_ISL_1921353). And P.1 (also known as Gamma; GISAID EPI_ISL_2777382).

[0057] Accordingly, in certain embodiments, the SARS-CoV-2 variants disclosed herein are selected from: BA.1, BA.2, BA.2.75, BA.2.75.2, BA.4.6.1, BF.7, BQ.1.1, XBB, XBB.1, XBB.1.16, XBB.2.3, EG.5, EG.5.1, B.1.1.7, B.1.351, B.1.617 and P.1.

[0058] SARS-CoV-2 spike protein and SARS-CoV-2 variant spike protein

[0059] The betacoronavirus genome encodes four major structural proteins: spike (S) protein, envelope (E) protein, membrane (M) protein, and nucleocapsid (N) protein. The present disclosure focuses on antigen-binding molecules that bind to the betacoronavirus spike protein.

[0060] The typical spike protein of SARS-CoV-2 (encoded by the nucleotide sequence in GenBank: MN908947.3) has the amino acid sequence shown in SEQ ID NO:1. The SARS-CoV-2 spike protein consists of two subunits: S1 (SEQ ID NO:6) and S2 (SEQ ID NO:9). The S1 subunit contains the minimal receptor binding domain (RBD; SEQ ID NO:7), through which SARS-CoV-2 binds to host cells expressing ACE2. The RBD, in turn, consists of the receptor binding motif (RBM; SEQ ID NO:8), the region of the RBD that binds to ACE2.

[0061] As used herein, "SARS-CoV-2 spike protein" refers to a polypeptide having the amino acid sequence of SEQ ID NO: 1. The RBD of the SARS-CoV-2 spike protein is the amino acid sequence of SEQ ID NO: 7. The RBM of the SARS-CoV-2 spike protein is the amino acid sequence of SEQ ID NO: 8.

[0062] A number of variants of the SARS-CoV-2 spike protein (encoded by variant SARS-CoV-2) have been reported, i.e., proteins containing one or more substitutions, deletions, or insertions of amino acids in the spike protein's amino acid sequence. These proteins are referred to herein as variant SARS-CoV-2 spike proteins.

[0063] As described in the present disclosure, the beta coronavirus spike protein refers to a polypeptide having an amino acid sequence that is at least 60% (one of ≥60%, ≥65%, ≥70%, ≥75%, ≥80%, ≥85%, ≥86%, ≥87%, ≥88%, ≥89%, ≥90%, ≥91%, ≥92%, ≥93%, ≥94%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99% or ≥100%) identical to SEQ ID NO:1. As used herein, the term "SARSr-CoV spike protein" refers to a polypeptide having an amino acid sequence that is at least 70% (one of ≥70%, ≥75%, ≥80%, ≥85%, ≥86%, ≥87%, ≥88%, ≥89%, ≥90%, ≥91%, ≥92%, ≥93%, ≥94%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99% or ≥100%) identical to SEQ ID NO:1.

[0064] As described in the present disclosure, the "SARS-CoV-2 variant spike protein" refers to a polypeptide having an amino acid sequence that is at least 70% (one of ≥70%, ≥75%, ≥80%, ≥85%, ≥86%, ≥87%, ≥88%, ≥89%, ≥90%, ≥91%, ≥92%, ≥93%, ≥94%, ≥95%, ≥96%, ≥97%, ≥98% or ≥99%) identical to the amino acid sequence of SEQ ID NO:1, and its amino acid sequence is not identical to SEQ ID NO:1.

[0065] In certain embodiments, the SARS-CoV-2 variant spike protein comprises an amino acid sequence that has at least 70% (one of ≥70%, ≥75%, ≥80%, ≥85%, ≥86%, ≥87%, ≥88%, ≥89%, ≥90%, ≥91%, ≥92%, ≥93%, ≥94%, ≥95%, ≥96%, ≥97%, ≥98%, or ≥99%) amino acid sequence identity to the amino acid sequence of SEQ ID NO:7, but its amino acid sequence is not identical to SEQ ID NO:7. In certain embodiments, the SARS-CoV-2 variant spike protein comprises an amino acid sequence that has at least 70% (one of ≥70%, ≥75%, ≥80%, ≥85%, ≥86%, ≥87%, ≥88%, ≥89%, ≥90%, ≥91%, ≥92%, ≥93%, ≥94%, ≥95%, ≥96%, ≥97%, ≥98%, or ≥99%) amino acid sequence identity to the amino acid sequence of SEQ ID NO:8, but its amino acid sequence is not identical to SEQ ID NO:8.

[0066] The following table summarizes the amino acid substitutions and deletions (Δ) in the spike protein amino acid sequences of the variants of primary concern, namely, SARS-CoV-2 variants. The SARS-CoV-2 variant spike protein variants shown in Table 1 are from outbreak.info (Gangavarapu et al., Nature Methods, 2023, 512-522). The numbering of the SARS-CoV-2 spike protein residues and variant positions as described in this disclosure can be determined by SEQ ID NO: 1.

[0067] Table 1

[0068]

[0069]

[0070]

[0071] In certain embodiments, the SARS-CoV-2 variant spike protein as described in the present disclosure contains an amino acid sequence that has at least 70% sequence identity with the amino acid sequence of SEQ ID NO:1, and contains one or more mutations as shown in Table 1 above.

[0072] In certain embodiments, the SARS-CoV-2 variant spike protein comprises or consists of an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 1, and comprises a variation as set forth in row 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 of column A of Table 1 above. By way of illustration, in certain embodiments, the SARS-CoV-2 variant spike protein comprises or consists of an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 1, and comprises N440K, S477N, T478K, E484A, Q493R, Q498R, N501Y, Y505H, G446S, and G496S (RBM variation of BA.1 set forth in row 1).

[0073] In certain embodiments, the SARS-CoV-2 variant spike protein comprises or consists of an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 1, and comprises a variation as set forth in row 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 of column B of Table 1 above. In certain embodiments, the SARS-CoV-2 variant spike protein comprises or consists of an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 1, and comprises a variation as set forth in row 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 of column C of Table 1 above.

[0074] In certain embodiments, the SARS-CoV-2 variant spike protein comprises or consists of an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 1, and comprises the variants set forth in columns A and B of Table 1, rows 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18. By way of illustration, in certain embodiments, the SARS-CoV-2 variant spike protein comprises or consists of an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 1, and comprises N440K, S477N, T478K, E484A, Q493R, Q498R, N501Y, Y505H, G446S, G496S, G339D, S373P, S375F, K417N, and S371L (RBD variants of BA.1 set forth in row 1).

[0075] In certain embodiments, the SARS-CoV-2 variant spike protein contains or consists of an amino acid sequence that is at least 70% sequence identical to the amino acid sequence of SEQ ID NO: 1 and contains the variations set forth in rows 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 of Table 1A, B, and C. By way of illustration, in certain embodiments, the SARS-CoV-2 variant spike protein contains or consists of an amino acid sequence that is at least 70% sequence identical to the amino acid sequence of SEQ ID NO: 1 and contains N440K, S477N, T478K, E484A, Q493R, Q498R, N501Y, Y505H, G446S, G496S, G339D, S373P, S375F, K417N, S371L, A67V, Δ69, Δ70, T95I, G142D, Δ143, Δ144, Δ145, Δ211, L212I, +214EPE, T547K, D614G, H655Y, N679K, P681H, N764K, D796Y, N856K, Q954H, N969K, and L981F (spike protein variations for BA.1 set forth in row 1).

[0076] In certain embodiments, the SARS-CoV-2 variant spike protein contains or consists of a spike protein amino acid sequence encoded by a SARS-CoV-2 variant selected from the group consisting of: BA.1, BA.2, BA.2.75, BA.2.75.2, BA.4.6.1, BF.7, BQ.1.1, XBB, XBB.1, XBB.1.16, XBB.2.3, EG.5, EG.5.1, B.1.1.7, B.1.351, B.1.617, and P.1.

[0077] In certain embodiments, the SARS-CoV-2 variant spike protein as described herein contains an amino acid sequence that is at least 70% (≥70%, ≥75%, ≥80%, ≥85%, ≥86%, ≥87%, ≥88%, ≥89%, ≥90%, ≥91%, ≥92%, ≥93%, ≥94%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99%, or ≥100% of one) sequence identical to the amino acid sequence of SEQ ID NO: 703, 704, 705, 706, 707, 708, 708, 710, 711, 712, 713, 714, 715, 716, 717, 718, or 719.

[0078] In certain embodiments, the SARS-CoV-2 variant spike protein as described herein contains an amino acid sequence that is at least 70% (one of ≥70%, ≥75%, ≥80%, ≥85%, ≥86%, ≥87%, ≥88%, ≥89%, ≥90%, ≥91%, ≥92%, ≥93%, ≥94%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99%, or ≥100%) identical to the amino acid sequence of SEQ ID NO: 686, 687, 688, 689, 690, 691, 692, 693, 394, 695, 696, 697, 698, 699, 700, 701, or 702.

[0079] In certain embodiments, the SARS-CoV-2 variant spike protein as described herein contains or consists of an amino acid sequence that is at least 70% (one of ≥70%, ≥75%, ≥80%, ≥85%, ≥86%, ≥87%, ≥88%, ≥89%, ≥90%, ≥91%, ≥92%, ≥93%, ≥94%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99% or ≥100%) identical to the amino acid sequence of SEQ ID NO: 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 or 27.

[0080] In certain embodiments, the SARS-CoV-2 variant spike protein comprises or consists of an amino acid sequence that is at least 70% (>70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, or >100% of one of SEQ ID NOs: 11, 12, 13, or 14), and comprises (i) the variation set forth in row 1 of column A of Table 1; (ii) the variation set forth in rows 1 of columns A and B of Table 1; or (iii) the variation set forth in rows 1 of columns A, B, and C of Table 1. In certain embodiments, the SARS-CoV-2 variant spike protein comprises or consists of an amino acid sequence that is at least 70% (>70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, or >100% of one of SEQ ID NOs: 11, 12, 13, or 14), and comprises (i) the variation set forth in row 2 of column A of Table 1; (ii) the variation set forth in rows 2 of columns A and B of Table 1; or (iii) the variation set forth in rows 2 of columns A, B, and C of Table 1. In certain embodiments, the SARS-CoV-2 variant spike protein comprises or consists of an amino acid sequence that is at least 70% (>70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, or >100% of one of SEQ ID NOs: 11, 12, 13, or 14), and comprises (i) the variation set forth in row 3 of column A of Table 1; (ii) the variation set forth in rows 3 of columns A and B of Table 1; or (iii) the variation set forth in rows 3 of columns A, B, and C of Table 1. In certain embodiments, the SARS-CoV-2 variant spike protein comprises or consists of an amino acid sequence that is at least 70% (>70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, or >100% of one of SEQ ID NOs: 11, 12, 13, or 14), and comprises (i) the variation set forth in row 4 of column A of Table 1; (ii) the variation set forth in rows 4 of columns A and B of Table 1; or (iii) the variation set forth in rows 4 of columns A, B, and C of Table 1.In certain embodiments, the SARS-CoV-2 variant spike protein comprises or consists of an amino acid sequence that is at least 70% (>70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, or >100% of one of SEQ ID NOs: 15, 16, 17, and 18), and comprises the mutation set forth in (i) row 5 of column A of Table 1; (ii) rows 5 of columns A and B of Table 1; or (iii) rows 5 of columns A, B, and C of Table 1. In certain embodiments, the SARS-CoV-2 variant spike protein comprises or consists of an amino acid sequence that is at least 70% (>70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, or >100% of one of SEQ ID NOs: 15, 16, 17, and 18), and comprises the mutation set forth in (i) row 6 of column A of Table 1; (ii) rows 6 of columns A and B of Table 1; or (iii) rows 6 of columns A, B, and C of Table 1. In certain embodiments, the SARS-CoV-2 variant spike protein comprises or consists of an amino acid sequence that is at least 70% (>70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, or >100% of one of SEQ ID NOs: 15, 16, 17, and 18), and comprises the mutation set forth in (i) row 7 of column A of Table 1; (ii) rows 7 of columns A and B of Table 1; or (iii) rows 7 of columns A, B, and C of Table 1. In certain embodiments, the SARS-CoV-2 variant spike protein comprises or consists of an amino acid sequence that is at least 70% (>70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, or >100% of one of SEQ ID NOs: 15, 16, 17, and 18), and comprises the mutation set forth in (i) row 8 of column A of Table 1; (ii) rows 8 of columns A and B of Table 1; or (iii) rows 8 of columns A, B, and C of Table 1.In certain embodiments, the SARS-CoV-2 variant spike protein comprises or consists of an amino acid sequence that is at least 70% (>70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, or >100% of one of SEQ ID NOs: 19, 20, 21, and 22), and comprises (i) the variation set forth in row 9 of column A of Table 1; (ii) the variation set forth in rows 9 of columns A and B of Table 1; or (iii) the variation set forth in rows 9 of columns A, B, and C of Table 1. In certain embodiments, the SARS-CoV-2 variant spike protein comprises or consists of an amino acid sequence that is at least 70% (>70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, or >100% of one of SEQ ID NOs: 19, 20, 21, and 22), and comprises (i) the variation set forth in row 10 of column A of Table 1; (ii) the variation set forth in rows 10 of columns A and B of Table 1; or (iii) the variation set forth in rows 10 of columns A, B, and C of Table 1. In certain embodiments, the SARS-CoV-2 variant spike protein comprises or consists of an amino acid sequence that is at least 70% (>70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, or >100% of one of SEQ ID NOs: 19, 20, 21, and 22), and comprises (i) the variation set forth in row 11 of column A of Table 1; (ii) the variation set forth in rows 11 of columns A and B of Table 1; or (iii) the variation set forth in rows 11 of columns A, B, and C of Table 1. In certain embodiments, the SARS-CoV-2 variant spike protein comprises or consists of an amino acid sequence that is at least 70% (>70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, or >100% of one of SEQ ID NOs: 19, 20, 21, and 22), and comprises (i) the variation set forth in row 12 of column A of Table 1; (ii) the variation set forth in rows 12 of columns A and B of Table 1; or (iii) the variation set forth in rows 12 of columns A, B, and C of Table 1.In certain embodiments, the SARS-CoV-2 variant spike protein comprises or consists of an amino acid sequence that is at least 70% (>70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, or >100%) identical to the amino acid sequence of SEQ ID NO: 23 and contains (i) the variation set forth in row 13 of column A of Table 1; (ii) the variation set forth in rows 13 of columns A and B of Table 1; or (iii) the variation set forth in rows 13 of columns A, B, and C of Table 1. In certain embodiments, the SARS-CoV-2 variant spike protein comprises or consists of an amino acid sequence that is at least 70% (>70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, or >100%) identical to the amino acid sequence of SEQ ID NO: 24 and contains (i) the variation set forth in row 14 of column A of Table 1; (ii) the variation set forth in rows 14 of columns A and B of Table 1; or (iii) the variation set forth in rows 14 of columns A, B, and C of Table 1. In certain embodiments, the SARS-CoV-2 variant spike protein comprises or consists of an amino acid sequence that is at least 70% (>70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, or >100%) identical to the amino acid sequence of SEQ ID NO: 25 and contains (i) the variation set forth in row 15 of column A of Table 1; (ii) the variation set forth in rows 15 of columns A and B of Table 1; or (iii) the variation set forth in rows 15 of columns A, B, and C of Table 1. In certain embodiments, the SARS-CoV-2 variant spike protein comprises or consists of an amino acid sequence that is at least 70% (>70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, or >100%) identical to the amino acid sequence of SEQ ID NO: 26 and contains (i) the variation set forth in row 16 of column A of Table 1; (ii) the variation set forth in rows 15 of columns A and B of Table 1; or (iii) the variation set forth in rows 16 of columns A, B, and C of Table 1.In certain embodiments, the SARS-CoV-2 variant spike protein comprises or consists of an amino acid sequence that is at least 70% (one of ≥70%, ≥75%, ≥80%, ≥85%, ≥86%, ≥87%, ≥88%, ≥89%, ≥90%, ≥91%, ≥92%, ≥93%, ≥94%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99%, or ≥100%) identical to the amino acid sequence of SEQ ID NO:27, and contains the variation set forth in (i) row 17 of column A of Table 1; (ii) row 17 of columns A and B of Table 1; or (iii) row 15 of columns A, B, and C of Table 1.

[0081] ACE2

[0082] Angiotensin-converting enzyme 2 (ACE2) is the entry point for SARSr-CoV to enter cells through the binding of its spike protein. The SARSr-CoV spike protein binds to the extracellular domain of ACE2 (Zhou et al., Nature, 2020, 579, 270-273; Hoffmann et al., Cell, 2020, 181, 271-280).

[0083] ACE2 is a single-pass, type I transmembrane carboxypeptidase found on the cell membranes of cells in the outer surface of the lungs, arteries, heart, kidneys, and intestines. The structure and function of ACE2 are described in Hamming et al., J Pathol, 2004, Vol. 203, No. 2, pp. 631-637, which is incorporated herein by reference in its entirety.

[0084] As used herein, "ACE2" refers to ACE2 in all species, including ACE2 subtypes, fragments, variants, or homologs of any species. In certain embodiments, the ACE2 refers to ACE2 from mammals (e.g., placental therians, eutherians, protherians, primates, or primates (rhesus macaques, cynomolgus macaques, non-human primates, or humans)). In certain embodiments, the ACE2 refers to ACE2 from humans, bats, pangolins, civets, or pigs. An ACE2 isoform, fragment, variant or homolog can be characterized as having at least 70% (one of ≥70%, ≥75%, ≥80%, ≥85%, ≥86%, ≥87%, ≥88%, ≥89%, ≥90%, ≥91%, ≥92%, ≥93%, ≥94%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99% or ≥100%) sequence identity to the amino acid sequence of an immature or mature ACE2 isoform of a particular species, such as human.

[0085] Human ACE2 isoform 1 is set forth in SEQ ID NO: 28, and human ACE2 isoform 2 is set forth in SEQ ID NO: 35. The extracellular domain of human ACE2 is set forth in SEQ ID NO: 30.

[0086] The ACE2 fragment can have a minimum length of one of 25, 50, 100, 200, 300, 400, 500, 600, 700, or 800 amino acids and a maximum length of one of 50, 100, 200, 300, 400, 500, 600, 700, or 800 amino acids. The ACE2 fragment can bind to a betacoronavirus spike protein (a SARSr-CoV spike protein, a SARS-CoV-2 spike protein, and / or one or more SARS-CoV-2 variant spike proteins).

[0087] In certain embodiments, the ACE2 comprises or consists of an amino acid sequence having a sequence identity of at least 70% or more, preferably one of 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to the amino acid sequence of SEQ ID NO: 28 or 35.

[0088] In certain embodiments, the ACE2 fragment comprises or consists of an amino acid sequence having a sequence identity of at least 70% or more, preferably one of 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to the amino acid sequence of SEQ ID NO: 30.

[0089] Antigen-binding molecules of the present disclosure

[0090] The present disclosure provides an antigen binding molecule that can bind to a betacoronavirus spike protein (a SARSr-CoV spike protein, a SARS-CoV-2 spike protein, and / or one or more SARS-CoV-2 variant spike proteins). Such an antigen binding molecule can also be referred to as an antigen binding molecule that can bind to a related protein.

[0091] The“antigen binding molecule” refers to a molecule that can bind to a given target antigen. Antigen binding molecules include antibodies (lgs) and antigen binding fragments thereof. As described herein,“antibodies” include monoclonal antibodies, polyclonal antibodies, monospecific and multispecific (e.g., bispecific, trispecific, etc.) antibodies, and antibody-derived antigen binding molecules, such as scFv, scFab, diabodies, triabodies, scFv-Fc, minibodies, single domain antibodies (VhH), etc. Antigen binding fragments of antibodies include, e.g., Fv, Fab, F(ab’)2, and F(ab’) fragments. In certain embodiments, the antigen binding molecule can be an antibody or an antigen binding fragment thereof.

[0092] Antigen binding molecules as described in the present disclosure also include antibody-derived molecules, such as molecules comprising antibody-derived antigen binding domains. The antibody-derived antigen binding molecules can comprise an antigen binding domain comprising or consisting of an antigen binding domain of an antibody, such as an antigen binding fragment of an antibody. In certain embodiments, the antigen binding domain of an antibody-derived antigen binding molecule can be or comprise an Fv (e.g., in the form of an scFv) or Fab region of an antibody, or a complete antibody. As such, antigen binding molecules as described in the present disclosure include antibody drug conjugates (ADCs) comprising a (cytotoxic) pharmacophore (as described below). Antigen binding molecules as described in the present disclosure also include multispecific antigen binding molecules, such as immune cell engager molecules comprising (effector) immune cell recruiting domains (see Goebeler and Bargou, Nat. Rev. Clin. Oncol. 2020 17:418-434 and Ellerman, Methods 2019 154:102-117, both of which are incorporated by reference herein in their entireties), including BiTEs, BiKEs, and TriKEs. Antigen binding molecules as described in the present disclosure also include chimeric antigen receptors (CARs), which are recombinant receptors capable of providing both antigen binding and T cell activation functions (see Dotti et al., Immunol Rev 2014 257:1 and Jayaraman et al., EBioMedicine 2020 58:102931, both of which are incorporated by reference herein in their entireties, for structure, function, and engineering of CARs).

[0093] An antigen binding molecule as described herein comprises one or more domains capable of binding to a target antigen. In certain embodiments, a domain capable of binding to a target antigen comprises an antibody heavy chain variable region (VH) and one antibody light chain variable region (LH) capable of specifically binding to a target antigen. In certain embodiments, a domain capable of binding to a target antigen as described herein comprises or consists of an aptamer capable of binding to a target antigen, such as a nucleic acid aptamer (see Zhou and Rossi, Nat Rev Drug Discov. 2017, 16(3): 181-202). In certain embodiments, a domain capable of binding to a target antigen comprises or consists of an antigen binding peptide / polypeptide, such as a peptide aptamer, thioredoxin, monobody, anticalin, Kunitz domain, avimer, knottin, fynomer, atrimer, DARPin, affibody, nanobody (single domain antibody (sdAb)), affilin, armadillo repeat protein (ArmRP), OBody, or fibronectin. See Reverdatto et al., Curr Top Med Chem. 2015, 15(12): 1082-1101, which is incorporated by reference in its entirety (see also Boersma et al., J Biol Chem. 2011, 286: 41273-41285 and Emanuel et al. Mabs. 2011, 3: 38-48).

[0094] A "peptide" as described herein refers to a linear molecule formed by linking two or more amino acids via peptide bonds. Peptides typically range in length from 2 to 50 amino acids. A "polypeptide" refers to a polymer chain consisting of two or more peptides. Polypeptides typically have more than 50 amino acids.

[0095] An antigen binding molecule as described herein typically comprises an antigen binding domain, which consists of a VH and VL of an antibody capable of specifically binding to a target antigen. An antigen binding domain consisting of a VH and VL is also referred to herein as an Fv region.

[0096] The antigen binding molecule can be or comprise an antigen binding polypeptide or an antigen binding polypeptide complex. An antigen binding molecule can comprise more than one polypeptide that collectively constitutes one antigen binding domain. Such polypeptides can be covalently or non-covalently bound. In certain embodiments, such polypeptides constitute one larger polypeptide chain of which they are a part (a scFv consisting of a VH and VL, or a scFab consisting of a VH-CH1 and XL-CL).

[0097] The antigen binding molecule can be a non-covalent or covalent complex of more than one polypeptide (e.g., 2, 3, 4, 6, or 8 polypeptides). For example, an Ig-G like antigen binding molecule composed of two heavy chain polypeptides and two light chain polypeptides.

[0098] Antigen binding molecules as described herein can be designed and prepared using sequences of monoclonal antibodies (mAbs). Antigen binding domains of antibodies, such as single chain variable region fragments (scFv), Fab, and F(ab’)2 fragments, can also be used / provided. The “antigen binding domain” refers to any fragment of an antibody that is capable of binding to a specific antibody target.

[0099] Antibodies typically contain six complementarity determining regions (CDRs). Three in the heavy chain variable region (VH): HC-CDR1, HC-CDR2, and HC-CDR3, and three in the light chain variable region (VL): LC-CDR1, LC-CDR2, and LC-CDR3. These six CDRs collectively make up the antigen binding site of an antibody, i.e., the part of the antibody that binds to a target antigen.

[0100] The VH and VL regions contain framework regions (FRs) located adjacent to and on the carboxy and amino termini of each CDR. The framework regions provide a framework for the CDRs. From N- to C-terminus, the VH region comprises the following structure: N-terminal - [HC-FR1] - [HC-CDR1] - [HC-FR2] - [HC-CDR2] - [HC-FR3] - [HC-CDR3] - [HC-FR4] - C-terminal; and the VL region comprises the following structure: N-terminal - [LC-FR1] - [LC-CDR1] - [LC-FR2] - [LC-CDR2] - [LC-FR3] - [LC-CDR3] - [LC-FR4] - C-terminal.

[0101] There are many different standards for defining CDRs and FRs, such as those described in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, Public Health Service, National Institutes of Health, Bethesda, Maryland, 1999, Chothia et al., J. Mol. Biol., 1987, 196, 901-917, and Retter et al., Nucl. Acids Res., 2005, 33 (Appendix 1), D671-D674 in the VBASE2 database. The CDRs and FRs of the VH and VL regions of the antibody clones described herein are defined according to the international IMGT (Immunogenetics) information system (LeFranc et al., Nucleic Acids Res. 2015, 43, D413-422), specifically using the IMGT V-DOMAIN numbering scheme described in Lefranc et al., Dev. Comp. Immunol. 2003, 27, 55-77. Preferably, the CDRs and FRs of the antigen-binding molecules described herein are defined according to the IMGT information system.

[0102] In certain embodiments, the antigen binding molecules comprise the CDRs of an antigen binding molecule that binds to a beta coronavirus spike protein (SARSr-CoV spike protein, SARS-CoV-2 spike protein, and / or one or more SARS-CoV-2 variant spike proteins). In certain embodiments, the antigen binding molecules comprise the FRs of an antigen binding molecule that binds to a beta coronavirus spike protein (SARSr-CoV spike protein, SARS-CoV-2 spike protein, and / or one or more SARS-CoV-2 variant spike proteins). In certain embodiments, the antigen binding molecules comprise the CDRs and FRs of an antigen binding molecule that binds to a beta coronavirus spike protein (SARSr-CoV spike protein, SARS-CoV-2 spike protein, and / or one or more SARS-CoV-2 variant spike proteins). That is, in certain embodiments, the antigen binding molecules comprise the VH and VL regions of an antigen binding molecule that binds to a beta coronavirus spike protein (SARSr-CoV spike protein, SARS-CoV-2 spike protein, and / or one or more SARS-CoV-2 variant spike proteins).

[0103] In certain embodiments, the antigen binding molecule contains CDRs, FRs, and / or VH and / or VL regions of an antibody described herein, such as an antibody listed in Table C, or are derived from CDRs, FRs, and / or VH and / or VL regions of an antibody described herein, such as an antibody listed in Table C.

[0104] In certain embodiments, the antigen binding molecule comprises:

[0105] a VH region comprising the HC-CDR1 (or a variant of the HC-CDR1 in which 1, 2, or 3 amino acids are replaced by other amino acids), HC-CDR2 (or a variant of the HC-CDR2 in which 1, 2, or 3 amino acids are replaced by other amino acids), and HC-CDR3 (or a variant of the HC- CDR3 in which 1, 2, or 3 amino acids are replaced by other amino acids) of row 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 6, 17, 18, 9, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or 51 of column A of Table A, wherein the HC-CDR1, HC-CDR2, and HC-CDR3 sequences of column A are selected from the same row of Table A.

[0106] By way of illustration, in certain embodiments, the antigen binding molecule comprises a VH region comprising a HC-CDR1 having the amino acid sequence of SEQ ID NO: 37 (or a variant of SEQ ID NO: 37 in which 1, 2, or 3 amino acids are replaced by other amino acids), a HC-CDR2 having the amino acid sequence of SEQ ID NO: 38 (or a variant of SEQ ID NO: 38 in which 1, 2, or 3 amino acids are replaced by other amino acids), and a HC-CDR3 having the amino acid sequence of SEQ ID NO: 39 (or a variant of SEQ ID NO: 39 in which 1, 2, or 3 amino acids are replaced by other amino acids). The HC-CDR1, HC-CDR2, and HC-CDR3 sequences described above are selected from the same row (row 1) of column A of Table A.

[0107] In certain embodiments, the antigen binding molecule comprises:

[0108] a VH region comprising an HC-FR1 (or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 6, 17, 18, 9, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or 51 of column A of Table B; 2 or 3 amino acids are replaced by other amino acids), HC-FR2 (or variants in which 1, 2 or 3 amino acids in HC-FR2 are replaced by other amino acids), HC-FR3 (or variants in which 1, 2 or 3 amino acids in HC-FR3 are replaced by other amino acids) and HC-FR4 (or variants in which 1, 2 or 3 amino acids in HC-FR4 are replaced by other amino acids), wherein the HC-FR1, HC-FR2, HC-FR3 and HC-FR4 sequences in column A are selected from the same row of Table B.

[0109] As an illustration, in certain embodiments, the antigen-binding molecule comprises a VH region comprising an HC-FR1 having an amino acid sequence of SEQ ID NO: 40 (or a variant in which 1, 2, or 3 amino acids in SEQ ID NO: 40 are replaced by other amino acids), an HC-FR2 having an amino acid sequence of SEQ ID NO: 41 (or a variant in which 1, 2, or 3 amino acids in SEQ ID NO: 41 are replaced by other amino acids), an HC-FR3 having an amino acid sequence of SEQ ID NO: 42 (or a variant in which 1, 2, or 3 amino acids in SEQ ID NO: 42 are replaced by other amino acids), and an HC-FR4 having an amino acid sequence of SEQ ID NO: 43 (or a variant in which 1, 2, or 3 amino acids in SEQ ID NO: 43 are replaced by other amino acids). The above HC-FR1, HC-FR2, HC-FR3, and HC-FR4 sequences are selected from the same row (row 1) of column A in Table B.

[0110] In certain embodiments, the antigen binding molecule comprises:

[0111] A VH region, the VH region comprising:

[0112] HC-C listed in row 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 6, 17, 18, 9, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or 51 of column A of Table A DR1 (or variants in which 1, 2 or 3 amino acids in HC-CDR1 are replaced by other amino acids), HC-CDR2 (or variants in which 1, 2 or 3 amino acids in HC-CDR2 are replaced by other amino acids) and HC-CDR3 (or variants in which 1, 2 or 3 amino acids in HC-CDR3 are replaced by other amino acids), wherein the HC-CDR1, HC-CDR2 and HC-CDR3 sequences in column A are selected from the same row of Table A; and

[0113] HC-FR1 (or 1, 2 or 3 of HC-FR1) listed in row 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 6, 17, 18, 9, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or 51 of column BA of Table substituted with other amino acids), HC-FR2 (or variants in which 1, 2 or 3 amino acids in HC-FR2 are substituted with other amino acids), HC-FR3 (or variants in which 1, 2 or 3 amino acids in HC-FR3 are substituted with other amino acids), and HC-FR4 (or variants in which 1, 2 or 3 amino acids in HC-FR4 are substituted with other amino acids), wherein the HC-FR1, HC-FR2, HC-FR3 and HC-FR4 sequences in column A are selected from the same row of Table B.

[0114] In certain embodiments, the antigen binding molecule comprises:

[0115] A VH region, the VH region comprising:

[0116] the HC-CDR1 (or variant having 1, 2, or 3 amino acids in the HC-CDR1 replaced by a different amino acid), HC-CDR2 (or variant having 1, 2, or 3 amino acids in the HC-CDR2 replaced by a different amino acid), and HC- CDR3 (or variant having 1, 2, or 3 amino acids in the HC-CDR3 replaced by a different amino acid) listed in Table A, row 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 6, 17, 18, 9, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or 51, Column A; and

[0117] the HC-FR1 (or variant having 1, 2, or 3 amino acids in the HC-FR1 replaced by a different amino acid), HC-FR2 (or variant having 1, 2, or 3 amino acids in the HC-FR2 replaced by a different amino acid), HC-FR3 (or variant having 1, 2, or 3 amino acids in the HC-FR3 replaced by a different amino acid), and HC-FR4 (or variant having 1, 2, or 3 amino acids in the HC-FR4 replaced by a different amino acid) listed in Table B, row 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 6, 17, 18, 9, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or 51, Column A;

[0118] wherein the HC-CDR1, HC-CDR2, and HC-CDR3 sequences in Table A, Column A, and the HC-FR1, HC-FR2, HC-FR3, and HC-FR4 sequences in Table B, Column B, are selected from rows having the same number.

[0119] By way of illustration, in certain embodiments, the antigen-binding molecule comprises a VH region comprising an HC-CDR1 having an amino acid sequence of SEQ ID NO: 37 (or a variant in which 1, 2, or 3 amino acids in SEQ ID NO: 37 are substituted with other amino acids), an HC-CDR2 having an amino acid sequence of SEQ ID NO: 38 (or a variant in which 1, 2, or 3 amino acids in SEQ ID NO: 38 are substituted with other amino acids), an HC-CDR3 having an amino acid sequence of SEQ ID NO: 39 (or a variant in which 1, 2, or 3 amino acids in SEQ ID NO: 39 are substituted with other amino acids), an HC-FR1 having an amino acid sequence of SEQ ID NO: 40 (or a variant in which 1, 2, or 3 amino acids in SEQ ID NO: 40 are substituted with other amino acids), an HC-FR2 having an amino acid sequence of SEQ ID NO: 41 (or a variant in which 1, 2, or 3 amino acids in SEQ ID NO: 41 are substituted with other amino acids), an HC-FR3 having an amino acid sequence of SEQ ID NO: 42 (or a variant in which 1, 2, or 3 amino acids in SEQ ID NO: The HC-CDR1, HC-CDR2, and HC-CDR3 sequences are selected from row 1 of column A of Table A2, and the HC-FR1, HC-FR2, HC-FR3, and HC-FR4 sequences are selected from the same row number (row 1) of column A of Table B.

[0120] In certain embodiments, the antigen binding molecule comprises a VH region having the same VH region as that of column A of Table C, Nos. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 6, 17, 18, 9, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, An amino acid sequence that has at least 70%, preferably ≥80%, ≥85%, ≥90%, ≥91%, ≥92%, ≥93%, ≥94%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% amino acid sequence identity to the amino acid sequence of the VH region listed in row 0, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or 51.

[0121] In certain embodiments, the antigen binding molecule comprises:

[0122] a VL region comprising a VL region comprising a VL region as defined in Table A, column B, row 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 6, 17, 18, 9, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or 51. Column B comprises the LC-CDR1 (or variants in which 1, 2 or 3 amino acids in LC-CDR1 are replaced by other amino acids), LC-CDR2 (or variants in which 1, 2 or 3 amino acids in LC-CDR2 are replaced by other amino acids) and LC-CDR3 (or variants in which 1, 2 or 3 amino acids in LC-CDR3 are replaced by other amino acids) of the aforementioned sequences, wherein the LC-CDR1, LC-CDR2 and LC-CDR3 sequences in column C are selected from the same row of Table A.

[0123] In certain embodiments, the antigen binding molecule comprises:

[0124] a VL region comprising an LC-FR1 (or an LC-FR1 in a VL region) listed in Table B, column B, row 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 6, 17, 18, 9, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or 51. 1, 2 or 3 amino acids in LC-FR1 are replaced by other amino acids), LC-FR2 (or variants in which 1, 2 or 3 amino acids in LC-FR2 are replaced by other amino acids), LC-FR3 (or variants in which 1, 2 or 3 amino acids in LC-FR3 are replaced by other amino acids) and LC-FR4 (or variants in which 1, 2 or 3 amino acids in LC-FR4 are replaced by other amino acids), wherein the LC-FR1, LC-FR2, LC-FR3 and LC-FR4 sequences in column B are selected from the same row of Table B.

[0125] In certain embodiments, the antigen binding molecule comprises:

[0126] The VL region comprises:

[0127] the LC-CDR1 (or variant having 1, 2, or 3 amino acids in the LC-CDR1 replaced by a different amino acid), LC-CDR2 (or variant having 1, 2, or 3 amino acids in the LC- CDR2 replaced by a different amino acid), and LC-CDR3 (or variant having 1, 2, or 3 amino acids in the LC-CDR3 replaced by a different amino acid) listed in row number 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 6, 17, 18, 9, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or 51 of column B of Table A, wherein the LC-CDR1, LC-CDR2, and LC-CDR3 sequences of column B are selected from the same row of Table A; and

[0128] the LC-FR1 (or variant having 1, 2, or 3 amino acids in the LC-FR1 replaced by a different amino acid), LC-FR2 (or variant having 1, 2, or 3 amino acids in the LC-FR2 replaced by a different amino acid), LC-FR3 (or variant having 1, 2, or 3 amino acids in the LC-FR3 replaced by a different amino acid), and LC-FR4 (or variant having 1, 2, or 3 amino acids in the LC-FR4 replaced by a different amino acid) listed in row number 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 6, 17, 18, 9, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or 51 of column B of Table B, wherein the LC-FR1, LC-FR2, LC-FR3, and LC-FR4 sequences of column B are selected from the same row of Table B.

[0129] In certain embodiments, the antigen binding molecule comprises:

[0130] a VL region, the VL region comprising:

[0131] the LC-CDR1 (or variant having 1, 2, or 3 amino acids in the LC-CDR1 replaced by a different amino acid), LC-CDR2 (or variant having 1, 2, or 3 amino acids in the LC-CDR2 replaced by a different amino acid), and LC-CDR3 (or variant having 1, 2, or 3 amino acids in the LC-CDR3 replaced by a different amino acid) listed in row 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 6, 17, 18, 9, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or 51, column B of Table A; and

[0132] the LC-FR1 (or variant having 1, 2, or 3 amino acids in the LC-FR1 replaced by a different amino acid), LC-FR2 (or variant having 1, 2, or 3 amino acids in the LC-FR2 replaced by a different amino acid), LC-FR3 (or variant having 1, 2, or 3 amino acids in the LC-FR3 replaced by a different amino acid), and LC-FR4 (or variant having 1, 2, or 3 amino acids in the LC-FR4 replaced by a different amino acid) listed in row 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 6, 17, 18, 9, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or 51, column B of Table B;

[0133] wherein the HC-CDR1, HC-CDR2, and HC-CDR3 sequences in column B of Table A and the HC-FR1, HC-FR2, HC-FR3, and HC-FR4 sequences in column B of Table B are selected from rows having the same number.

[0134] In certain embodiments, the antigen binding molecule comprises a VL region having an amino acid sequence that is at least 70% or more, preferably >80%, >85%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100% sequence identical to one of the VL region sequences listed in Column B, row 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 6, 17, 18, 9, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or 51 of Table C.

[0135] In certain embodiments, the antigen binding molecule contains a VH region as in any of the embodiments described herein, a VL region as in any of the embodiments described herein.

[0136] In embodiments of the disclosure, one or more amino acids can be replaced with other amino acids. A replacement includes the replacement of an amino acid residue with a different "replacement" amino acid residue. The replacement amino acid residue in a replacement as described herein can be a natural amino acid residue (an amino acid encoded by the genetic code) that is different from the amino acid residue at the corresponding position of the equivalent, non-replaced amino acid sequence, and can be: alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamine (Gln), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (lie), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), valine (Val). In certain embodiments, the replacement amino acid can be a non-natural amino acid residue, i.e., an amino acid residue other than those listed above. Non-natural amino acids include norleucine, ornithine, norvaline, homoserine, 2-amino isobutyric acid, and other amino acid residue analogs as described in Ellman, et al., Meth. Enzym. 202 (1991) 301-336.

[0137] In certain embodiments, the replacement can be biochemically conservative. In certain embodiments, the amino acid to be replaced is one of the amino acids listed in rows 1-5 of the table below, and the replacement amino acid is a different other amino acid in the same row:

[0138]

[0139] As an illustration, in certain embodiments where a Met residue is replaced, the replacement amino acid can be Ala, Val, Leu, He, Trp, Tyr, Phe, and methionine.

[0140] In certain embodiments, the replacement amino acid in a substitution can have the same side chain polarity as the amino acid residue it replaces. In certain embodiments, the replacement amino acid in a substitution can have the same side chain charge (at pH 7.4) as the amino acid it replaces:

[0141]

[0142] That is, in certain embodiments, a non-polar amino acid is replaced with another different non-polar amino acid. In certain embodiments, a polar amino acid is replaced with another different polar amino acid. In certain embodiments, an acidic polar amino acid is replaced with another different acidic polar amino acid. In certain embodiments, a basic polar amino acid is replaced with another different basic polar amino acid. In certain embodiments, a neutral amino acid is replaced with another different neutral amino acid. In certain embodiments, a positively charged amino acid is replaced with another different positively charged amino acid. In certain embodiments, a negatively charged amino acid is replaced with another different negatively charged amino acid.

[0143] In certain embodiments, a substitution can be function-conservative. That is, in certain embodiments, a substitution does not affect (or does not significantly affect) one or more functional properties (such as target binding) of the antigen binding molecule in which the substitution occurs, as compared to the equivalent non-substituted molecule.

[0144] The VH and VL regions in an antibody antigen binding domain collectively make up the Fv region. In certain embodiments, an antigen binding molecule as described in the present disclosure comprises or consists of an Fv region that can bind to a betacoronavirus spike protein (SARSr-CoV spike protein; SARS-CoV-2 spike protein and / or one or more SARS-CoV-2 variant spike proteins). In certain embodiments, the VH and VL regions of the Fv region can form a single polypeptide via a linker sequence, i.e., a single chain Fv (scFv).

[0145] In the antibody antigen binding domain, the VL and light chain constant region (CL), VH and heavy chain constant region 1 (CH1) together constitute the Fab region. In certain embodiments, the antigen binding molecule comprises a Fab region having a VH, CH1, VL and CL, such as CK or CL. In certain embodiments, the Fab comprises a polypeptide consisting of VH and CH1 (VH-CH1 fusion polypeptide), and a polypeptide consisting of VL and CL (VL-CL fusion polypeptide). In certain embodiments, the Fab region comprises a polypeptide consisting of VH and CL (VH-CL fusion polypeptide), and a polypeptide consisting of VL and CH1 (VL-CH1 fusion polypeptide). That is, in certain embodiments, the Fab region is a CrossFab structure. In certain embodiments, the VH, CH1, VL and CL regions of the Fab or CrossFab are formed as a single polypeptide by a linker region, i.e. a single chain Fab (scFab) or a single chain CrossFab (scCrossFab).

[0146] In certain embodiments, the antigen binding molecules described herein comprise or consist of a whole antibody that binds to a coronavirus type 2 spike protein (SARSr-CoV spike protein; SARS-CoV-2 spike protein and / or one or more SARS-CoV-2 variant spike protein). A “whole antibody” as described herein refers to an antibody that is substantially similar in structure to an immunoglobulin (Ig). The classes of immunoglobulins and their structures are described in Schroeder and Cavacini, J Allergy Clin Immunol. 2010 125:S41-S52, which is incorporated by reference herein in its entirety.

[0147] G-type immunoglobulins (IgG) are glycoproteins of about 150 kDa, consisting of two heavy chains and two light chains. From N- to C-terminus, the heavy chain consists of a heavy chain constant region composed of VH followed by three constant regions (CH1, CH2 and CH3), and similarly, the light chain consists of VL followed by a CL region. Depending on the heavy chain, immunoglobulins can be classified as IgG (such as IgG1, IgG2, IgG3, IgG4), IgA (such as IgA1, IgA2), IgD, IgE or IgM. Depending on the light chain, they can be classified as kappa or lambda.

[0148] As used herein, the term "CH1 domain" refers to the amino acid sequence corresponding to the CH1 domain of an immunoglobulin (Ig). According to the EU numbering system (see Edelman et al., Proc Natl Acad Sci USA, 1969, Vol. 63, No. 1, pp. 78-85), the CH1 domain is the region consisting of amino acids 118-215 of the immunoglobulin constant region domain on an Ig. The term "hinge domain" refers to the amino acid sequence corresponding to the hinge domain of an Ig. According to the EU numbering system, the hinge domain is the region consisting of amino acids 216-230 of the immunoglobulin constant region domain on an Ig. The term "CH2 domain" refers to the amino acid sequence corresponding to the CH2 domain of an Ig. According to the EU numbering system, the hinge domain is the region consisting of amino acids 231-340 of the immunoglobulin constant region domain on an Ig. The term "CH3 domain" refers to the amino acid sequence corresponding to the CH3 domain of an immunoglobulin (Ig). According to the EU numbering system, the CH3 domain is the region of the immunoglobulin constant region consisting of amino acids 341-447. The term "CH2-CH3 domain" refers to the amino acid sequence corresponding to the CH2 and CH3 domains of an immunoglobulin (Ig). According to the EU numbering system, the CH2-CH3 domain is the region of the immunoglobulin constant region consisting of amino acids 231-447.

[0149] In certain embodiments, the antigen binding molecules described herein comprise or consist of IgG (e.g., IgG1, IgG2, IgG3, IgG4), IgA (e.g., IgA1, IgA2), IgD, IgE, or IgM that bind to a betacoronavirus spike protein (SARSr-CoV spike protein; SARS-CoV-2 spike protein and / or one or more SARS-CoV-2 variant spike proteins).

[0150] In certain embodiments, the antigen binding molecules as described herein comprise one or more regions of an immunoglobulin heavy chain constant sequence (e.g., CH1, CH2, CH3, etc.). In certain embodiments, the immunoglobulin heavy chain constant sequence is or is derived from the heavy chain constant sequence of IgG (e.g., IgG1, IgG2, IgG3, IgG4), IgA (e.g., IgA1, IgA2), IgD, IgE, or IgM, such as human IgG (e.g., hIgG1, hIgG2, hIgG3, hIgG4), hIgA (e.g., hIgA1, hIgA2), hIgD, hIgE, or hIgM. In certain embodiments, the immunoglobulin heavy chain constant region is or is derived from the heavy chain constant sequence of a human IgG1 allotype (G1m1, G1m2, G1m3, or G1m17).

[0151] In certain embodiments, the antigen binding molecule comprises (e.g., comprises one or more polypeptides) a CH1 region. In certain embodiments, the CH1 region comprises or consists of an amino acid sequence that is at least 70% or more (e.g., >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 671 or 676.

[0152] In certain embodiments, the antigen binding molecule comprises (e.g., comprises one or more polypeptides) a CH1 region. In certain embodiments, the CH1 region comprises or consists of an amino acid sequence that is at least 70% or more (e.g., >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 671 or 676.

[0153] In certain embodiments, the antigen binding molecule comprises (e.g., comprises one or more polypeptides) a CH2 region. In certain embodiments, the CH2 region comprises or consists of an amino acid sequence that is at least 70% or more (e.g., >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 673.

[0154] In certain embodiments, the antigen binding molecule comprises (e.g., comprises one or more polypeptides) a CH3 region. In certain embodiments, the CH3 region comprises or consists of an amino acid sequence that is at least 70% or more (e.g., >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 674 or 677.

[0155] In certain embodiments, the antigen binding molecule as described herein comprises an Fc region.

[0156] An “Fc region” as described herein refers to a polypeptide complex formed by the interaction of two polypeptides, each of which comprises a CH2-CH3 region of an immunoglobulin (Ig) heavy chain constant sequence.

[0157] In certain embodiments, the CH2 region, CH3 region and / or CH2-CH3 region as described herein correspond to the CH2 region, CH3 region and / or CH2-CH3 region of IgG (e.g., IgG1, IgG2, IgG3, IgG4), IgA (IgA1, IgA2), IgD, IgE or IgM. In certain embodiments, the CH2 region, CH3 region and / or CH2-CH3 region correspond to the CH2 region, CH3 region and / or CH2-CH3 region of human IgG (hIgG1, hIgG2, hIgG3, hIgG4), hIgA (hIgA1, hIgA2), hIgD, hIgE or hIgM. In certain embodiments, the CH2 region, CH3 region and / or CH2-CH3 region correspond to the CH2 region, CH3 region and / or CH2-CH3 region of human IgG1 allotype (G1m1, G1m2, G1m3 or G1m17).

[0158] The Fc region can interact with Fc receptors and other molecules of the immune system to produce a variety of functional effects. Jefferis et al., Immunol Rev, 1998, vol. 163, pp. 59-76 (incorporated herein by reference in its entirety), reviewed Fc-mediated effector functions, which are achieved through the following mechanisms: Fc region binds to Fc receptors expressed by immune cells (macrophages, dendritic cells, neutrophils, basophils, eosinophils, platelets, mast cells, NK cells, and T cells), thereby recruiting and activating immune cells; Fc region binds to complement protein C1q to recruit complement pathway components, thereby activating the complement cascade. Functions mediated by the Fc region include Fc receptor binding, antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), membrane attack complex (MAC) formation, cell degranulation, cytokine and / or chemokine formation, and antigen processing and presentation.

[0159] A variety of antibody Fc region modifications that affect Fc-mediated functions are known in the art, such as those described in Wang et al., Protein Cell, Vol. 9, No. 1, pp. 63-73, 2018, which is incorporated herein by reference in its entirety. Table 1 in Wang et al., Protein Cell, Vol. 9, No. 1, pp. 63-73, 2018 summarizes typical Fc region modifications known to affect antibody effector functions. In certain embodiments, the antigen-binding molecules described herein include an Fc region comprising modifications that increase or decrease Fc-mediated functions compared to antigen-binding molecules comprising corresponding unmodified Fc regions. When the Fc region comprises a modification, the modification may occur on one or both polypeptide chains that together form the Fc region.

[0160] In certain embodiments, the antigen binding molecule comprises (e.g., comprises one or more polypeptides) a CH2-CH3 region. The CH2-CH3 region may comprise or consist of an amino acid sequence that is at least 70% (e.g., one of ≥70%, ≥75%, ≥80%, ≥85%, ≥86%, ≥87%, ≥88%, ≥89%, ≥90%, ≥91%, ≥92%, ≥93%, ≥94%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 678 or 679.

[0161] In certain embodiments, the antigen binding molecule comprises (e.g., comprises one or more polypeptides) a CH1-hinge-CH2-CH3 region. The CH1-hinge-CH2-CH3 region may comprise or consist of an amino acid sequence that is at least 70% (e.g., one of ≥70%, ≥75%, ≥80%, ≥85%, ≥86%, ≥87%, ≥88%, ≥89%, ≥90%, ≥91%, ≥92%, ≥93%, ≥94%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 670.

[0162] In certain embodiments, the antigen binding molecules as described herein comprise one or more regions of an immunoglobulin light chain constant sequence. In certain embodiments, the immunoglobulin light chain constant sequence is a human immunoglobulin kappa constant region (IGKC; CK). In certain embodiments, the immunoglobulin light chain constant sequence is a human immunoglobulin lambda constant region (IGLC; Cλ), such as IGLC1, IGLC2, IGLC3, IGLC6, or IGLC7.

[0163] In certain embodiments, the antigen-binding molecule comprises (e.g., comprises one or more polypeptides) a CL region. The CL region may comprise or consist of an amino acid sequence that is at least 70% (e.g., one of ≥70%, ≥75%, ≥80%, ≥85%, ≥86%, ≥87%, ≥88%, ≥89%, ≥90%, ≥91%, ≥92%, ≥93%, ≥94%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 680, 681, 682, 683, 684, or 685.

[0164] In certain embodiments, the antigen binding molecule is or comprises a monoclonal antibody or an antigen binding fragment thereof.

[0165] In certain embodiments, the molecule can be or comprise a fully human antibody or antibody fragment. Such fully human antibodies / antibody fragments can be encoded by human nucleic acid sequences. Such fully human antibodies / antibody fragments do not contain any non-human amino acid sequences.

[0166] Aspects of the disclosure relate to multispecific antigen binding molecules. "Multispecific" refers to the ability of the antigen binding molecule to specifically bind to multiple targets. In certain embodiments, the antigen binding molecule is a bispecific antigen binding molecule. In certain embodiments, such molecules comprise at least two different antigen binding domains (at least two antigen binding domains containing different VHand VL).

[0167] In certain embodiments, the antigen binding molecule is capable of simultaneously binding to a betacoronavirus spike protein (a SARSr-CoV spike protein, a SARS-CoV-2 spike protein, and / or one or more SARS-CoV-2 variant spike proteins) and a target other than a betacoronavirus spike protein, thereby having at least bispecificity. The term "bispecific" refers to the ability of the antigen binding molecule to specifically bind to at least two different antigenic determinants.

[0168] It should be understood that an antigen binding molecule (multispecific antigen binding molecule) as described herein can comprise an antigen binding molecule capable of binding to a target for which the antigen binding molecule has specificity. For example, an antigen binding molecule capable of binding to a betacoronavirus spike protein (a SARSr-CoV spike protein, a SARS-CoV-2 spike protein, and / or one or more SARS-CoV-2 variant spike proteins) and a target other than a betacoronavirus spike protein includes: (i) an antigen binding molecule capable of binding to a SARS-CoV-2 spike protein and / or a SARS-CoV-2 variant spike protein; (ii) an antigen binding molecule capable of binding to a target other than a betacoronavirus spike protein.

[0169] It should also be noted that an antigen binding molecule (multispecific antigen binding molecule) as described herein can comprise an antigen binding polypeptide or antigen binding polypeptide complex capable of binding to a target for which the antigen binding molecule has specificity.

[0170] In certain embodiments, an antigen binding molecule component of a larger antigen binding molecule (multispecific antigen binding molecule) can be referred to as an "antigen binding domain" or "antigen binding region" of the larger antigen binding molecule.

[0171] In certain embodiments, the antigen binding molecule is an immune cell adapter. Immune cell adapters can be found in Goebeler and Bargou, Nat. Rev. Clin. Oncol. [Nature Review Clinical Oncology] 2020, Vol. 17, pp. 418-434 and Ellerman, Methods [Methodology] 2019, Vol. 154, pp. 102-117, both of which are incorporated herein by reference in their entirety. The immune cell adapter comprises an antigen binding region that targets the target antigen and an antigen binding region for recruiting / activating specific immune cells. The immune cell adapter recruits / activates immune cells through the specific antigen binding region of immune cell surface molecules.

[0172] The most intensively studied immune cell engager is the bispecific T cell engager (BiTEs), which contains a target antigen binding domain and a CD3 polypeptide (usually CD3ε) binding domain. BiTEs recruit T cells through the binding domain. BiTEs bind to their target antigens and CD3 polypeptides expressed by T cells, activating T cells and ultimately guiding T cell effectors to kill cells expressing the target antigen. Other types of immune cell engagers known in the art include natural killer cell engagers that can recruit and activate NK cells, such as bispecific killer engagers (BiKEs).

[0173] In certain embodiments, the immune cell activated by the immune cell engager is a T cell or a NK cell. In certain embodiments, the immune cell engager is a T cell engager.

[0174] The multispecific antigen-binding molecules described herein have various suitable formats, such as those described in Brinkmann and Kontermann, MAbs [monoclonal antibodies], Vol. 9, No. 2, 2017, pp. 182-212, which is incorporated herein by reference in its entirety. Suitable formats include those described in Brinkmann and Kontermann, MAbs [monoclonal antibodies], Vol. 9, No. 2, 2017, pp. 182-212. Figure 2Format: Antibody conjugates, such as IgG2, F(ab')2, and CovX-Body; IgG or IgG-like molecules, such as IgG, chimeric IgG, kappa lambda-body common HC; CH1 / CL fusion proteins, such as scFv2-CH1 / CL, VHH2-CH1 / CL; variable region bispecific antigen binding molecules, such as tandem scFv (taFV), triabody, diabody (Db), dsDb, Db(kih), DART, scDB, dsFv-dsFv, tandAbs, triple heads, tandem dAb / VHH, tetravalent dAb.VHH; non-Ig fusion proteins, such as scFv2-albumin, scDb-albumin, taFv-albumin, taFv-toxin, minibody, DNL-Fab2, DNL-Fab2-scFv, DNL-Fab2-IgG-cytokine2, ImmTAC (TCR-scFv); modified Fc and CH3 fusion proteins, such as scFv-Fc(kih), scFv-Fc(CH3 charge pair), scFv-Fc(EW-RVT), scFv-fc(HA-TF), scFv-Fc(SEEDbody), taFv-Fc(kih), scFv-Fc(kih)-Fv, Fab-Fc(kih)-scFv, Fab-scFv-Fc(kih), Fab-scFv-Fc(BEAT), Fab-scFv-Fc(SEEDbody), DART-Fc, scFv-CH3(kih), TriFabs; Fc fusion proteins, such as Di-bispecific antibody, scDb-Fc, taFv-Fc, scFv-Fc-scFv, HCAb-VHH, Fab-scFv-Fc, scFv4-Ig, scFv2-Fcab; CH3 fusion proteins, such as Dia-bispecific antibody, scDb-CH3; IgE / IgM CH2 fusion proteins, such as scFv-EHD2-scFv, scFvMHD2-scFv; Fab fusion proteins, such as Fab-scFv (bispecific antibody), Fab-scFv2 (trispecific antibody), Fab-Fv, Fab-dsFv, Fab-VHH, orthogonal Fab-Fab;non-Ig fusion proteins such as DNL-Fab3, DNL-Fab2-scFv, DNL-Fab2-IgG-cytokine2, asymmetric IgG or IgG-like molecules such as IgG(kih), IgG(kih) common LC, ZW1 IgG common LC, bispecific cell line common LC, CrossMab, CrossMab(kih), scFab-IgG(kih), Fab-scFab-IgG(kih), orthogonal Fab IgG(kih), DuetMab, CH3 charge pair + CH1 / CL charge pair, hinge region / CH3 charge pair, SEED-body, Duobody, quad CrossMab(kih), LUZ-Y common LC; LUZ-Y scFab-IgG, FcFc*; additional and Fc-modified IgGs such as IgG(kih)-Fv, IgG HA-TF-Fv, IgG(kih) scFab, scFab-Fc(kih)-scFv2, scFab-Fc(kih)-scFv, half DVD-Ig, DVI-Ig (quad), CrossMab-Fab; modified Fc and CH3 fusion proteins such as Fab-Fc(kih)-scFv, Fab-scFv-Fc(kih), Fab-scFv-Fc(BEAT), Fab-scFv-Fc-SEEDbody, TriFab; additional IgGs - HC fusion proteins such as IgG-HC, scFv, IgG-dAb, IgG-taFV, IgG-CrossFab, IgG orthogonal Fab, IgG-(CαCβ)Fab, scFv-HC-IgG, tandem Fab-IgG (orthogonal Fab), Fab-IgG(CαCβ Fab), Fab-IgG(CR3), Fab-hinge region-IgG(CR3); additional IgGs - LC fusion proteins such as IgG-scFv(LC), scFv(LC)-IgG, dAb-IgG; additional IgGs - HC and LC fusion proteins such as DVD-Ig, TVD-Ig, CODV-Ig, scFv4-IgG, Zybody; Fc fusion proteins such as Fab-scFv-Fc, scFv4-Ig; F(ab')2 fusion proteins such as F(ab')2-scFv2; CH1 / CL fusion proteins such as scFv2-CH1-hinge region / CL; modified IgGs such as DAF (dual IgG), DutaMab, Mab2; and non-Ig fusion proteins such as DNL-Fab4-IgG. One of skill in the art can readily design and make multispecific antigen-binding molecules.

[0175] The present disclosure also provides a chimeric antigen receptor (CARs). CARs are recombinant receptors with antigen binding and T cell activation functions. The structure and construction method of CAR are shown in Dotti et al., Immunol Re [Immunology Review] 2014, Vol. 257, No. 1, which is incorporated herein by reference in its entirety. CAR comprises an antigen binding region and a signal transduction region connected to a cell membrane anchoring region. An optional hinge region can be used to separate the antigen binding region and the cell membrane anchoring region and can serve as a flexible connector.

[0176] The antigen binding domain of the CAR as described in the present disclosure comprises or consists of an antigen binding molecule capable of binding to a beta coronavirus spike protein (SARSr-CoV spike protein, SARS-CoV-2 spike protein and / or one or more SARS-CoV-2 variant spike protein) as described herein. Therefore, the CAR as described in the present disclosure comprises an antigen binding molecule as described in the present disclosure.

[0177] It should be understood that the antigen binding molecules as described herein may constitute or be included in the antigen binding domain of a CAR. Therefore, in certain embodiments, the antigen binding molecules as described herein are contained in the CAR.

[0178] It should be understood that the antigen binding molecules as described in the present disclosure may be CAR. When CAR has an antigen binding domain comprising or consisting of an antigen binding molecule as described in the present disclosure (such as an Fv region that can bind to type B coronavirus spike protein (SARSr-CoV spike protein; SARS-CoV-2 spike protein and / or SARS-CoV-2 variant spike protein)), it is the antigen binding molecule. The antigen binding domain of CAR as described in the present disclosure can be a variety of applicable forms, such as scFv, scFab, etc.

[0179] The cell membrane anchoring region in the CAR is located between the antigen binding region and the signal transduction region, and can be used to anchor the CAR to the cell membrane of the CAR-expressing cell, so that the antigen binding region is distributed in the extracellular space and the signal transduction region is located inside the cell. In certain embodiments, the CAR comprises a cell membrane anchoring region, which includes or consists of an amino acid sequence, and the amino acid sequence includes or consists of a transmembrane amino acid sequence such as CD3-ζ, CD4, CD8 or CD28 and its derivative sequence. The region "derived from" the reference amino acid sequence as described herein refers to an amino acid sequence that comprises at least 60%, such as 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence homology to the reference amino acid sequence.

[0180] The signaling region of the CAR can activate T cells. The signaling region of the CAR contains amino acid sequences from the intracellular domain of CD3-ζ, which provide tyrosine-based immunoreceptor activation motifs (ITAMs) for phosphorylation and activation of CAR-expressing T cells. CARs may also contain signaling regions that include other ITAM protein sequences, such as FcγRI (Haynes et al., J Immunol. 2001, Vol. 166, No. 1, pp. 182-187). The signaling region of CARs may also contain costimulatory sequences derived from the signaling region of costimulatory molecules to promote activation of CAR-expressing T cells upon binding to the target protein. Common costimulatory molecules include CD28, OX40, 4-1BB, ICOS, and CD27. In some cases, CARs are designed to provide costimulation for different intracellular signaling pathways. For example, signals associated with CD28 costimulation preferentially activate the phosphatidylinositol 3-kinase (PI3K) pathway, while 4-1BB-mediated signals are transmitted through the TNF receptor-associated factor (TRAF) adaptor protein. Therefore, some CAR designs combine multiple costimulatory molecule sequences to synergistically activate T cells. Therefore, the signal transduction region of CARs sometimes includes costimulatory sequences derived from multiple costimulatory molecules. In certain embodiments, as described in the present disclosure, CAR includes one or more costimulatory sequences, which include or consist of an amino acid sequence, which includes or consists of an amino acid sequence of an intracellular domain of one or more of CD28, OX40, 4-1BB, ICOS and CD27 or is derived.

[0181] The optional hinge region can be used to separate the antigen binding domain and the transmembrane domain and can serve as a flexible connector. The hinge region is derived from IgG1 or IgG4. In certain embodiments, the CAR described herein comprises a hinge region comprising or consisting of an amino acid sequence comprising or consisting of an amino acid sequence of an IgG1 or IgG4 hinge region or derived therefrom.

[0182] The present disclosure also provides a cell containing a CAR as described herein. The CAR as described herein can be used to generate CAR-expressing immune cells, such as CAR-T or CAT-NK cells. CARs can be implanted into immune cells during in vitro culture.

[0183] Functional properties of the antigen binding molecules described in the present disclosure

[0184] The antigen binding molecules described herein may be characterized by reference to certain functional properties. In certain embodiments, the antigen binding molecules described herein may have one or more of the following properties:

[0185] binding to a spike protein of a betacoronavirus (a SARSr-CoV spike protein; a SARS-CoV-2 spike protein and / or one or more SARS-CoV-2 variant spike proteins);

[0186] inhibiting the interaction of a spike protein of a betacoronavirus (a SARSr-CoV spike protein; a SARS-CoV-2 spike protein and / or one or more SARS-CoV-2 variant spike proteins) and ACE2; and / or

[0187] inhibiting infection of an ACE2-expressing cell by a betacoronavirus (a SARSr-CoV; SARS-CoV-2 and / or one or more SARS-CoV-2 variants).

[0188] It will be appreciated that the antigen binding molecules can have a variety of properties as described in the preceding paragraph. The antigen binding molecules can be assayed for the properties described in the preceding paragraph using suitable assays. The assays can be in vitro assays, cell-based assays or cell-free assays. In certain embodiments, the assays can be in vivo assays, i.e. assays in a non-human animal. In certain embodiments, the assays can be in vitro assays, i.e. using cells / tissues / organs obtained from a subject.

[0189] When the assays are cell-based assays, they can comprise treating cells with the antigen binding molecules to determine whether the antigen binding molecules exhibit one or more of the properties described. The assays can employ species labelled with a detectable entity to facilitate detection. The assays can comprise determining the properties after treating the cells with different amounts / concentrations of the antigen binding molecules, e.g. a dilution series. It will be appreciated that the cells can preferably express the target antigen of the antigen binding molecules, i.e. a spike protein of a betacoronavirus (a SARS-CoV-2 spike protein / a SARS-CoV-2 variant spike protein).

[0190] Analysis of the results of such assays can comprise determining the concentration at which 50% of the maximum level of the relevant activity is achieved. The concentration of a reagent at which 50% of the maximum level of the relevant activity is achieved can be referred to as the "half maximal effective concentration" of the reagent with respect to the relevant activity, and can also be referred to as the "EC 50 ".

[0191] Depending on the property, the EC 50 may also be referred to as the "half maximal inhibitory concentration" or "IC 50 ", i.e. the concentration of a reagent at which 50% of the maximum inhibition of a given property is observed.

[0192] The antigen binding molecules described herein are capable of binding to a spike protein of a betacoronavirus (a SARSr-CoV spike protein; a SARS-CoV-2 spike protein and / or one or more SARS-CoV-2 variant spike proteins).

[0193] The ability of the antigen-binding molecule to specifically bind to a given peptide / polypeptide can be assayed according to methods known in the art, such as ELISA, surface plasmon resonance (SPR; see Hearty et al., Methods Mol Biol 2012, Vol. 907, pp. 411-442), biofilm interferometry (BLI; see Lad et al., J Biomol Screen 2015, Vol. 20, No. 4, pp. 498-507), flow cytometry, or enzyme-linked immunosorbent assay (RIA) by radiolabeled antigen binding assay. By these analytical methods, the ability to bind to a given molecule can be measured and quantified. In certain embodiments, the binding can be detected by a response in a specific assay.

[0194] In certain embodiments, the antigen binding molecules described herein can bind to the SARS-CoV-2 spike protein. In certain embodiments, the antigen binding molecules described herein can bind to a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0195] In certain embodiments, the antigen binding molecules described herein can bind to the SARS-CoV-2 variant spike protein described herein. In certain embodiments, the antigen binding molecules described herein can bind to a polypeptide comprising or consisting of an amino acid sequence that has at least 70% (e.g., one of ≥70%, ≥75%, ≥80%, ≥85%, ≥86%, ≥87%, ≥88%, ≥89%, ≥90%, ≥91%, ≥93%, ≥94%, ≥95%, ≥96%, ≥97%, ≥98%, or ≥99%) amino acid sequence identity to SEQ ID NO: 1, wherein the amino acid sequence is different from SEQ ID NO: 1. In certain embodiments, the antigen binding molecules described herein can bind to a polypeptide comprising or consisting of SEQ ID NO: 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27.

[0196] In certain embodiments, the antigen binding molecule can bind to a polypeptide comprising or consisting of SEQ ID NO: 18. In certain embodiments, the antigen binding molecule can bind to a polypeptide comprising or consisting of SEQ ID NO: 19. In certain embodiments, the antigen binding molecule can bind to a polypeptide comprising or consisting of SEQ ID NO: 20. In certain embodiments, the antigen binding molecule can bind to a polypeptide comprising or consisting of SEQ ID NO: 21. In certain embodiments, the antigen binding molecule can bind to a polypeptide comprising or consisting of SEQ ID NO: 26. In certain embodiments, the antigen binding molecule can bind to a polypeptide comprising or consisting of SEQ ID NO: 27.

[0197] In certain embodiments, the antigen binding molecules as described herein can bind to a polypeptide comprising or consisting of an amino acid sequence that has at least 70% (e.g., one of ≥70%, ≥75%, ≥80%, ≥85%, ≥86%, ≥87%, ≥88%, ≥89%, ≥90%, ≥91%, ≥93%, ≥94%, ≥95%, ≥96%, ≥97%, ≥98%, or ≥99%) amino acid sequence identity to SEQ ID NO: 7, wherein the amino acid sequence differs from SEQ ID NO: 7. In certain embodiments, the antigen binding molecules as described herein can bind to a polypeptide comprising or consisting of SEQ ID NO: 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, or 702.

[0198] In certain embodiments, the antigen binding molecule can bind to a polypeptide comprising SEQ ID NO: 693. In certain embodiments, the antigen binding molecule can bind to a polypeptide comprising SEQ ID NO: 694. In certain embodiments, the antigen binding molecule can bind to a polypeptide comprising SEQ ID NO: 695. In certain embodiments, the antigen binding molecule can bind to a polypeptide comprising SEQ ID NO: 696. In certain embodiments, the antigen binding molecule can bind to a polypeptide comprising SEQ ID NO: 697. In certain embodiments, the antigen binding molecule can bind to a polypeptide comprising SEQ ID NO: 698.

[0199] In certain embodiments, the antigen binding molecules as described herein can bind to a polypeptide comprising or consisting of an amino acid sequence that is at least 70% (e.g., one of ≥70%, ≥75%, ≥80%, ≥85%, ≥86%, ≥87%, ≥88%, ≥89%, ≥90%, ≥91%, ≥93%, ≥94%, ≥95%, ≥96%, ≥97%, ≥98%, or ≥99%) identical to the amino acid sequence of SEQ ID NO: 8, wherein the amino acid sequence is different from SEQ ID NO: 8. In certain embodiments, the antigen binding molecules as described herein can bind to a polypeptide comprising or consisting of SEQ ID NO: 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, or 719.

[0200] In certain embodiments, the antigen binding molecule can bind to a polypeptide comprising SEQ ID NO: 710. In certain embodiments, the antigen binding molecule can bind to a polypeptide comprising SEQ ID NO: 711. In certain embodiments, the antigen binding molecule can bind to a polypeptide comprising SEQ ID NO: 712. In certain embodiments, the antigen binding molecule can bind to a polypeptide comprising SEQ ID NO: 713. In certain embodiments, the antigen binding molecule can bind to a polypeptide comprising SEQ ID NO: 714. In certain embodiments, the antigen binding molecule can bind to a polypeptide comprising SEQ ID NO: 715.

[0201] In certain embodiments, the antigen binding molecules described herein are capable of (independently) binding to two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more) proteins selected from the SARS-CoV-2 spike protein and the SARS-CoV-2 variant spike protein. That is, in certain embodiments, when the antigen binding molecule binds to a (first) protein selected from the SARS-CoV-2 spike protein and the SARS-CoV-2 variant spike protein, it may also bind to one or more proteins (second, third, etc.) selected from the SARS-CoV-2 spike protein and the SARS-CoV-2 variant spike protein, wherein the amino acid sequence of the one or more proteins is different from the amino acid sequence of the first protein. Such antigen binding molecules can be said to have "cross-reactivity" with the first protein and the other protein, or to exhibit "cross-reactivity" or "cross-reactive binding" or "binding cross-reactivity" with the first and other proteins.

[0202] In certain embodiments, the antigen binding molecules described herein can cross-reactively bind to two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all 18) of the following polypeptides: a polypeptide consisting of the amino acid sequence of SEQ ID NO: 1, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 11, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 12, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 13, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 14, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 15, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 16, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 17, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 18, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 19, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 20, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 21, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 22, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 23, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 24, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 25, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 26 A polypeptide consisting of the amino acid sequence of SEQ ID NO: 24, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 25, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 26, and a polypeptide consisting of the amino acid sequence of SEQ ID NO: 27.

[0203] In certain embodiments, the antigen binding molecules described herein can cross-reactively bind to two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all 18) of the following polypeptides: a polypeptide comprising the amino acid sequence of SEQ ID NO: 7, a polypeptide comprising the amino acid sequence of SEQ ID NO: 686, a polypeptide comprising the amino acid sequence of SEQ ID NO: 687, a polypeptide comprising the amino acid sequence of SEQ ID NO: 688, a polypeptide comprising the amino acid sequence of SEQ ID NO: 689, a polypeptide comprising the amino acid sequence of SEQ ID NO: 690, a polypeptide comprising the amino acid sequence of SEQ ID NO: 691, a polypeptide comprising the amino acid sequence of SEQ ID NO: 692, a polypeptide comprising the amino acid sequence of SEQ ID NO: 693, a polypeptide comprising the amino acid sequence of SEQ ID NO: 694, a polypeptide comprising the amino acid sequence of SEQ ID NO: 695, a polypeptide comprising the amino acid sequence of SEQ ID NO: 696, a polypeptide comprising the amino acid sequence of SEQ ID NO: 697, a polypeptide comprising the amino acid sequence of SEQ ID NO: 698, a polypeptide comprising the amino acid sequence of SEQ ID NO: 699, a polypeptide comprising the amino acid sequence of SEQ ID NO: 700, a polypeptide comprising the amino acid sequence of SEQ ID NO: 701, a polypeptide comprising the amino acid sequence of SEQ ID NO: 702, a polypeptide comprising the amino acid sequence of SEQ ID NO: 703, a polypeptide comprising the amino acid sequence of SEQ ID NO: 704, a polypeptide comprising the amino acid sequence of SEQ ID NO: 705 A polypeptide containing the amino acid sequence of SEQ ID NO: 698, a polypeptide containing the amino acid sequence of SEQ ID NO: 699, a polypeptide containing the amino acid sequence of SEQ ID NO: 700, a polypeptide containing the amino acid sequence of SEQ ID NO: 701, and a polypeptide containing the amino acid sequence of SEQ ID NO: 702.

[0204] In certain embodiments, the antigen binding molecules as described herein are capable of cross-reactive binding to two or more (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all 18) of the polypeptides selected from the group consisting of: a polypeptide comprising the amino acid sequence of SEQ ID NO: 8, a polypeptide comprising the amino acid sequence of SEQ ID NO: 703, a polypeptide comprising the amino acid sequence of SEQ ID NO: 704, a polypeptide comprising the amino acid sequence of SEQ ID NO: 705, a polypeptide comprising the amino acid sequence of SEQ ID NO: 706, a polypeptide comprising the amino acid sequence of SEQ ID NO: 707, a polypeptide comprising the amino acid sequence of SEQ ID NO: 708, a polypeptide comprising the amino acid sequence of SEQ ID NO: 709, a polypeptide comprising the amino acid sequence of SEQ ID NO: 710, a polypeptide comprising the amino acid sequence of SEQ ID NO: 711, a polypeptide comprising the amino acid sequence of SEQ ID NO: 712, a polypeptide comprising the amino acid sequence of SEQ ID NO: 713, a polypeptide comprising the amino acid sequence of SEQ ID NO: 714, a polypeptide comprising the amino acid sequence of SEQ ID NO: 715, a polypeptide comprising the amino acid sequence of SEQ ID NO: 716, a polypeptide comprising the amino acid sequence of SEQ ID NO: 717, a polypeptide comprising the amino acid sequence of SEQ ID NO: 718, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 719.

[0205] In preferred embodiments, the antigen binding molecules as described in the present disclosure can bind to (cross-reactivity with): a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 11, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 12, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 13, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 14, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 15, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 16, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 17. In preferred embodiments, the antigen binding molecules as described in the present disclosure can bind to (cross-reactivity with): a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 11, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 12, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 13, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 14, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 15, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 16, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 17, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 18, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 19. In preferred embodiments, the antigen binding molecules as described in the present disclosure can bind to (cross-reactivity with): a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 11, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 12, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 13, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 14, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 15, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 16, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 17, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 18, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 19, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 20, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 21, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 26, a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 27.

[0206] In preferred embodiments, the antigen binding molecules as described herein can bind to (cross- reactivity) a polypeptide comprising the amino acid sequence of SEQ ID NO: 7, a polypeptide comprising the amino acid sequence of SEQ ID NO: 686, a polypeptide comprising the amino acid sequence of SEQ ID NO: 687, a polypeptide comprising the amino acid sequence of SEQ ID NO: 688, a polypeptide comprising the amino acid sequence of SEQ ID NO: 689, a polypeptide comprising the amino acid sequence of SEQ ID NO: 690, a polypeptide comprising the amino acid sequence of SEQ ID NO: 691, a polypeptide comprising the amino acid sequence of SEQ ID NO: 692. In preferred embodiments, the antigen binding molecules as described herein can bind to (cross- reactivity) a polypeptide comprising the amino acid sequence of SEQ ID NO: 7, a polypeptide comprising the amino acid sequence of SEQ ID NO: 686, a polypeptide comprising the amino acid sequence of SEQ ID NO: 687, a polypeptide comprising the amino acid sequence of SEQ ID NO: 688, a polypeptide comprising the amino acid sequence of SEQ ID NO: 689, a polypeptide comprising the amino acid sequence of SEQ ID NO: 690, a polypeptide comprising the amino acid sequence of SEQ ID NO: 691, a polypeptide comprising the amino acid sequence of SEQ ID NO: 692, a polypeptide comprising the amino acid sequence of SEQ ID NO: 693, a polypeptide comprising the amino acid sequence of SEQ ID NO: 694. In preferred embodiments, the antigen binding molecules as described herein can bind to (cross- reactivity) a polypeptide comprising the amino acid sequence of SEQ ID NO: 7, a polypeptide comprising the amino acid sequence of SEQ ID NO: 686, a polypeptide comprising the amino acid sequence of SEQ ID NO: 687, a polypeptide comprising the amino acid sequence of SEQ ID NO: 688, a polypeptide comprising the amino acid sequence of SEQ ID NO: 689, a polypeptide comprising the amino acid sequence of SEQ ID NO: 690, a polypeptide comprising the amino acid sequence of SEQ ID NO: 691, a polypeptide comprising the amino acid sequence of SEQ ID NO: 692, a polypeptide comprising the amino acid sequence of SEQ ID NO: 693, a polypeptide comprising the amino acid sequence of SEQ ID NO: 694, a polypeptide comprising the amino acid sequence of SEQ ID NO: 695, a polypeptide comprising the amino acid sequence of SEQ ID NO: 696, a polypeptide comprising the amino acid sequence of SEQ ID NO: 697, a polypeptide comprising the amino acid sequence of SEQ ID NO: 698.

[0207] In a preferred example, the antigen-binding molecules described in the present disclosure can bind to the following (cross-reactivity): a polypeptide containing the amino acid sequence of SEQ ID NO: 8, a polypeptide containing the amino acid sequence of SEQ ID NO: 703, a polypeptide containing the amino acid sequence of SEQ ID NO: 704, a polypeptide containing the amino acid sequence of SEQ ID NO: 705, a polypeptide containing the amino acid sequence of SEQ ID NO: 706, a polypeptide containing the amino acid sequence of SEQ ID NO: 707, a polypeptide containing the amino acid sequence of SEQ ID NO: 708, and a polypeptide containing the amino acid sequence of SEQ ID NO: 709. In a preferred example, the antigen-binding molecules described in the present disclosure can bind to the following (cross-reactivity): a polypeptide containing the amino acid sequence of SEQ ID NO: 8, a polypeptide containing the amino acid sequence of SEQ ID NO: 703, a polypeptide containing the amino acid sequence of SEQ ID NO: 704, a polypeptide containing the amino acid sequence of SEQ ID NO: 705, a polypeptide containing the amino acid sequence of SEQ ID NO: 706, a polypeptide containing the amino acid sequence of SEQ ID NO: 707, a polypeptide containing the amino acid sequence of SEQ ID NO: 708, a polypeptide containing the amino acid sequence of SEQ ID NO: 709, a polypeptide containing the amino acid sequence of SEQ ID NO: 710, and a polypeptide containing the amino acid sequence of SEQ ID NO: 711. In a preferred example, the antigen-binding molecules described in the present disclosure can bind to the following (cross-reactivity): a polypeptide containing the amino acid sequence of SEQ ID NO: 8, a polypeptide containing the amino acid sequence of SEQ ID NO: 703, a polypeptide containing the amino acid sequence of SEQ ID NO: 704, a polypeptide containing the amino acid sequence of SEQ ID NO: 705, a polypeptide containing the amino acid sequence of SEQ ID NO: 706, a polypeptide containing the amino acid sequence of SEQ ID NO: 707, a polypeptide containing the amino acid sequence of SEQ ID NO: 708, a polypeptide containing the amino acid sequence of SEQ ID NO: 709, a polypeptide containing the amino acid sequence of SEQ ID NO: 710, a polypeptide containing the amino acid sequence of SEQ ID NO: 711, a polypeptide containing the amino acid sequence of SEQ ID NO: 712, a polypeptide containing the amino acid sequence of SEQ ID NO: 713, a polypeptide containing the amino acid sequence of SEQ ID NO: 714, and a polypeptide containing the amino acid sequence of SEQ ID NO: 715.

[0208] The antigen-binding molecules and antigen-binding domains described herein preferably exhibit specific binding to the betacoronavirus spike protein (SARSr-CoV spike protein; SARS-CoV-2 spike protein and / or one or more SARS-CoV-2 variant spike proteins). As used herein, "specific binding" refers to selective binding to an antigen, as distinguished from non-specific binding to non-target antigens. Antigen-binding molecules / domains that specifically bind to a target molecule bind to the target molecule with greater affinity and / or for a longer duration than they bind to other non-target molecules.

[0209] In certain embodiments, the degree of binding of the antigen-binding molecule to the non-target molecule should be about 10% lower than the degree of binding to the target molecule as measured by ELISA, SPR, BLI, or RIA. Alternatively, binding specificity can also be reflected by binding affinity, wherein the dissociation constant (KD) of the antigen-binding molecule when binding is at least 0.1 orders of magnitude greater than the KD value of the antigen-binding molecule for the non-target molecule (i.e., 0.1×10n, where n is an integer representing an order of magnitude). It can be at least one of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, or 2.0.

[0210] In certain embodiments, the antigen binding molecules described herein bind with micromolar affinity, i.e., KD = 9.9 × 10 -4 to 1×10 -6 M, binds to the betacoronavirus spike protein (SARSr-CoV spike protein; SARS-CoV-2 spike protein and / or one or more SARS-CoV-2 variant spike protein). In certain embodiments, the antigen-binding molecules described herein bind with submicromolar affinity, i.e., KD < 1×10 -6 M, binds to the betacoronavirus spike protein (SARSr-CoV spike protein; SARS-CoV-2 spike protein and / or one or more SARS-CoV-2 variant spike proteins). In certain embodiments, the antigen-binding molecules described herein bind with nanomolar affinity, i.e., KD = 9.9 × 10 -7 to 1×10 -9 M, binds to the betacoronavirus spike protein (SARSr-CoV spike protein; SARS-CoV-2 spike protein and / or one or more SARS-CoV-2 variant spike proteins). In certain embodiments, the antigen-binding molecules described herein bind with subnanomolar affinity, i.e., KD < 1 × 10 -9M, binds to a SARSr-CoV spike protein; a SARS-CoV-2 spike protein; and / or one or more SARS-CoV-2 variant spike proteins. In certain embodiments, an antigen binding molecule described herein binds to a SARSr-CoV spike protein; a SARS-CoV-2 spike protein; and / or one or more SARS-CoV-2 variant spike proteins with a sub-picomolar affinity, i.e., KD< 1 x 10 -10 M, binds to a SARSr-CoV spike protein; a SARS-CoV-2 spike protein; and / or one or more SARS-CoV-2 variant spike proteins. In certain embodiments, an antigen binding molecule described herein binds to a SARSr-CoV spike protein; a SARS-CoV-2 spike protein; and / or one or more SARS-CoV-2 variant spike proteins with a sub-picomolar affinity, i.e., KD< 1 x 10 -12 M, binds to a SARSr-CoV spike protein; a SARS-CoV-2 spike protein; and / or one or more SARS-CoV-2 variant spike proteins. In certain embodiments, an antigen binding molecule described herein binds to a SARSr-CoV spike protein; a SARS-CoV-2 spike protein; and / or one or more SARS-CoV-2 variant spike proteins with a sub-picomolar affinity, i.e., KD< 1 x 10 -12 M, binds to a SARSr-CoV spike protein; a SARS-CoV-2 spike protein; and / or one or more SARS-CoV-2 variant spike proteins.

[0211] An antigen binding molecule as described in the disclosure can bind to a specific region of interest of a SARSr-CoV spike protein; a SARS-CoV-2 spike protein; and / or one or more SARS-CoV-2 variant spike proteins. An antigen binding molecule as described in the disclosure can bind to a linear epitope of a SARSr-CoV spike protein; a SARS-CoV-2 spike protein; and / or one or more SARS-CoV-2 variant spike proteins, which is composed of a contiguous sequence of amino acids (amino acid primary sequence). In certain embodiments, the antigen binding molecule can bind to a conformational epitope of a SARSr-CoV spike protein; a SARS-CoV-2 spike protein; and / or one or more SARS-CoV-2 variant spike proteins, which is composed of noncontiguous amino acid residues in the amino acid sequence.

[0212] A skilled artisan can use a variety of methods well known in the art to determine the region of a particular target molecule to which an antigen binding molecule binds, including X-ray co-crystallographic analysis of antibody-antigen complexes, peptide scanning, mutation mapping, hydrogen deuterium exchange mass spectrometry, phage display techniques, competitive ELISA, and protease-based "protection" methods. These methods are described in Gershoni et al., BioDrugs 2007, Vol. 21, No. 3, pp. 145-156, which is incorporated by reference herein in its entirety.

[0213] In certain embodiments, the antigen binding molecule is capable of binding to the same region or overlapping region of a SARSr-CoV spike protein; a SARS-CoV-2 spike protein; and / or one or more SARS-CoV-2 variant spike protein as an antibody comprising a VH and VL region as set forth in Table C.

[0214] The ability of a test antigen binding molecule to bind to the same or overlapping region of a particular target as a reference antigen binding molecule can be assessed by analyzing: (i) the interaction of the test antigen binding molecule with the target in the absence of the reference binding molecule; and (ii) the interaction of the test antigen binding molecule with the target in the presence of the reference antigen binding molecule or after pre-incubation of the target with the reference antigen binding molecule. A decrease in the level of interaction of the test antigen binding molecule with the target according to analysis (ii) as compared to (i) can support the inference that the test antigen binding molecule binds to the same or overlapping region of the target as the reference antigen binding molecule. Suitable detection methods for such analysis include competitive ELISA assays and epitope sorting experiments.

[0215] In certain embodiments, an antigen binding molecule as described herein can bind to a region of a SARSr-CoV spike protein; a SARS-CoV-2 spike protein; and / or one or more SARS-CoV-2 variant spike protein that is proximal to a protein interaction partner of the SARSr-CoV spike protein; the SARS-CoV-2 spike protein; and / or the one or more SARS-CoV-2 variant spike protein (e.g., ACE2). In certain embodiments, the antigen binding molecule reduces / inhibits the interaction between a SARSr-CoV spike protein; a SARS-CoV-2 spike protein; and / or one or more SARS-CoV-2 variant spike protein and a SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein interaction partner (e.g., ACE2). In certain embodiments, the antigen binding molecule is a competitive inhibitor of the binding of a SARSr-CoV spike protein; a SARS-CoV-2 spike protein; and / or one or more SARS-CoV-2 variant spike protein to a SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein interaction partner (e.g., ACE2). In certain embodiments, the antigen binding molecule can bind to a region of a SARSr-CoV spike protein; a SARS-CoV-2 spike protein; and / or one or more SARS-CoV-2 variant spike protein that is proximal to a polypeptide comprising or consisting of the sequence set forth in SEQ ID NO: 30

[0216] Antigen binding molecules that can inhibit the interaction of ACE2 with a SARS-CoV-2 spike protein can be referred to as inhibitors / antagonists of the interaction, and also as neutralizing antigen binding molecules for SARS-CoV-2.

[0217] In certain embodiments, an antigen binding molecule as described herein can inhibit the interaction between ACE2 and a SARS-CoV-2 spike protein. In certain embodiments, an antigen binding molecule as described herein can inhibit the interaction between ACE2 and a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0218] In certain embodiments, the antigen binding molecule can inhibit the interaction between ACE2 and a SARS-CoV-2 variant spike protein. In certain embodiments, the antigen binding molecule can inhibit the interaction between ACE2 and a polypeptide comprising or consisting of an amino acid sequence that is at least 70% (e.g., >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >93%, >94%, >95%, >96%, >97%, >98%, or >99%) identical to the amino acid sequence of SEQ ID NO: 1, and the amino acid sequence of which differs from SEQ ID NO: 1. In certain embodiments, the antigen binding molecule can inhibit the interaction between ACE2 and a polypeptide comprising or consisting of SEQ ID NO: 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27.

[0219] In certain embodiments, the antigen binding molecule can inhibit the interaction between ACE2 and a polypeptide comprising or consisting of SEQ ID NO: 18. In certain embodiments, the antigen binding molecule can inhibit the interaction between ACE2 and a polypeptide comprising or consisting of SEQ ID NO: 19. In certain embodiments, the antigen binding molecule can inhibit the interaction between ACE2 and a polypeptide comprising or consisting of SEQ ID NO: 20. In certain embodiments, the antigen binding molecule can inhibit the interaction between ACE2 and a polypeptide comprising or consisting of SEQ ID NO: 21. In certain embodiments, the antigen binding molecule can inhibit the interaction between ACE2 and a polypeptide comprising or consisting of SEQ ID NO: 26. In certain embodiments, the antigen binding molecule can inhibit the interaction between ACE2 and a polypeptide comprising or consisting of SEQ ID NO: 27.

[0220] In certain embodiments, the antigen binding molecule can inhibit the interaction between ACE2 and a polypeptide comprising or consisting of an amino acid sequence that is at least 70% (e.g., > 70%, > 75%, > 80%, > 85%, > 86%, > 87%, > 88%, > 89%, > 90%, > 91%, > 93%, > 94%, > 95%, > 96%, > 97%, > 98%, or > 99%) identical to SEQ ID NO: 7, and the amino acid sequence of which differs from SEQ ID NO: 7. In certain embodiments, the antigen binding molecule can inhibit the interaction between ACE2 and a polypeptide comprising or consisting of SEQ ID NO: 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, or 702.

[0221] In certain embodiments, the antigen binding molecule can inhibit the interaction between ACE2 and a polypeptide comprising SEQ ID NO: 693. In certain embodiments, the antigen binding molecule can inhibit the interaction between ACE2 and a polypeptide comprising SEQ ID NO: 694. In certain embodiments, the antigen binding molecule can inhibit the interaction between ACE2 and a polypeptide comprising SEQ ID NO: 695. In certain embodiments, the antigen binding molecule can inhibit the interaction between ACE2 and a polypeptide comprising SEQ ID NO: 696. In certain embodiments, the antigen binding molecule can inhibit the interaction between ACE2 and a polypeptide comprising SEQ ID NO: 697. In certain embodiments, the antigen binding molecule can inhibit the interaction between ACE2 and a polypeptide comprising SEQ ID NO: 698.

[0222] In certain embodiments, the antigen binding molecule can inhibit the interaction between ACE2 and a polypeptide comprising an amino acid sequence that is at least 70% (e.g., >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >93%, >94%, >95%, >96%, >97%, >98%, or >99%) identical to SEQ ID NO: 8, and the amino acid sequence of which differs from SEQ ID NO: 8. In certain embodiments, the antigen binding molecule can inhibit the interaction between ACE2 and a polypeptide comprising or consisting of SEQ ID NO: 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, or 719.

[0223] In certain embodiments, the antigen binding molecule can inhibit the interaction between ACE2 and a polypeptide comprising SEQ ID NO: 710. In certain embodiments, the antigen binding molecule can inhibit the interaction between ACE2 and a polypeptide comprising SEQ ID NO: 711. In certain embodiments, the antigen binding molecule can inhibit the interaction between ACE2 and a polypeptide comprising SEQ ID NO: 712. In certain embodiments, the antigen binding molecule can inhibit the interaction between ACE2 and a polypeptide comprising SEQ ID NO: 713. In certain embodiments, the antigen binding molecule can inhibit the interaction between ACE2 and a polypeptide comprising SEQ ID NO: 714. In certain embodiments, the antigen binding molecule can inhibit the interaction between ACE2 and a polypeptide comprising SEQ ID NO: 715.

[0224] In certain embodiments, the antigen binding molecule as described in the present disclosure is capable of inhibiting the interaction between ACE2 and two or more (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more) (independently) selected from the group consisting of SARS-CoV-2 spike protein and SARS-CoV-2 variant spike protein. That is, in certain embodiments, the antigen binding molecule, which can inhibit the interaction between ACE2 and a given (first) protein selected from the group consisting of SARS-CoV-2 spike protein and SARS-CoV-2 variant spike protein, also inhibits the interaction between ACE2 and one or more other (second, third, etc.) proteins selected from the group consisting of SARS-CoV-2 spike protein and SARS-CoV-2 variant spike protein, wherein the one or more other proteins have an amino acid sequence that is different from the amino acid sequence of the first protein.

[0225] In certain embodiments, the antigen binding molecules as described in the present disclosure can inhibit the interaction between ACE2 and two or more (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or all 18) polypeptides selected from the group consisting of a polypeptide consisting of the amino acid sequence of SEQ ID NO: 1, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 11, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 12, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 13, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 14, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 15, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 16, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 17, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 18, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 19, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 20, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 21, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 22, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 23, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 24 A polypeptide consisting of the amino acid sequence of SEQ ID NO: 23, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 24, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 25, a polypeptide consisting of the amino acid sequence of SEQ ID NO: 26, and a polypeptide consisting of the amino acid sequence of SEQ ID NO: 27.

[0226] In certain embodiments, an antigen binding molecule as described herein can inhibit the interaction between ACE2 and two or more (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all 18) polypeptides selected from the group consisting of a polypeptide comprising the amino acid sequence of SEQ ID NO: 7, a polypeptide comprising the amino acid sequence of SEQ ID NO: 686, a polypeptide comprising the amino acid sequence of SEQ ID NO: 687, a polypeptide comprising the amino acid sequence of SEQ ID NO: 688, a polypeptide comprising the amino acid sequence of SEQ ID NO: 689, a polypeptide comprising the amino acid sequence of SEQ ID NO: 690, a polypeptide comprising the amino acid sequence of SEQ ID NO: 691, a polypeptide comprising the amino acid sequence of SEQ ID NO: 692, a polypeptide comprising the amino acid sequence of SEQ ID NO: 693, a polypeptide comprising the amino acid sequence of SEQ ID NO: 694, a polypeptide comprising the amino acid sequence of SEQ ID NO: 695, a polypeptide comprising the amino acid sequence of SEQ ID NO: 696, a polypeptide comprising the amino acid sequence of SEQ ID NO: 697, a polypeptide comprising the amino acid sequence of SEQ ID NO: 698, a polypeptide comprising the amino acid sequence of SEQ ID NO: 699, a polypeptide comprising the amino acid sequence of SEQ ID NO: 700, a polypeptide comprising the amino acid sequence of SEQ ID NO: 701, a polypeptide comprising the amino acid sequence of SEQ ID NO: 702.

[0227] In certain embodiments, an antigen binding molecule as described herein can inhibit the interaction between ACE2 and two or more (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all 18) polypeptides selected from the group consisting of: a polypeptide comprising the amino acid sequence of SEQ ID NO: 8, a polypeptide comprising the amino acid sequence of SEQ ID NO: 703, a polypeptide comprising the amino acid sequence of SEQ ID NO: 704, a polypeptide comprising the amino acid sequence of SEQ ID NO: 705, a polypeptide comprising the amino acid sequence of SEQ ID NO: 706, a polypeptide comprising the amino acid sequence of SEQ ID NO: 707, a polypeptide comprising the amino acid sequence of SEQ ID NO: 708, a polypeptide comprising the amino acid sequence of SEQ ID NO: 709, a polypeptide comprising the amino acid sequence of SEQ ID NO: 710, a polypeptide comprising the amino acid sequence of SEQ ID NO: 711, a polypeptide comprising the amino acid sequence of SEQ ID NO: 712, a polypeptide comprising the amino acid sequence of SEQ ID NO: 713, a polypeptide comprising the amino acid sequence of SEQ ID NO: 714, a polypeptide comprising the amino acid sequence of SEQ ID NO: 715, a polypeptide comprising the amino acid sequence of SEQ ID NO: 716, a polypeptide comprising the amino acid sequence of SEQ ID NO: 717, a polypeptide comprising the amino acid sequence of SEQ ID NO: 718, a polypeptide comprising the amino acid sequence of SEQ ID NO: 719.

[0228] In a preferred example, the antigen-binding molecule as described in the present disclosure: can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 1; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 11; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 12; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 13; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 14; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 15; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 16; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 17. In a preferred example, the antigen-binding molecule as described in the present disclosure: can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 1; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 11; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 12; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 13; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 14; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 15; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 16; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 17; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 18; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 19.In a preferred embodiment, the antigen-binding molecule as described in the present invention can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 1; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 11; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 12; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 13; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 14; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 15; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 16; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 17; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 18; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 19; can inhibit the interaction between ACE2 and a polypeptide containing or consisting of the amino acid sequence of SEQ ID NO: 20. NO:20; it can inhibit the interaction between ACE2 and a polypeptide containing or consisting of an amino acid sequence of SEQ ID NO:21; it can inhibit the interaction between ACE2 and a polypeptide containing or consisting of an amino acid sequence of SEQ ID NO:26; it can inhibit the interaction between ACE2 and a polypeptide containing or consisting of an amino acid sequence of SEQ ID NO:27.

[0229] In preferred embodiments, the antigen binding molecule as described in the present disclosure: can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 7; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 686; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 687; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 688; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 689; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 690; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 691; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 692. In preferred embodiments, the antigen binding molecule as described in the present disclosure: can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 7; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 686; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 687; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 688; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 689; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 690; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 691; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 692; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 693; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 694.In a preferred embodiment, the antigen-binding molecule as described in the present disclosure: can inhibit the interaction between ACE2 and a polypeptide containing the amino acid sequence of SEQ ID NO: 7; can inhibit the interaction between ACE2 and a polypeptide containing the amino acid sequence of SEQ ID NO: 686; can inhibit the interaction between ACE2 and a polypeptide containing the amino acid sequence of SEQ ID NO: 687; can inhibit the interaction between ACE2 and a polypeptide containing the amino acid sequence of SEQ ID NO: 688; can inhibit the interaction between ACE2 and a polypeptide containing the amino acid sequence of SEQ ID NO: 689; can inhibit the interaction between ACE2 and a polypeptide containing the amino acid sequence of SEQ ID NO: 690; can inhibit the interaction between ACE2 and a polypeptide containing the amino acid sequence of SEQ ID NO: 691; can inhibit the interaction between ACE2 and a polypeptide containing the amino acid sequence of SEQ ID NO: 692; can inhibit the interaction between ACE2 and a polypeptide containing the amino acid sequence of SEQ ID NO: 693; can inhibit the interaction between ACE2 and a polypeptide containing the amino acid sequence of SEQ ID NO: 694; can inhibit the interaction between ACE2 and a polypeptide containing the amino acid sequence of SEQ ID NO: NO:695; can inhibit the interaction between ACE2 and a polypeptide containing the amino acid sequence of SEQ ID NO:696; can inhibit the interaction between ACE2 and a polypeptide containing the amino acid sequence of SEQ ID NO:697; can inhibit the interaction between ACE2 and a polypeptide containing the amino acid sequence of SEQ ID NO:698.

[0230] In preferred embodiments, the antigen binding molecule as described in the present disclosure: can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 8; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 703; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 704; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 705; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 706; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 707; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 708; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 709. In preferred embodiments, the antigen binding molecule as described in the present disclosure: can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 8; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 703; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 704; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 705; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 706; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 707; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 708; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 709; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 710; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 711.In preferred embodiments, the antigen binding molecule as described in the disclosure: can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 8; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 703; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 704; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 705; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 706; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 707; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 708; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 709; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 710; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 711; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 712; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 713; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 714; can inhibit the interaction between ACE2 and a polypeptide comprising the amino acid sequence of SEQ ID NO: 715.

[0231] The ability of a particular antigen binding molecule to inhibit the interaction between SARS-CoV-2 spike protein and / or a particular SARS-CoV-2 variant spike protein and ACE2 can be determined by analyzing the interaction with the interaction partner in the presence of the antigen binding molecule or after incubation of one or both with the antigen binding molecule. An antigen binding molecule that inhibits the interaction of SARS-CoV-2 spike protein / a particular SARS-CoV-2 variant spike protein with ACE2 can be defined as reducing / decreasing the level of interaction observed between the interaction partner in the presence of the antigen binding molecule compared to the level of interaction observed in the absence of the antigen binding molecule (or in the presence of a suitable control antigen binding molecule known not to affect the interaction between SARS-CoV-2 spike protein / a SARS-CoV-2 variant spike protein and ACE2) or after incubation of the interaction partner with the antigen binding molecule. Suitable assays can be performed in vitro, e.g., using recombinant interaction partner, or using interaction partner-expressing cells. The cells expressing the interaction partner can be endogenous or nucleic acids can be introduced into the cells to achieve expression. For the purpose of the assay, one or both of the interaction partner and / or the antigen binding molecule can be labeled or used in conjunction with a detectable entity for the purpose of detecting and / or determining the level of interaction.

[0232] The ability of a given antigen binding molecule to inhibit the interaction between ACE2 and a betacoronavirus spike protein (SARS-CoV-2 spike protein / a SARS-CoV-2 variant spike protein) can be assessed by a pseudovirus neutralization assay. Pseudovirus neutralization assays can employ a vesicular stomatitis virus (VSV) or a retrovirus (RV) vector pseudotyped with SARS-CoV-2 spike protein or a SARS-CoV-2 variant spike protein. Pseudovirus neutralization assays can be used to assess the ability of a given antigen binding molecule to inhibit the interaction between ACE2 and a betacoronavirus spike protein (SARS-CoV-2 spike protein / a SARS-CoV-2 variant spike protein) are documented in Donofrio et al., Vaccines (Basel) 2021, vol. 9, no. 4, p. 389, Nie et al., Emerg. Microbes Infect. 2020, vol. 9, p. 680-686, Chia et al., Sci Adv 2023, vol. 9, no. 30, eade3470, Tan et al., Nature Biotechnology 2020, vol. 38, p. 1073-1078, all of which are incorporated by reference in their entirety.

[0233] The ability of the antigen binding molecule to inhibit the interaction between ACE2 and a betacoronavirus spike protein (SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein) can also be assessed by surrogate virus neutralization test (sVNT). Surrogate virus neutralization test detects the binding of SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein (or a domain thereof, such as RBD) to ACE2 by using a marker species based on ELISA technology, thereby inferring the degree of interaction inhibition. Surrogate virus neutralization test can be used to assess the ability of a given antigen binding molecule to inhibit the interaction between ACE2 and a betacoronavirus spike protein (SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein) is recorded in, for example, Chia et al., Sci Adv. 2023 9(30) eade3470, Tan et al., Nature Biotechnology 2020 38 1073-1078, Springer et al., Diagnostics (Basel). 2023 13(13) 2278, the entire contents of which are incorporated herein by reference.

[0234] In certain embodiments, the ability of the antigen binding molecule to inhibit the interaction between ACE2 and a betacoronavirus spike protein (SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein) is analyzed essentially as described in Example 1.2 herein. In certain embodiments, the ability of the antigen binding molecule to inhibit the interaction between ACE2 and a betacoronavirus spike protein (SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein) is analyzed essentially as described in Example 1.3 herein.

[0235] In certain embodiments, the antigen binding molecules described herein can reduce / inhibit the level of interaction between the SARS-CoV-2 spike protein / a given SARS-CoV-2 variant spike protein and ACE2 to the level of SARS-CoV-2 spike protein / a given SARS-CoV-2 variant ... The level of interaction between the S-CoV-2 variant spike protein and ACE2 is less than 1 times, such as ≤0.99 times, ≤0.95 times, ≤0.9 times, ≤0.85 times, ≤0.8 times, ≤0.75 times, ≤0.7 times, ≤0.65 times, ≤0.6 times, ≤0.55 times, ≤0.5 times, ≤0.45 times, ≤0.4 times, ≤0.35 times, ≤0.3 times, ≤0.25 times, ≤0.2 times, ≤0.15 times, ≤0.1 times, ≤0.05 times or ≤0.01 times.

[0236] In certain embodiments, the IC of an antigen binding molecule capable of inhibiting the interaction between the SARS-CoV-2 spike protein / a given SARS-CoV-2 variant spike protein and ACE2 is 50 Less than 1ug / ml, preferably ≤800ng / ml, ≤700ng / ml, ≤600ng / ml, ≤500ng / ml, ≤400ng / ml, ≤300ng / ml, ≤200ng / ml, ≤100ng / ml , ≤90ng / ml, ≤80ng / ml, ≤70ng / ml, ≤60ng / ml, ≤50ng / ml, ≤40ng / ml, ≤30ng / ml, ≤20ng / ml, ≤10ng / ml, ≤9ng / ml, One of ≤8 ng / ml, ≤7 ng / ml, ≤6 ng / ml, ≤5 ng / ml, ≤4 ng / ml, ≤3 ng / ml, ≤2 ng / ml, ≤1 ng / ml, ≤900 pg / ml, ≤800 pg / ml, ≤700 pg / ml, ≤600 pg / ml, ≤500 pg / ml, ≤400 pg / ml, ≤300 pg / ml, ≤200 pg / ml or ≤100 pg / ml as determined in a pseudovirus neutralization assay as described in Example 1.2 herein. In some embodiments, the IC of an antigen-binding molecule capable of inhibiting the interaction between the SARS-CoV-2 spike protein / a given SARS-CoV-2 variant spike protein and ACE2 50one of less than 1 ug / ml, preferably < 800 ng / ml, < 700 ng / ml, < 600 ng / ml, < 500 ng / ml, < 400 ng / ml, < 300 ng / ml, < 200 ng / ml, < 100 ng / ml, < 90 ng / ml, < 80 ng / ml, < 70 ng / ml, < 60 ng / ml, < 50 ng / ml, < 40 ng / ml, < 30 ng / ml, < 20 ng / ml, < 10 ng / ml, < 9 ng / ml, < 8 ng / ml, < 7 ng / ml, < 6 ng / ml, < 5 ng / ml, < 4 ng / ml, < 3 ng / ml, < 2 ng / ml, < 1 ng / ml, < 900 pg / ml, < 800 pg / ml, < 700 pg / ml, < 600 pg / ml, < 500 pg / ml, < 400 pg / ml, < 300 pg / ml, < 200 pg / ml, or < 100 pg / ml, as determined in the surrogate virus neutralization test as described in Example 1.3 herein.

[0237] In certain embodiments, an antigen binding molecule as described herein can reduce / inhibit infection of an ACE2-expressing cell by a betacoronavirus (SARSr-CoV, SARS-CoV-2, and / or one or more SARS-CoV-2 variants). Such an antigen binding molecule can be described as inhibiting / antagonizing infection of an ACE2-expressing cell, or can neutralize infection of the cell by a betacoronavirus.

[0238] In certain embodiments, an antigen binding molecule as described herein can reduce / inhibit infection of an ACE2-expressing cell by a SARS-CoV-2 variant selected from the group consisting of BA.1, BA.2, BA.5, BA.2.75, BA.2.75.2, BA.4.6.1, bb.7, BQ.1.1, XBB, XBB.1, XBB.1.16, XBB.2.3, EG.5, EG.5.1, B.1.1.7, B.1.351, B.1.617.2, and P.1.

[0239] In certain embodiments, the antigen binding molecules as described herein are capable of (independently) inhibiting infection of ACE2-expressing cells by two or more (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more) SARSr-CoVs selected from the group consisting of SARS-CoV-2 and SARS-CoV-2 variants. That is, in certain embodiments, the antigen binding molecules, which can inhibit infection of ACE2-expressing cells by a given (first) SARSr-CoV selected from the group consisting of SARS-CoV-2 and SARS-CoV-2 variants, can also inhibit infection of ACE2-expressing cells by one or more other (second, third, etc.) SARSr-CoVs selected from the group consisting of SARS-CoV-2 and SARS-CoV-2 variants, wherein the one or more other SARSr-CoVs have a nucleotide sequence that differs from the nucleotide sequence of the first SARSr-CoV.

[0240] In certain embodiments, the antigen binding molecules as described herein can inhibit infection of ACE2-expressing cells by two or more (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all 18) SARSr-CoVs selected from the group consisting of SARS-CoV-2, BA.1, BA.2, BA.5, BA.2.75, BA.2.75.2, BA.4.6.1, BF.7, BQ.1.1, XBB, XBB.1, XBB.1.16, XBB.2.3, EG.5, EG.5.1, B.1.1.7, B.1.351, B.1.617.2, and P.1.

[0241] In preferred embodiments, the antigen binding molecules as described herein can inhibit infection of ACE2-expressing cells by SARS-CoV-2, BA.1, BA.2, BA.5, BA.2.75, BA.2.75.2, BA.4.6.1, and BF.7. In preferred embodiments, the antigen binding molecules as described herein can inhibit infection of ACE2-expressing cells by SARS-CoV-2, BA.1, BA.2, BA.5, BA.2.75, BA.2.75.2, BA.4.6.1, BF.7, BQ.1.1, and XBB.1. In preferred embodiments, the antigen binding molecules as described herein can inhibit infection of ACE2-expressing cells by SARS-CoV-2, BA.1, BA.2, BA.5, BA.2.75, BA.2.75.2, BA.4.6.1, BF.7, BQ.1.1, XBB.1, XBB.1.16, XBB.2.3, EG.5, and EG.5.1.

[0242] The ability of a given antigen binding molecule to inhibit the infection of ACE2 expressing cells by SARS-CoV-2 / SARS-CoV-2 variant can be analyzed by determining / quantifying the infection of ACE2 expressing cells by SARS-CoV-2 / SARS-CoV-2 variant (or pseudovirus pseudotyped with spike protein encoded by SARS-CoV-2 / SARS-CoV-2 variant) in the presence of the antigen binding molecule and comparing it to the level of infection observed in the absence of the antigen binding molecule (and / or to the level of infection observed in the presence of a known appropriate control antigen binding molecule that does not affect the infection of ACE2 expressing cells by the relevant virus). This method can comprise determining the absolute number or proportion of cells infected (e.g. comprising) by the relevant virus.

[0243] The ability of a given antigen binding molecule to inhibit the infection of ACE2 expressing cells by SARS-CoV-2 / SARS-CoV-2 variant can be analyzed by a pseudovirus neutralization assay as described in Chia et al., Sci Adv. 2023 9(30) eade3470 or Tan et al., Nature Biotechnology 2020 38 1073-1078.

[0244] In certain embodiments, an antigen binding molecule as described in the present disclosure can reduce / inhibit the level of infection of ACE2 expressing cells by SARS-CoV-2 / SARS-CoV-2 variant (or pseudovirus pseudotyped with spike protein encoded by SARS-CoV-2 / SARS-CoV-2 variant) to be less than 1-fold, such as < 0.99-fold, < 0.95-fold, < 0.9-fold, < 0.85-fold, < 0.8-fold, < 0.75-fold, < 0.7-fold, < 0.65-fold, < 0.6-fold, < 0.55-fold, < 0.45-fold, < 0.35-fold, < 0.3-fold, < 0.25-fold; < 0.2-fold, < 0.15-fold, < 0.1-fold, < 0.05-fold or < 0.01-fold of the level of infection of ACE2 expressing cells observed in the absence of the antigen binding molecule (or in the presence of a known appropriate control antigen binding molecule that does not affect the infection of ACE2 expressing cells by SARS-CoV-2 / SARS-CoV-2 variant).

[0245] In certain embodiments, the IC50 of an antigen binding molecule capable of inhibiting the infection of ACE2 expressing cells by SARS-CoV-2 / SARS-CoV-2 variant (or pseudovirus pseudotyped with spike protein encoded by SARS-CoV-2 / SARS-CoV-2 variant) is less than 1 mM, such as < 0.9 mM, < 0.8 mM, < 0.7 mM, < 0.6 mM, < 0.5 mM, < 0.4 mM, < 0.3 mM, < 0.2 mM, < 0.1 mM, < 0.05 mM or < 0.01 mM. 50one of less than 1 ug / ml, preferably one of < 800 ng / ml, < 700 ng / ml, < 600 ng / ml, < 500 ng / ml, < 400 ng / ml, < 300 ng / ml, < 200 ng / ml, < 100 ng / ml, < 90 ng / ml, < 80 ng / ml, < 70 ng / ml, < 60 ng / ml, < 50 ng / ml, < 40 ng / ml, < 30 ng / ml, < 20 ng / ml, < 10 ng / ml, < 9 ng / ml, < 8 ng / ml, < 7 ng / ml, < 6 ng / ml, < 5 ng / ml, < 4 ng / ml, < 3 ng / ml, < 2 ng / ml, < 1 ng / ml, < 900 pg / ml, < 800 pg / ml, < 700 pg / ml, < 600 pg / ml, < 500 pg / ml, < 400 pg / ml, < 300 pg / ml, < 200 pg / ml, or < 100 pg / ml, as determined in a pseudovirus neutralization assay as described in Example 1.2 herein.

[0246] In certain embodiments, the antigen binding molecules as described in the present disclosure have one or more novel, similar or improved functional properties compared to known antigen binding molecules that can bind to SARS-CoV-2 spike protein and / or one or more SARS-CoV-2 variant spike proteins.

[0247] In certain embodiments, the antigen binding molecules have one or more novel, similar or improved functional properties compared to SS6V11-E7 (also referred to as “E7”) described in WO 2022 / 245288 A1. For comparison of the functional properties in the following paragraphs, “SS6V11-E7” refers to the antigen binding molecule formed by the binding of two polypeptides consisting of SEQ ID NO: 837 and two polypeptides consisting of SEQ ID NO: 838.

[0248] In certain embodiments, the antigen binding molecules have one or more novel, similar or improved functional properties compared to LyCov-1404 (also referred to as bebtelovimab; Drug Bank Accession No. NO.DB16755). For comparison of the functional properties in the following paragraphs, “LyCov-1404” refers to the antigen binding molecule formed by the binding of two polypeptides consisting of SEQ ID NO: 854 and two polypeptides consisting of SEQ ID NO: 855.

[0249] In certain embodiments, the antigen binding molecules described herein have one or more of the following properties:

[0250] bind to SARS-CoV-2 variant spike proteins that cannot be bound by SS6V11-E7 and / or LyCov-1404;

[0251] It can inhibit the interaction between ACE2 and the spike protein of SARS-CoV-2 variants, while SS6V11-E7 and / or LyCov-1404 cannot inhibit the interaction between the spike protein and ACE2;

[0252] It can inhibit the infection of ACE2-expressing cells by betacoronavirus (such as SARS-CoV-2 variants), while SS6V11-E7 and / or LyCov-1404 cannot inhibit the infection of ACE2-expressing cells by the virus;

[0253] Binds to the relevant protein with similar or higher affinity (similar or lower KD) compared to the affinity of SS6V11-E7 and / or LyCov-1404 for the betacoronavirus spike protein (SARSr-CoV spike protein; SARS-CoV-2 spike protein and / or one or more SARS-CoV-2 variant spike proteins);

[0254] Compared to the potency of SS6V11-E7 and / or LyCov-1404 in inhibiting the interaction between the betacoronavirus spike protein (SARSr-CoV spike protein; SARS-CoV-2 spike protein and / or one or more SARS-CoV-2 variant spike protein) and ACE2, the inhibitory effect is similar or higher (similar or lower IC 50 ) inhibit the corresponding interaction;

[0255] Compared to the efficacy of SS6V11-E7 and / or LyCov-1404 in inhibiting infection of ACE2-expressing cells by betacoronaviruses (SARSr-CoV, SARS-CoV-2 and / or one or more SARS-CoV-2 variants), the inhibitory effect was similar or higher (similar or lower IC 50 ) to inhibit such infections.

[0256] KD / IC50 "similar" to the reference KD / IC50 described in the previous paragraph 50 It can be ≥0.5-fold and ≤2-fold, such as ≥0.55-fold and ≤1.9-fold, ≥0.6-fold and ≤1.8-fold, ≥0.65-fold and ≤1.7-fold, ≥0.7-fold and ≤1.6-fold, ≥0.75-fold and ≤1.5-fold, ≥0.8-fold and ≤1.4-fold, ≥0.85-fold and ≤1.3-fold, ≥0.9-fold and ≤1.2-fold, or ≥0.95-fold and ≤1.1-fold the reference KD / IC 50 Relative to the reference KD / IC 50 "Low" KD / IC 50The value can be less than 1 times, such as ≤0.99 times, ≤0.95 times, ≤0.9 times, ≤0.85 times, ≤0.8 times, ≤0.75 times, ≤0.7 times, ≤0.65 times, ≤0.6 times, ≤0.55 times, ≤0.5 times, ≤0.45 times, ≤0.4 times, ≤0.35 times, ≤0.3 times, ≤0.25 times, ≤0.2 times, ≤0.15 times, ≤0.1 times, ≤0.05 times or ≤0.01 times the KD / IC 50 .

[0257] It will be appreciated that for the purpose of making such an assessment, equal amounts / concentrations of the antigen binding molecule and SS6V11-E7 and / or LyCov-1404 are compared.

[0258] In certain embodiments, the antigen-binding molecules described herein bind to the SARS-CoV-2 spike protein and / or a given SARS-CoV-2 variant spike protein with a KD that is similar to or smaller than the KD of SS6V11-E7 and / or LyCov-1404 binding to the relevant protein as determined by the same method. In certain embodiments, the antigen binding molecules described in the present disclosure bind to the SARS-CoV-2 spike protein and / or a given SARS-CoV-2 variant spike protein with a KD that is ≥0.5 times and ≤2 times, such as ≥0.55 times and ≤1.9 times, ≥0.6 times and ≤1.8 times, ≥0.65 times and ≤1.7 times, ≥0.7 times and ≤1.6 times, ≥0.75 times and ≤1.5 times, ≥0.8 times and ≤1.4 times, ≥0.85 times and ≤1.3 times, ≥0.9 times ≤1.2 times, or ≥0.95 times and ≤1.1 times the KD value of SS6V11-E7 and / or LyCov-1404 binding to the relevant protein. In certain embodiments, the antigen binding molecules described herein bind to the SARS-CoV-2 spike protein and / or a given SARS-CoV-2 variant spike protein with a KD of less than 1 fold, e.g., ≤0.99 fold, ≤0.95 fold, ≤0.9 fold, ≤0.85 fold, ≤0.8 fold, ≤0.75 fold, ≤0.7 fold, ≤0.65 fold, ≤0.6 fold, ≤0.55 fold, ≤0.45 fold, ≤0.4 fold, ≤0.35 fold, ≤0.3 fold, ≤0.25 fold, ≤0.2 fold, ≤0.15 fold, ≤0.1 fold, ≤0.05 fold, or ≤0.01 fold, compared to the KD of SS6V11-E7 and / or LyCov-1404 binding to the relevant protein determined by the same method.

[0259] In certain embodiments, the antigen binding molecules described herein inhibit the IC of the interaction between the SARS-CoV-2 spike protein and / or a given SARS-CoV-2 variant spike protein and ACE2. 50, and the IC values ​​of SS6V11-E7 and / or LyCov-1404 for inhibiting the interaction between related proteins and ACE2 determined by the same method 50 In certain embodiments, the antigen binding molecule inhibits the IC of the SARS-CoV-2 spike protein and / or the interaction of a given SARS-CoV-2 variant spike protein with ACE2. 50 The IC values ​​of SS6V11-E7 and / or LyCov-1404 for inhibiting the interaction between related proteins and ACE2 were determined by the same method. 50 In certain embodiments, the antigen binding molecule inhibits the IC of the SARS-CoV-2 spike protein and / or the interaction of the spike protein of a given SARS-CoV-2 variant with ACE2. 50 The IC values ​​of SS6V11-E7 and / or LyCov-1404 for inhibiting the interaction between related proteins and ACE2 determined by the same method were lower than those of SS6V11-E7 and / or LyCov-1404 for inhibiting the interaction between related proteins and ACE2. 50 times, such as ≤0.99 times, ≤0.95 times, ≤0.9 times, ≤0.85 times, ≤0.8 times, ≤0.75 times, ≤0.7 times, ≤0.65 times, ≤0.6 times, ≤0.55 times, ≤0.45 times, ≤0.4 times, ≤0.35 times, ≤0.3 times, ≤0.25 times, ≤0.2 times, ≤0.15 times, ≤0.1 times, ≤0.05 times or ≤0.01 times.

[0260] In certain embodiments, the antigen binding molecules described herein inhibit the IC of ACE2-expressing cells infected with SARS-CoV-2 / SARS-CoV-2 variants (or pseudotyped viruses of spike proteins encoded by SARS-CoV-2 / SARS-CoV-2 variants). 50 , and the IC values ​​of SS6V11-E7 and / or LyCov-1404 for inhibiting the interaction between related proteins and ACE2 determined by the same method 50 In certain embodiments, the antigen binding molecules inhibit the IC of ACE2-expressing cells infected with SARS-CoV-2 / SARS-CoV-2 variants (or pseudoviruses pseudotyped with spike proteins encoded by SARS-CoV-2 / SARS-CoV-2 variants). 50 The IC values ​​of SS6V11-E7 and / or LyCov-1404 for inhibiting infection of these cells by related SARSr-CoV were determined by the same method.50 ≥ 0.5 fold, > 0.55 fold and < 1.9 fold, > 0.6 fold and < 1.8 fold, > 0.65 fold and < 1.7 fold, > 0.7 fold and < 1.6 fold, > 0.75 fold and < 1.5 fold, > 0.8 fold and < 1.4 fold, > 0.85 fold and < 1.3 fold, > 0.9 fold and < 1.2 fold or > 0.95 fold and < 1.1 fold. In certain embodiments, the antigen binding molecule inhibits the infection of ACE2 expressing cells by SARS-CoV-2 / SARS-CoV-2 variants (or pseudoviruses pseudotyped with the spike protein encoded by SARS-CoV-2 / SARS-CoV-2 variants) by an IC 50 less than the IC with which SS6V11-E7 and / or LyCov- 1404 inhibits the infection of such cells by a related SARSr-CoV as determined in the same method 50 1 fold, such as < 0.99 fold, < 0.95 fold, < 0.9 fold, < 0.85 fold, < 0.8 fold, < 0.75 fold, < 0.7 fold, < 0.65 fold, < 0.6 fold, < 0.55 fold, < 0.45 fold, < 0.4 fold, < 0.35 fold, < 0.3 fold, < 0.25 fold, < 0.2 fold, < 0.15 fold, < 0.1 fold, < 0.05 fold or < 0.01 fold.

[0261] Specific Examples of Antigen-Binding Molecules and Peptides

[0262] The present disclosure also provides a polypeptide consisting of an antigen binding molecule. The polypeptide is in isolated or substantially purified form.

[0263] The antigen binding molecule as described in the present disclosure can be or can comprise a polypeptide complex.

[0264] A polypeptide comprising a plurality of domains or regions in the present specification can also be understood as the plurality of domains / regions preferably present in the same polypeptide chain. That is, a polypeptide comprising more than one domain / region is a fusion polypeptide comprising the domain / region.

[0265] In certain embodiments, the polypeptide as described in the present disclosure comprises or consists of a VH as described herein. In certain embodiments, the polypeptide as described in the present disclosure comprises or consists of a VL as described herein.

[0266] In certain embodiments, the polypeptide additionally comprises one or more antibody heavy chain constant regions (CH). In certain embodiments, the polypeptide additionally comprises one or more antibody light chain constant regions (CL). In certain embodiments, the polypeptide comprises a CH1, a CH2 region and / or a CH3 region of an immunoglobulin (Ig).

[0267] In certain embodiments, the polypeptide comprises one or more regions of an immunoglobulin heavy chain constant sequence. In certain embodiments, the polypeptide comprises a CH1 region as described herein. In certain embodiments, the polypeptide comprises a hinge region as described herein. In certain embodiments, the polypeptide comprises a CH2 region as described herein. In certain embodiments, the polypeptide comprises a CH3 region as described herein. In certain embodiments, the polypeptide comprises a CH2-CH3 region as described herein. In certain embodiments, the polypeptide comprises a CH1-hinge region-CH2-CH3 region as described herein.

[0268] In certain embodiments, the polypeptide comprises one or more regions of an immunoglobulin light chain constant sequence. In certain embodiments, the polypeptide comprises a CL region as described herein.

[0269] In certain embodiments, a polypeptide as described herein comprises the following structure from N- to C-terminus:

[0270] (i) VH

[0271] (ii) VL

[0272] (iii) VH-CH1

[0273] (iv) VL-CL

[0274] (v) VL-CH1

[0275] (vi) VH-CL

[0276] (vii) VH-CH1-CH2-CH3

[0277] (viii) VL-CL-CH2-CH3

[0278] (ix) VL-CH1-CH2-CH3

[0279] (x) VH-CL-CH2-CH3

[0280] The present disclosure also provides an antigen binding molecule consisting of polypeptides as described by the present disclosure. In certain embodiments, an antigen binding molecule as described by the present disclosure comprises a combination of polypeptides as follows:

[0281] (A) VH + VL

[0282] (B) VH-CH1 + VL-CL

[0283] (C) VL-CH1 + VH-CL

[0284] (D) VH-CH1-CH2-CH3 + VL-CL

[0285] (E) VH-CL-CH2-CH3 + VL-CH1

[0286] (F) VL-CH1-CH2-CH3 + VH-CL

[0287] (G) VL-CL-CH2-CH3 + VH-CH1

[0288] (H) VH-CH1-CH2-CH3 + VL-CL-CH2-CH3

[0289] (I) VH-CL-CH2-CH3 + VL-CH1-CH2-CH3

[0290] In certain embodiments, the antigen binding molecule comprises a plurality of polypeptide combinations as set forth in (A) through (I) above. For example, with reference to (D) above, in certain embodiments, the antigen binding molecule comprises two polypeptides comprising a VH-CH1-CH2-CH3 structure and two polypeptides comprising a VL-CL structure.

[0291] In (i) through (x) and (A) through (I) above, “VH” refers to a VH region as described herein, and “VL” refers to a VL region as described herein.

[0292] In certain embodiments, the antigen binding molecule as described herein comprises a polypeptide comprising or consisting of an amino acid sequence that is at least 70% (e.g., one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, or 100%) identical to SEQ ID NO: 36, 52, 67, 83, 96, 105, 120, 136, 149, 164, 179, 193, 206, 220, 235, 249, 262, 274, 285, 299, 312, 325, 336, 350, 362, 368, 381, 393, 405, 416, 427, 436, 453, 464, 475, 487, 496, 508, 522, 535, 547, 559, 572, 584, 592, 600, 614, 627, 643, or 656.

[0293] In certain embodiments, an antigen binding molecule as described herein comprises a polypeptide comprising or consisting of an amino acid sequence that is at least 70% (e.g., one of > 70%, > 75%, > 80%, > 85%, > 86%, > 87%, > 88%, > 89%, > 90%, > 91%, > 92%, > 93%, > 94%, > 95%, > 96%, > 97%, > 98%, > 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 44, 59, 75, 89, 102, 113, 128, 144, 157, 171, 187, 200, 213, 228, 242, 256, 270, 280, 291, 305, 318, 331, 343, 355, 366, 374, 388, 400, 411, 423, 432, 443, 451, 460, 471, 481, 491, 502, 515, 529, 542, 554, 567, 579, 587, 596, 607, 621, 635, 651, 663.

[0294] In certain embodiments, an antigen binding molecule as described herein comprises a polypeptide comprising or consisting of an amino acid sequence that is at least 70% (e.g., one of > 70%, > 75%, > 80%, > 85%, > 86%, > 87%, > 88%, > 89%, > 90%, > 91%, > 92%, > 93%, > 94%, > 95%, > 96%, > 97%, > 98%, > 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 720, 722, 724, 726, 728, 730, 732, 734, 736, 738, 740, 742, 744, 746, 748, 750, 752, 754, 756, 758, 760, 762, 764, 766, 768, 770, 772, 774, 776, 778, 782, 784, 786, 788, 792, 794, 796, 798, 800, 802, 804, 806, 808, 810, 812, 814, 816, 818, or 820.

[0295] In certain embodiments, an antigen binding molecule as described herein comprises a polypeptide comprising or consisting of an amino acid sequence that is at least 70% (e.g., >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, or 100%) identical to SEQ ID NO: 721, 723, 725, 727, 729, 731, 733, 735, 737, 739, 741, 743, 745, 747, 749, 751, 753, 755, 757, 759, 761, 763, 765, 767, 769, 771, 773, 775, 7779, 781, 783, 785, 787, 789, 791, 793, 795, 797, 799, 801, 803, 805, 807, 809, 813, 815, 817, 819, or 821.

[0296] In certain embodiments, an antigen binding molecule as described herein comprises one or more polypeptides comprising a VH region comprising heavy chain CDRs and a VL region comprising light chain CDRs selected from the antibodies as shown in Table A herein. That is, in certain embodiments, the antigen binding molecule comprises one or more polypeptides comprising: (i) a VH region comprising a HC-CDR1, a HC-CDR2, and a HC-CDR3 as shown in column A of Table A, and (ii) a VL region comprising a LC-CDR1, a LC-CDR2, and a LC-CDR3 as shown in column B of Table A, wherein the sequences of column A and column B are selected from the same row of Table A. In certain embodiments, an antigen binding molecule as described herein comprises one or more polypeptides comprising a VH region comprising heavy chain CDRs and a VL region comprising light chain CDRs selected from the antibodies as shown in Table A herein. In certain embodiments, an antigen binding molecule as described herein comprises one or more polypeptides comprising a VH region comprising heavy chain CDRs and a VL region comprising light chain CDRs selected from the antibodies as shown in Table A herein.

[0297] In certain embodiments, an antigen binding molecule as described herein contains one or more polypeptides comprising a VH region containing heavy chain FRs and a VL region containing light chain FRs selected from the antibodies as shown in Table B herein. That is, in certain embodiments, the antigen binding molecule contains one or more polypeptides comprising: (i) a VH region comprising HC-FR1, HC-FR2, HC-FR3, and HC-FR4 as shown in column A of Table B, and (ii) a VL region comprising LC-FR1, LC-CDR2, LC-CDR3, and LC-FR4 as shown in column B of Table B, wherein the sequences of column A and column B are selected from the same row of Table B. In certain embodiments, an antigen binding molecule as described herein includes one or more polypeptides comprising a VH region containing heavy chain FRs and a VL region containing light chain FRs selected from the antibodies as shown in Table B herein. In certain embodiments, an antigen binding molecule as described herein includes one or more polypeptides comprising a VH region containing heavy chain FRs and a VL region containing light chain FRs selected from the antibodies as shown in Table B herein.

[0298] In certain embodiments, an antigen binding molecule as described herein contains one or more polypeptides comprising: (i) an amino acid sequence that is at least 70% (e.g., one of ≥ 70%, ≥ 75%, ≥ 80%, ≥ 85%, ≥ 86%, ≥ 87%, ≥ 88%, ≥ 89%, ≥ 90%, ≥ 91%, ≥ 92%, ≥ 93%, ≥ 94%, ≥ 95%, ≥ 96%, ≥ 97%, ≥ 99%, or 100%) identical to the amino acid sequence shown in column A of Table C, and (ii) an amino acid sequence that is at least 70% (e.g., one of ≥ 70%, ≥ 75%, ≥ 80%, ≥ 85%, ≥ 86%, ≥ 87%, ≥ 88%, ≥ 89%, ≥ 90%, ≥ 91%, ≥ 92%, ≥ 93%, ≥ 94%, ≥ 95%, ≥ 96%, ≥ 97%, ≥ 99%, or 100%) identical to the amino acid sequence shown in column B of Table C, wherein the sequences of column A and column B are selected from the same row of Table C.

[0299] In certain embodiments, an antigen binding molecule as described herein contains one or more polypeptides comprising a VH region and a VL region selected from the antibodies as shown in Table C herein. That is, in certain embodiments, the antigen binding molecule contains one or more polypeptides comprising: (i) a VH region comprising an amino acid sequence as shown in column A of Table C, and (ii) a VL region comprising an amino acid sequence as shown in column B of Table C, wherein the sequences of column A and column B are selected from the same row of Table C. In certain embodiments, an antigen binding molecule as described herein includes one or more polypeptides comprising a VH region and a VL region selected from the antibodies as shown in Table C herein. In certain embodiments, an antigen binding molecule as described herein includes one or more polypeptides comprising a VH region and a VL region selected from the antibodies as shown in Table C herein.

[0300] In certain embodiments, an antigen binding molecule as described herein comprises: (i) a polypeptide comprising or consisting of an amino acid sequence that is at least 70% (e.g., one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >99%, or 100%) identical to the amino acid sequence as set forth in column A of Table D, and (ii) a polypeptide comprising or consisting of an amino acid sequence that is at least 70% (e.g., one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >99%, or 100%) identical to the amino acid sequence as set forth in column B of Table D, wherein the sequences of column A and column B are selected from the same row of Table D.

[0301] In certain embodiments, an antigen binding molecule as described herein comprises polypeptides of an antigen binding molecule as set forth in Table D herein. That is, in certain embodiments, the antigen binding molecule comprises: (i) a polypeptide comprising or consisting of an amino acid sequence as set forth in column A of Table D, and (ii) a polypeptide comprising or consisting of an amino acid sequence as set forth in column B of Table D, wherein the sequences of column A and column B are selected from the same row of Table D.

[0302] In certain embodiments, an antigen binding molecule as described herein comprises:

[0303] (1) (i) a polypeptide comprising or consisting of an amino acid sequence that is at least 70% identical to SEQ ID NO: 722, and (ii) a polypeptide comprising or consisting of an amino acid sequence that is at least 70% identical to SEQ ID NO: 723;

[0304] (2) (i) a polypeptide comprising or consisting of an amino acid sequence that is at least 70% identical to SEQ ID NO: 720, and (ii) a polypeptide comprising or consisting of an amino acid sequence that is at least 70% identical to SEQ ID NO: 721;

[0305] (3) (i) a polypeptide comprising or consisting of an amino acid sequence that is at least 70% identical to SEQ ID NO: 724, and (ii) a polypeptide comprising or consisting of an amino acid sequence that is at least 70% identical to SEQ ID NO: 725;

[0306] (4) (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 726, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 727;

[0307] (5) (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 794, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 795;

[0308] (6) (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 752, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 753;

[0309] (7) (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 748, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 749;

[0310] (8) (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 740, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 741;

[0311] (9) (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 754, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 754;

[0312] (10) (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 766, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 767;

[0313] (11) (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 774, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 775;

[0314] (12) (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 776, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 777;

[0315] (13) (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 778, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 779;

[0316] (14) (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 780, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 781;

[0317] (15) (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 784, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 785;

[0318] (16) (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 786, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 787;

[0319] (17) (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 728, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 729;

[0320] (18) (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 790, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 791; or

[0321] (19) (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 806, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 807.

[0322] Known SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein binding antigen binding molecules

[0323] Aspects and embodiments of the present disclosure also relate to known SARS-CoV-2 Spike protein / SARS-CoV-2 variant Spike protein binding antigen binding molecules and derivatives thereof. It is important to note that the “antigen binding molecules as described herein” as described herein do not include these known antigen binding molecules.

[0324] In certain embodiments, the known SARS-CoV-2 Spike protein / SARS-CoV-2 variant Spike protein binding antigen binding molecule refers to SS6V11-E7 or a derivative thereof. SS6V11-E7 (also referred to herein as “E7”) is recorded in WO2022 / 245288 Al. E7 comprises a VH region as set forth in SEQ ID NO: 824 and a VL region as set forth in SEQ ID NO: 830. The HC-CDR1, HC-CDR2, and HC-CDR3 of E7 (respectively) are set forth in SEQ ID NOs: 825, 826, and 827, and the LC-CDR1, LC-CDR2, and LC- CDR3 of E7 (respectively) are set forth in SEQ ID NOs: 831, 832, and 832. The HC-FR1, HC-FR2, HC-FR3, and HC-FR4 of E7 (respectively) are set forth in SEQ ID NOs: 266, 828, 829, and 112, and the LC-FR1, LC-FR2, LC-FR3, and LC-FR4 of E7 (respectively) are set forth in SEQ ID NOs: 834, 835, 826, and 486. In E7, the kappa light chain form is formed by the combination of two polypeptides comprising the sequence of SEQ ID NO: 837 and two polypeptides comprising the sequence of SEQ ID NO: 838.

[0325] In certain embodiments, the SS6V11-E7 or derivative thereof comprises: (i) a VH region comprising a HC-CDR1 identical to SEQ ID NO: 825 (or a variant having 1, 2, or 3 amino acids in HC-CDR1 replaced by a different amino acid), a HC-CDR2 identical to SEQ ID NO: 826 (or a variant having 1, 2, or 3 amino acids in HC-CDR2 replaced by a different amino acid), and a HC-CDR3 identical to SEQ ID NO: 827 (or a variant having 1, 2, or 3 amino acids in HC-CDR3 replaced by a different amino acid); and (ii) a VL region comprising a LC-CDR1 identical to SEQ ID NO: 831 (or a variant having 1, 2, or 3 amino acids in LC-CDR1 replaced by a different amino acid), a LC-CDR2 identical to SEQ ID NO: 832 (or a variant having 1, 2, or 3 amino acids in LC-CDR2 replaced by a different amino acid), and a LC-CDR3 identical to SEQ ID NO: 833 (or a variant having 1, 2, or 3 amino acids in LC-CDR3 replaced by a different amino acid). In certain embodiments, the SS6V11-E7 or derivative thereof comprises: (i) a VH region comprising an amino acid sequence that is at least 70%, preferably >80%, >85%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, or 100% identical to SEQ ID NO: 824; and (ii) a VL region comprising an amino acid sequence that is at least 70%, preferably >80%, >85%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, or 100% identical to SEQ ID NO: 830.

[0326] In certain embodiments, the known SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein binding antigen-binding molecule is LyCov-1404 or a derivative thereof. LyCov-1404 (also known as betrovir monoclonal antibody; Drugbank accession number DB16755) comprises a VH region as shown in SEQ ID NO: 839 and a VL region as shown in SEQ ID NO: 846. The HC-CDR1, HC-CDR2, and HC-CDR3 of LyCov-1404 are shown in SEQ ID NOs: 840, 841, and 842, respectively, and the LC-CDR1, LC-CDR2, and LC-CDR3 of LyCov-1404 are shown in SEQ ID NOs: 847, 848, and 849, respectively. LyCov-1404's HC-FR1, HC-FR2, HC-FR3, and HC-FR4 (respectively) are represented by SEQ ID NOs: 843, 844, 829, 45, and 112, and LyCov-1404's LC-FR1, LC-FR2, LC-FR3, and LC-FR4 (respectively) are represented by SEQ ID NOs: 850, 851, 852, and 853. In the human IgG1 (G1m3) heavy chain of LyCov-1404, the CλCL2 light chain is formed by the combination of two polypeptides containing the sequence of SEQ ID NO: 854 and two polypeptides containing the sequence of SEQ ID NO: 855.

[0327] In certain embodiments, LyCoV-1404 or a derivative thereof comprises: (i) a VH region comprising a HC-CDR1 identical to SEQ ID NO: 840 (or a variant having 1, 2, or 3 amino acid substitutions in HC-CDR1), a HC-CDR2 identical to SEQ ID NO: 841 (or a variant having 1, 2, or 3 amino acid substitutions in HC-CDR2), and a HC-CDR3 identical to SEQ ID NO: 842 (or a variant having 1, 2, or 3 amino acid substitutions in HC-CDR3); and (ii) a VL region comprising a LC-CDR1 identical to SEQ ID NO: 847 (or a variant having 1, 2, or 3 amino acid substitutions in LC-CDR1), a LC-CDR2 identical to SEQ ID NO: 848 (or a variant having 1, 2, or 3 amino acid substitutions in LC-CDR2), and a LC-CDR3 identical to SEQ ID NO: 849 (or a variant having 1, 2, or 3 amino acid substitutions in LC-CDR3). In certain embodiments, LyCoV-1404 or a derivative thereof comprises: (i) a VH region comprising an amino acid sequence that is at least 70%, preferably > 80%, > 85%, > 90%, > 91%, > 92%, > 93%, > 94%, 95%, > 96%, > 97%, > 98%, > 99%, or 100% identical to SEQ ID NO: 839; (ii) a VL region comprising an amino acid sequence that is at least 70%, preferably > 80%, > 85%, > 90%, > 91%, > 92%, > 93%, > 94%, > 95%, > 96%, > 9%, > 98%, > 99%, or 100% identical to SEQ ID NO: 846.

[0328] In certain embodiments, the known SARS-CoV-2 Spike protein / SARS-CoV-2 variant Spike protein binding antigen binding molecule comprises:

[0329] (A) (i) a polypeptide comprising or consisting of an amino acid sequence that is at least 70% (e.g., one of > 70%, > 75%, > 80%, > 85%, > 86%, > 87%, > 88%, > 89%, > 9%, > 91%, > 92%, > 93%, > 94%, > 95%, > 96%, > 97%, 98%, > 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 824, and (ii) a polypeptide comprising or consisting of an amino acid sequence that is at least 70% (e.g., one of > 70%, > 75%, > 80%, > 85%, > 86%, > 87%, > 88%, > 89%, > 90%, > 91%, > 92%, > 93%, > 94%, > 95%, > 96%, > 97%, > 98%, > 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 830;

[0330] (B) (i) a polypeptide comprising or consisting of an amino acid sequence that is at least 70% (e.g., one of > 70%, > 75%, > 80%, > 85%, > 86%, > 87%, > 88%, > 89%, > 9%, > 91%, > 92%, > 93%, > 94%, > 95%, > 96%, > 97%, 98%, > 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 839, and (ii) a polypeptide comprising or consisting of an amino acid sequence that is at least 70% (e.g., one of > 70%, > 75%, > 80%, > 85%, > 86%, > 87%, > 88%, > 89%, > 90%, > 91%, > 92%, > 93%, > 94%, > 95%, > 96%, > 97%, > 98%, > 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 846;

[0331] (C) (i) a polypeptide comprising or consisting of an amino acid sequence that is at least 70% (e.g., one of > 70%, > 75%, > 80%, > 85%, > 86%, > 87%, > 88%, > 89%, > 9%, > 91%, > 92%, > 93%, > 94%, > 95%, > 96%, > 97%, 98%, > 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 837, and (ii) a polypeptide comprising or consisting of an amino acid sequence that is at least 70% (e.g., one of > 70%, > 75%, > 80%, > 85%, > 86%, > 87%, > 88%, > 89%, > 90%, > 91%, > 92%, > 93%, > 94%, > 95%, > 96%, > 97%, > 98%, > 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 838; or

[0332] (D) (i) a polypeptide comprising or consisting of an amino acid sequence that is at least 70% (e.g., one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >9%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, 98%, >99%, or 100%) identical to SEQ ID NO: 854, and (ii) a polypeptide comprising or consisting of an amino acid sequence that is at least 70% (e.g., one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, or 100%) identical to SEQ ID NO: 855.

[0333] Connector peptide and additional sequence

[0334] The antigen binding molecules and polypeptides as described herein can additionally comprise other amino acids or amino acid sequences.

[0335] The antigen binding molecules and polypeptides as described herein can include a linker peptide sequence between one or more of the amino acid sequences. For example, a linker peptide sequence can be present between a VH sequence and a VL sequence, for linking the VH and VL regions (as in a scFv molecule).

[0336] Linker peptide sequences are well known to the skilled person, as described in Chen et al., Adv Drug Deliv Rev 2013, vol. 65, issue 10, pages 1357-1369, which is incorporated herein by reference in its entirety. In certain embodiments, the linker peptide sequence can be a flexible linker peptide sequence. A flexible linker peptide sequence can allow for relative movement of the amino acid sequences connected by the linker peptide sequence. Flexible linker peptides are well known to the skilled person, and several are described in Chen et al., Adv Drug Deliv Rev 2013, vol. 65, issue 10, pages 1357-1369. Flexible linker peptide sequences typically comprise a high proportion of glycine and / or serine residues.

[0337] In certain embodiments, the linker peptide sequence comprises at least one glycine residue and / or at least one serine residue. In certain embodiments, the linker peptide sequence comprises or consists of glycine and serine residues. In certain embodiments, the linker peptide sequence has the following structure: (GxS)n or (GxS)nGm; wherein G is glycine, S is serine, x is 3 or 4, n is 2, 3, 4, 5, or 6, and m is 0, 1, 2, or 3. In certain embodiments, the linker peptide sequence comprises one or more (e.g., 1, 2, 3, 4, 5, or 6) copies of the G4S sequence motif (in tandem). In certain embodiments, the linker peptide sequence comprises or consists of (G4S)4 or (G4S)6. In certain embodiments, the linker peptide sequence is 1-2, 1-3, 1-4, 1-5, 1-10, 1-15, 1-20, 1-25, or 1-30 amino acids in length.

[0338] Antigen binding molecules and polypeptides as described herein can comprise an amino acid sequence that can facilitate antigen binding molecule / polypeptide expression, folding, transport, processing, purification, or detection. For example, antigen binding molecules and polypeptides as described herein can additionally comprise an amino acid sequence that forms a detectable label, as described below.

[0339] Antigen binding molecules and polypeptides as described herein can additionally comprise a signal peptide (also known as a leader sequence or signal sequence). Signal peptides generally consist of a sequence of 5-30 hydrophobic amino acids and form a single alpha helix. Secreted proteins and proteins expressed at the cell surface often comprise a signal peptide. Signal peptides of a variety of proteins are known and recorded in databases such as GenBank, UniProt, and Ensembl, and / or can be identified / predicted using amino acid sequence analysis tools such as SignalP (Petersen et al., Nature Methods 2011, Vol. 8, 785-786) or Signal-BLAST (Frank and Sippl, Bioinformatics 2008, 24, 2172-2176).

[0340] Signal peptides can be present at the N-terminus of an antigen binding molecule / polypeptide and can be present in newly synthesized antigen binding molecules / polypeptides. Signal peptides serve for efficient transport of antigen binding molecules / polypeptides. Signal peptides are generally removed by cleavage and are thus not comprised in the mature antigen binding molecule / polypeptide.

[0341] Signal peptides of various proteins are known and documented in databases such as GenBank, UniProt, Swiss-Prot, TrEMBL, Protein Information Resource, Protein Data Bank, Ensembl and InterPro and / or can be recognized / predicted using amino acid sequence analysis tools such as SignalP (Petersen et al., Nature Methods 8, 2011, 785-786) or Signal-BLAST (Frank and Sippl, Bioinformatics 24, 2008, 2172-2176).

[0342] Labels and conjugates

[0343] In certain embodiments, the antigen binding molecule or polypeptide as described herein comprises a detectable label.

[0344] In certain embodiments, the detectable label is a fluorescent label, a phosphorescent label, a luminescent label, an immuno-detection label (e.g. epitope tag), a radioactive label, a chemical modification label, a nucleic acid or an enzymatic label. The antigen binding molecule or polypeptide can be covalently or non-covalently labeled with a detectable label.

[0345] Fluorescent labels include fluorescein, rhodamine, allophycocyanin, eosin and NDB, green fluorescent protein (GFP), rare earth chelates such as europium (Eu), terbium (Tb) and samarium (Sm), tetramethylrhodamine, Texas Red, 4-methylumbelliferone, 7-amino-4-methylcoumarin, Cy3 and Cy5. Radioactive labels include radioisotopes such as hydrogen 3 , sulfur 35 , carbon 14 , phosphorus 32 , iodine 123 , iodine 125 , iodine 126 , iodine 131 , iodine 133 , bromine 77 , technetium 99m , indium 111 , indium 113m , gallium 67 , gallium 68 , ruthenium 95 , ruthenium 97 , ruthenium 103 , ruthenium 105 , mercury 207 , mercury 203 , rhenium 99m , rhenium 101 , rhenium 105 , scandium 47 , tellurium 121m , tellurium 122m , tellurium125m Thulium 165 Thulium 167 Thulium 168 Copper 67 Fluorine 18 Yttrium 90 Palladium 100 Bismuth 217 And antimony 211 Luminescent labels include radioluminescent, chemiluminescent (e.g. acridinium ester, luminol, isoluminol) and bioluminescent labels. Immunoassay labels include haptens, peptides / polypeptides, antibodies, receptors and ligands such as biotin, avidin, streptavidin or genin. Nucleic acid labels include aptamers.

[0346] In certain embodiments, the antigen binding molecule / polypeptide comprises an epitope tag, for example His (e.g. 6XHis), FLAG, c-Myc, StrepTag, hemagglutinin, E, calmodulin binding protein (CBP), glutathione s transferase (GST), maltose binding protein (MBP), thioredoxin, S peptide, T7 peptide, SH2 domain, avidin, streptavidin and haptens (e.g. biotin, genin, dinitrophenol), which can preferably be located at the N- or C-terminus of the antigen binding molecule / polypeptide.

[0347] In certain embodiments, the antigen binding molecule / polypeptide comprises a group with a detectable activity, such as an enzymatic group. Enzymatic groups include luciferase, glucose oxidase, galactosidase (e.g. beta-galactosidase), glucuronidase, phosphatase (e.g. alkaline phosphatase), peroxidase (e.g. horseradish peroxidase) and cholinesterase.

[0348] In certain embodiments, the antigen binding molecule or polypeptide as described in the present disclosure comprises a chemical group. In certain embodiments, the antigen binding molecule / polypeptide as described in the present disclosure is coupled to a chemical group.

[0349] The chemical group can be a group with a therapeutic effect, i.e. a drug group. The drug group can be a small molecule (e.g. a low molecular weight (<1000 Daltons, typically between 300-700 Daltons) organic compound). Drug groups are described in Parslow et al., Biomedicines 2016, Vol. 4, Issue 3, p14 (which is incorporated by reference in its entirety). In certain embodiments, the drug group can be or comprise a cytotoxic agent. In certain embodiments, the drug group can be or comprise a chemotherapeutic agent. Drug groups include calicheamicin, DM1, DM4, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), SN-38, doxorubicin, duocarmycin, D6.5 and PBD.

[0350] Nucleic acids and vectors

[0351] The present disclosure provides a nucleic acid or multiple nucleic acids that can encode an antigen-binding molecule or polypeptide as described in the present disclosure. In certain embodiments, the nucleic acid comprises or consists of DNA and / or RNA.

[0352] Antigen binding molecules or polypeptides as described herein can be generated by translating RNA encoding the polypeptide in a cell.Antigen binding molecules or polypeptides as described herein can be generated by transcribing a nucleic acid encoding the polypeptide in a cell and then translating the transcribed RNA.

[0353] In certain embodiments, the nucleic acid may be, or may contain / be comprised in, a vector or vectors. A "vector" as used herein is a nucleic acid molecule that is used as a vehicle for transferring exogenous nucleic acid into a cell.

[0354] Thus, the present disclosure also provides a vector or vectors comprising a nucleic acid or nucleic acids as described herein. The vector can facilitate delivery of a nucleic acid encoding a polypeptide as described herein to a cell. The vector can be an expression vector comprising elements required for expression of a polypeptide as described herein. The vector can contain elements that facilitate integration of the nucleic acid into the genomic DNA of a cell into which the vector is introduced.

[0355] Nucleic acids and vectors as described herein can be in purified or isolated form, ie, separated from other nucleic acids or naturally occurring biological materials.

[0356] The vector can be a vector (i.e., an expression vector) for nucleic acid expression in a cell. These vectors can include a promoter sequence that is operably connected to the nucleotide sequence encoding the antigen binding molecules and polypeptide as described in the present disclosure. The vector can also include a terminator codon (3' end in the nucleotide sequence of the vector encoding the nucleotide sequence of the polypeptide) and an expression enhancer. Any applicable vector, promoter, enhancer, and terminator known in the art can be used to express a peptide or polypeptide from a vector as described in the present disclosure.

[0357] The term "operably linked" can include situations where a nucleic acid encoding a polypeptide as described herein and a regulatory nucleic acid sequence (e.g., a promoter and / or enhancer) are covalently linked in such a manner that expression of the nucleic acid encoding the polypeptide is placed under the influence or control of the regulatory nucleic acid sequence (thereby forming an expression cassette). Thus, a regulatory sequence is operably linked to a nucleic acid sequence if the regulatory sequence is capable of affecting the transcription of the nucleic acid sequence. The resulting transcript is then translated into the desired polypeptide.

[0358] Vectors relevant to the present disclosure include DNA vectors, RNA vectors, plasmids (e.g., conjugative plasmids (e.g., F plasmids)), non-conjugative plasmids, R plasmids, col plasmids, episomes), viral vectors (e.g., retroviral vectors, such as gamma retroviral vectors (e.g., murine leukemia virus (MLV)-derived vectors, such as SFG vectors), lentiviral vectors, adenoviral vectors, adeno-associated viral vectors, vaccinia viral vectors, and herpes viral vectors), transposon vectors, artificial chromosomes (e.g., yeast artificial chromosomes), as described in Maus et al., Annu Rev Immunol 32:189-225 (2014) and Morgan and Boyerinas, Biomedicines 4:9 (2016), both of which are incorporated by reference herein in their entireties. In certain embodiments, a vector as described herein is a lentiviral vector.

[0359] In certain embodiments, the vector can be a eukaryotic vector, i.e., a vector that contains protein expression essential elements from a eukaryotic cell vector. In certain embodiments, the vector can be a mammalian vector, such as one that contains a cytomegalovirus (CMV) or SV40 promoter to drive protein expression.

[0360] The constituent polypeptides of an antigen binding molecule as described herein can be encoded by different nucleic acids in a plurality of nucleic acids, or by different vectors in a plurality of vectors.

[0361] Preparation of antigen-binding molecules and peptides

[0362] Antigen binding molecules and polypeptides as described herein can be prepared according to polypeptide production methods known to the skilled person.

[0363] Antigen binding molecules and polypeptides can be prepared by chemical synthesis, such as liquid or solid phase synthesis. For example, peptides / polypeptides can be synthesized using methods described in Chandrudu et al., Molecules 18:4373-4388 (2013), which is incorporated by reference herein in its entirety.

[0364] Alternatively, the antigen binding molecules and polypeptides can be produced by recombinant expression. Molecular biology techniques suitable for recombinant production of polypeptides are well known in the art, such as the methods described in Green and Sambrook, Molecular Cloning: A Laboratory Manual (4th ed.), Cold Spring Harbor Press, 2012, and in Nat Methods 2008, vol. 5, no. 2, pages 135-146, both of which are incorporated herein by reference in their entirety. Frenzel et al., Front Immunol 2013, vol. 4, page 217, and Kunert and Reinhart, Appl Microbiol Biotechnol 2016, vol. 100, pages 3451-3461, describe methods for recombinant production of antigen binding molecules, both of which are incorporated herein by reference in their entirety.

[0365] In certain cases, the antigen binding molecules as described in the present disclosure contain more than one polypeptide chain. In such cases, production of the antigen binding molecules can involve transcription and translation of more than one polypeptide, and subsequent association of the polypeptide chains to form the antigen binding molecule.

[0366] For recombinant production as described in the present disclosure, any cell suitable for polypeptide expression can be used. The cell can be a prokaryotic cell or a eukaryotic cell. In certain embodiments, the cell is a prokaryotic cell, such as an archaeal or bacterial cell. In certain embodiments, the bacteria can be a Gram-negative bacteria, such as a bacterium of the Enterobacteriaceae family, such as Escherichia coli. In certain embodiments, the cell is a eukaryotic cell, such as a yeast cell, a plant cell, an insect cell, or a mammalian cell, such as the cells described above.

[0367] In certain cases, the cell is not a prokaryotic cell, as certain prokaryotic cells are not capable of the same folding or post-translational modifications as eukaryotic cells. Furthermore, very high expression levels can be possible in eukaryotic cells, and proteins can be more easily purified from eukaryotic cells using appropriate tags. Specific plasmids can also be utilized to increase secretion of the protein into the culture medium.

[0368] In certain embodiments, the polypeptides can be prepared by cell-free protein synthesis (CFPS), such as the methods described in Zemella et al., Chembiochem 2015, vol. 16, no. 17, pages 2420-2431, which is incorporated herein by reference in its entirety.

[0369] Production can involve the culture or fermentation of eukaryotic cells modified to express a polypeptide of interest. Culture or fermentation can be performed in a bioreactor with appropriate supplies of nutrients, air / oxygen, and / or growth factors. Secreted proteins can be collected by separating the culture / fermentation broth from the cells, extracting the protein fraction, and purifying the secreted polypeptide by separating individual proteins. Culture, fermentation, and separation techniques are well known to those of skill in the art, as described in Green and Sambrook, Molecular Cloning: A Laboratory Manual (Fourth Edition, incorporated herein by reference above).

[0370] A bioreactor comprises one or more vessels in which cells are cultured. Culturing in a bioreactor can be performed continuously, with reactants continuously flowing in and culture cells continuously flowing out of the reactor. Or culturing can be performed in batches. A bioreactor can be monitored and regulated for environmental conditions such as pH, oxygen, flow rates in and out, and agitation within the vessel, to provide optimal conditions for cell culture.

[0371] After culturing cells expressing a polypeptide of interest, the polypeptide of interest is isolated. Any method known in the art for isolating proteins from cells can be used. To isolate a polypeptide, the cells must be separated from the nutrient medium. If the polypeptide is secreted by the cells, the cells can be separated from the medium containing the secreted polypeptide of interest by centrifugation. If the polypeptide of interest is present within the cells, protein isolation should include centrifugation to separate the cells from the cell culture medium, treatment of the cell pellet with a lysis buffer, and disruption of the cells by methods such as sonication, freeze-thaw, or osmotic lysis.

[0372] The polypeptide of interest must then be isolated from the supernatant or medium, which can contain other proteins and non-protein components. A common method for isolating protein components from supernatant or medium is precipitation. Proteins of different solubility are precipitated at different concentrations of a precipitant, such as ammonium sulfate. For example, low concentrations of precipitant can extract water-soluble proteins. Thus, proteins of different solubility can be distinguished by adding different concentrations of precipitant. The ammonium sulfate can then be removed from the isolated proteins by dialysis.

[0373] Other methods for isolating proteins known in the art, such as ion exchange chromatography and size chromatography. These methods can be used instead of or in conjunction with precipitation.

[0374] Once the polypeptide of interest has been isolated from the medium, it can be desirable or necessary to concentrate the polypeptide. Various methods for concentrating proteins are known in the art, such as ultrafiltration or lyophilization techniques.

[0375] Cells containing / expressing antigen-binding molecules and polypeptides

[0376] The present disclosure also provides a cell comprising or expressing an antigen binding molecule or polypeptide as described herein, and a cell comprising or expressing a nucleic acid, a plurality of nucleic acids, a vector, or a plurality of vectors as described herein.

[0377] It is noted that the singular forms of cells ("a cell") include plural referents unless the context clearly dictates otherwise.

[0378] The cell can be a eukaryotic cell, such as a mammalian cell. The mammal can be a primate (rhesus, cynomolgus, non-human primate, or human) or a non-human mammal (e.g., a rabbit, a guinea pig, a rat, a mouse, or other rodent (including all animals in the order Rodentia), a cat, a dog, a pig, a sheep, a goat, a cow (including a bovine, such as a cow, or all animals of the genus Bos), a horse (including all animals of the family Equidae), a donkey, and other non-human primates).

[0379] In certain embodiments, the cell is or is derived from a cell type commonly used to express polypeptides for human therapy. Exemplary cells, as described in Kunert and Reinhart, Appl Microbiol Biotechnol. 2016 100:3451-3461 (the entire contents of which are incorporated herein by reference), include CHO, HEK 293, PER.C6, NS0, and BHK cells, among others. In preferred embodiments, the cell is or is derived from a CHO cell.

[0380] The present disclosure also provides a method of making a cell comprising or expressing a nucleic acid or vector as described herein, comprising introducing a nucleic acid, a plurality of nucleic acids, a vector, or a plurality of vectors as described herein into a cell. In certain embodiments, introducing a nucleic acid or vector as described herein into a cell comprises transformation, transfection, electroporation, or transduction (e.g., retroviral transduction).

[0381] The present disclosure also provides a method of making a cell expressing / containing an antigen binding molecule or polypeptide as described herein, comprising introducing a nucleic acid, a plurality of nucleic acids, a vector, or a plurality of vectors as described herein into a cell. In certain embodiments, the method further comprises culturing the cell under conditions suitable for expression of the nucleic acid or vector. In certain embodiments, the method is performed in vitro.

[0382] The present disclosure also provides a cell obtained / obtainable by a method as described herein.

[0383] Antigen-binding molecules that bind to known SARS-CoV-2 spike proteins / SARS-CoV-2 variant spike proteins combination of

[0384] The present disclosure also provides a combination comprising: (i) an antigen binding molecule as described herein, and (ii) a known SARS-CoV-2 Spike protein / SARS-CoV-2 variant Spike protein binding antigen binding molecule. The present disclosure also provides a composition comprising: (i) an antigen binding molecule as described herein, and (ii) a known SARS-CoV-2 Spike protein / SARS-CoV-2 variant Spike protein binding antigen binding molecule.

[0385] It is to be understood that the antigen binding molecule of (i) the preceding paragraph can be an antigen binding molecule of any of the embodiments described in the section of this document entitled "Antigen Binding Molecules of the Present Disclosure". It is also to be understood that the antigen binding molecule of (ii) the preceding paragraph can be a known SARS-CoV-2 Spike protein / SARS-CoV-2 variant Spike protein binding antigen binding molecule of any of the embodiments described in the section of this document entitled "Known SARS-CoV-2 Spike protein / SARS-CoV-2 variant Spike protein binding antigen binding molecules".

[0386] In certain embodiments, a combination / composition as described herein comprises: (i) an antigen binding molecule of one of (1) to (19) described in the section of this document entitled "Particular Exemplary Antigen Binding Molecules and Polypeptides", and (ii) an antigen binding molecule of one of (A) to (D) described in the section of this document entitled "Known SARS-CoV-2 Spike protein / SARS-CoV-2 variant Spike protein binding antigen binding molecules".

[0387] In certain aspects and embodiments, the combination is a pharmaceutical combination. A "pharmaceutical combination" as described herein refers to a product that comprises more than one (typically two) different active (i.e., therapeutic / prophylactic) ingredients, wherein the ingredients are intended for combined use. The ingredients of a pharmaceutical combination can be co-produced or separately produced, but are typically packaged together, and will usually contain a package insert stating that the ingredients are intended for combined use.

[0388] In certain embodiments, the ingredients of a pharmaceutical combination are contained in a single composition, such as a pharmaceutical combination that contains both ingredients simultaneously. In certain embodiments, the ingredients of a pharmaceutical combination are contained in different compositions, such as a pharmaceutical combination that can exist in the form of (i) a pharmaceutical composition comprising an antigen binding molecule as described herein, and (ii) a pharmaceutical composition comprising a known SARS-CoV-2 Spike protein / SARS-CoV-2 variant Spike protein binding antigen binding molecule.

[0389] The present disclosure also provides a composition (such as a pharmaceutical composition and a medicament) comprising an article of manufacture as described herein (above (i) and (ii)). These compositions can comprise the relevant items in a formulation suitable for clinical use.

[0390] The present disclosure also provides a combination (and compositions comprising the combination) of an antigen binding molecule as described in (A) or (B) and an antigen binding molecule as described in (C) or (D) (as described in the section herein entitled “Known SARS-CoV-2 Spike / SARS-CoV-2 Variant Spike Binding Antigen Binding Molecules”). In certain embodiments, the combination comprises an antigen binding molecule as described in (A) and an antigen binding molecule as described in (B). In certain embodiments, the combination comprises an antigen binding molecule as described in (C) and an antigen binding molecule as described in (D).

[0391] Functional properties of the combination as described in the present disclosure

[0392] Combinations and compositions comprising such combinations as described herein (hereinafter referred to in this section as “combinations / compositions”) can be characterized by reference to certain functional properties. In certain embodiments, the combinations described herein can have one or more of the following properties:

[0393] Inhibit the interaction between a SARS-CoV-2 Spike protein and ACE2 with greater potency (lower IC 50 ) than the potency (IC 50 ) with which a single component of the combination / composition alone inhibits the interaction between the respective protein and ACE2, as determined in the same method.

[0394] Inhibit infection of ACE2-expressing cells by a SARS-CoV-2 (and / or one or more SARS-CoV-2 variants) with greater potency (lower IC 50 ) than the potency (IC 50 ) with which a single component of the combination / composition alone inhibits infection of ACE2-expressing cells by the respective virus, as determined in the same method.

[0395] In certain embodiments, a combination / composition as described in the present disclosure inhibits the interaction between a SARS-CoV-2 Spike protein and / or a given SARS-CoV-2 variant Spike protein and ACE2 with an IC 50 that is less than 1-fold, such as ≤ 0.99-fold, ≤ 0.95-fold, ≤ 0.9-fold, ≤ 0.85-fold, ≤ 0.8-fold, ≤ 0.75-fold, ≤ 0.7-fold, ≤ 0.65-fold, ≤ 0.6-fold, ≤ 0.55-fold, ≤ 0.5-fold, ≤ 0.45-fold, ≤ 0.4-fold, ≤ 0.35-fold, ≤ 0.3-fold, ≤ 0.25-fold, ≤ 0.2-fold, ≤ 0.15-fold, ≤ 0.1-fold, ≤ 0.05-fold, or ≤ 0.01-fold, of the IC 50 with which a single component of the combination / composition alone inhibits the interaction between the respective protein and ACE2, as determined in the same method.

[0396] In certain embodiments, the combination / composition as described herein inhibits the IC of infection of ACE2-expressing cells by a betacoronavirus (SARSr-CoV; SARS-CoV-2 and / or one or more SARS-CoV-2 variants) by 50 less than 1-fold, such as < 0.99-fold, < 0.95-fold, < 0.9-fold, < 0.85-fold, < 0.8-fold, < 0.75-fold, < 0.7-fold, < 0.65-fold, < 0.6-fold, < 0.55-fold, < 0.5-fold, < 0.45-fold, < 0.4-fold, < 0.35-fold, < 0.3-fold, < 0.25-fold, < 0.2-fold, < 0.15-fold, < 0.1-fold, < 0.05-fold or < 0.01-fold of the IC of infection of ACE2-expressing cells by the respective SARSr-CoV determined in the same method when using the single component of the combination / composition alone. 50

[0397] In certain embodiments, the combination / composition as described herein synergistically inhibits the interaction between SARS-CoV-2 spike protein and / or a given SARS-CoV-2 variant spike protein and ACE2. In certain embodiments, the combination / composition as described herein synergistically inhibits the infection of ACE2-expressing cells by a betacoronavirus (SARSr-CoV; SARS-CoV-2 and / or one or more SARS-CoV-2 variants). That is, in certain embodiments, the combination / composition has a synergistic (superadditive) level of inhibition compared to the effect observed when using the antigen binding molecule as described herein alone, and / or compared to the effect observed when using a known SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein binding antigen binding molecule alone.

[0398] A “synergistic” or “superadditive” level of a relevant effect (inhibition of interaction, inhibition of infection) of a given combination / composition as described herein refers to a level of effect that is greater than the sum of the effects observed when using the single components of the combination / composition alone.

[0399] ​Quantitative methods for assessing synergy are described in Tallarida, Genes Cancer 2011, Vol. 2, Issue 11, pp. 1003-1008 and Chou, Cancer Res 2010, Vol. 70, pp. 440-446, both of which are incorporated herein by reference in their entirety. Additive, synergistic, or antagonistic effects can be assessed in experiments in which a range of different doses of the combination / composition and its individual components are tested for levels of efficacy. Dose-response curves are plotted and analyzed to determine whether the combination / composition achieves a synergistic level of the relevant effect compared to the individual components of the combination / composition used alone. In certain embodiments, the Chou-Talalay method described in Chou, Cancer Res 2010, Vol. 70, pp. 440-446 can be employed to calculate a combination / composition index (CI) to assess synergistic effects. According to the Chou-Talalay method, a CI = 1 for a given combination / composition indicates an additive effect, CI < 1 indicates a synergistic effect, and CI > 1 indicates an antagonistic effect.

[0400] Composition

[0401] The present disclosure also provides compositions comprising the antigen binding molecules, polypeptides, nucleic acids, expression vectors, and / or cells as described herein.

[0402] The antigen binding molecules, polypeptides, nucleic acids, expression vectors, and cells as described herein can be formulated into a pharmaceutical composition or medicament for clinical use, and it can comprise a pharmaceutically acceptable carrier, diluent, excipient, or adjuvant. Accordingly, the present disclosure also provides a pharmaceutical composition / medicament comprising the antigen binding molecules, polypeptides, nucleic acids / multiple nucleic acids, expression vectors / multiple expression vectors, or cells as described herein.

[0403] The compositions as described in the present disclosure can include one or more pharmaceutically acceptable carriers (liposomes, micelles, microspheres, nanoparticles), diluents / excipients (starch, cellulose, cellulose derivatives, polyols, glucose, maltodextrin, magnesium stearate), adjuvants, fillers, buffers, preservatives (vitamin A, vitamin E, vitamin C, retinol palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methyl paraben, propyl paraben), antioxidants (vitamin A, vitamin E, vitamin C, retinol palmitate, selenium), lubricants (magnesium stearate, talc, silicon dioxide, stearic acid, vegetable stearate), binders (sucrose, lactose, starch, cellulose, gelatin, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), xylitol, sorbitol, mannitol), stabilizers, solubilizers, surfactants (e.g., wetting agents), masking agents, or coloring agents (e.g., titanium dioxide).

[0404] The phrase "pharmaceutically acceptable" as used herein means that the compound, ingredient, material, composition, dosage form, etc. is, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject (human subject) involved with no undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio, as described herein. Each carrier, diluent, excipient, adjuvant, filler, buffer, preservative, antioxidant, lubricant, binder, stabilizer, solubilizer, surfactant, masking agent, coloring agent, flavoring agent, or sweetener in the compositions as described in the present disclosure must also be "acceptable" and can be compatible with the other ingredients in the formulation. Suitable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, binders, stabilizers, solubilizers, surfactants, masking agents, coloring agents, flavoring agents, or sweeteners can be found in the standard pharmaceutical literature, Remington's The Science and Practice of Pharmacy (A. Adejare, ed.), 23rdedition (2020), Academic Press.

[0405] The compositions can be formulated for topical, parenteral, systemic, intracavitary, intravenous, intraarterial, intramuscular, intrathecal, intraocular, intracorneal, subcutaneous, intradermal, intrathecal, oral, or transdermal routes of administration. In certain embodiments, the pharmaceutical compositions / agents can be configured for administration by injection or infusion, or by ingestion.

[0406] Suitable formulations include the relevant ingredients in sterile or isotonic medium. The agents and pharmaceutical compositions can be formulated in fluid form, including gel form. Fluid formulations can be formulated for administration by injection or infusion (through a catheter) to a specified region of the human or animal body.

[0407] In certain embodiments, the compositions are formulated for injection or infusion, e.g., into a blood vessel, tissue / organ of interest.

[0408] The present disclosure also provides methods for producing a pharmaceutical composition and an agent. These methods include one or more steps selected from the group consisting of: producing an antigen binding molecule, polypeptide, nucleic acid (or multiple thereof) as described herein, an expression vector (or multiple thereof), or a cell; isolating an antigen binding molecule, polypeptide, nucleic acid (or multiple thereof) as described herein, an expression vector (or multiple thereof), or a cell; and / or mixing an antigen binding molecule, polypeptide, nucleic acid (or multiple thereof) as described herein, an expression vector (or multiple thereof), or a cell with a pharmaceutically acceptable carrier, adjuvant, excipient, or diluent.

[0409] For example, another aspect of the present disclosure relates to a method of formulating or producing a medicament or pharmaceutical composition for treating a disease / disorder (e.g., a disease / disorder described herein), the method comprising formulating the pharmaceutical composition or medicament by mixing an antigen binding molecule, polypeptide, nucleic acid (or plurality thereof), expression vector (or plurality thereof), or cell as described herein with a pharmaceutically acceptable carrier, adjuvant, excipient, or diluent.

[0410] Therapeutic and preventive uses

[0411] Antigen binding molecules, polypeptides, nucleic acids, expression vectors, cells, combinations, and compositions as described herein are useful in therapeutic and prophylactic methods.

[0412] The present disclosure provides an antigen binding molecule, polypeptide, nucleic acid (or plurality thereof), expression vector (or plurality thereof), cell, combination, or composition as described herein for use in a method of medical treatment or prevention. Also provided is an antigen binding molecule, polypeptide, nucleic acid (or plurality thereof), expression vector (or plurality thereof), cell, combination, or composition as described herein for use in a method of treating or preventing a disease or disorder as described herein. Also provided is a method of using an antigen binding molecule, polypeptide, nucleic acid (or plurality thereof), expression vector (or plurality thereof), cell, combination, or composition as described herein for the manufacture of a medicament for treating or preventing a disease or disorder as described herein. Also provided is a method of treating or preventing a disease or disorder as described herein comprising administering to a subject a therapeutically or prophylactically effective amount of an antigen binding molecule, polypeptide, nucleic acid (or plurality thereof), expression vector (or plurality thereof), cell, combination, or composition as described herein.

[0413] The present disclosure also provides an antigen binding molecule as described by the present disclosure for use in a method of treating or preventing a disease / disorder as described herein, the method comprising administering a known SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein binding antigen binding molecule. Also provided is a method of using a known SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein binding antigen binding molecule for the treatment or prevention of a disease / disorder as described herein, the method comprising administering an antigen binding molecule as described by the present disclosure.

[0414] Also provided is the use of an antigen-binding molecule as described herein in the manufacture of a medicament for treating or preventing a disease / condition as described herein, the method comprising administering a known SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein-binding antigen-binding molecule. Also provided is the use of a known SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein-binding antigen-binding molecule in the manufacture of a medicament for treating or preventing a disease / condition as described herein, the method comprising administering an antigen-binding molecule as described herein.

[0415] Also provided is a method for treating or preventing a disease / disorder as described herein, comprising administering a therapeutically or prophylactically effective amount of (i) an antigen binding molecule as described herein and (ii) a known SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein-binding antigen binding molecule to a subject in need of treatment.

[0416] The present disclosure also provides (i) antigen binding molecules as described in the present disclosure and (ii) known SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein binding antigen binding molecules for treating or preventing a disease / condition as described herein in a subject. Also provided are uses of (i) antigen binding molecules as described in the present disclosure and (ii) known SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein binding antigen binding molecules in the manufacture of a medicament for treating or preventing a disease / condition as described herein in a subject. Also provided are methods for treating or preventing a disease / condition as described herein in a subject, comprising administering to a subject a therapeutic or prophylactic effective amount of (i) antigen binding molecules as described in the present disclosure and (ii) known SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein binding antigen binding molecules.

[0417] In embodiments consistent with the aspects of the preceding paragraph, (i) and (ii) may be administered as a combination therapy. In certain embodiments, (i) and (ii) may be administered simultaneously or sequentially.

[0418] The products, methods and uses as described herein can effectively slow down the occurrence or progression of a disease / disorder, alleviate the symptoms of a disease / disorder or reduce the pathological damage of a disease / disorder. The products, methods and uses can effectively prevent the development of a disease / disorder, such as preventing the deterioration of a disease / disorder or slowing down its rate of development. In certain embodiments, the products, methods and uses can improve a disease / disorder, such as alleviating the symptoms of a disease / disorder or reducing the severity / activity of some other related disease / disorder. In certain embodiments, the products, methods and uses prevent a disease / disorder from developing to a late stage (such as a chronic disease stage).

[0419] It should be understood that the articles described in the present disclosure can be used to treat / prevent any disease / condition for which a therapeutic or prophylactic benefit is obtained by reducing the level of a betacoronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant) or reducing the number of cells infected by a betacoronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant). For example, the disease / condition can be a disease / condition for which infection by a betacoronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant) is positively correlated with the onset, development or progression of the disease / condition and / or the severity of one or more symptoms of the disease / condition, or for which infection by a betacoronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant) is a risk factor for the onset, development or progression of the disease / condition.

[0420] In certain embodiments, the disease / condition to be treated / prevented as described in the present disclosure is a disease / condition characterized by infection by a betacoronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant), such as COVID-19. In certain embodiments, the disease / condition is a disease / condition caused by infection by a betacoronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant), such as COVID-19.

[0421] The clinical features of COVID-19 are described in Lechien et al., Journal of Internal Medicine, 2020, 288, 335–344; the International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) COVID-19 Report: May 19, 2020: ISARIC; Docherty et al., BMJ, 2020, 369, m1985; and Bhardwaj et al., Int Rev Immunol, 2021, 1–36, all of which are incorporated herein by reference in their entirety. Common symptoms include cough, fever, headache, dyspnea, anosmia, pharyngitis, nasal congestion, runny nose, fatigue, myalgia, arthralgia, taste dysfunction, abdominal pain, vomiting, and diarrhea. Most patients present with mild / moderate symptoms, but sometimes hospitalization is required, particularly in elderly patients and / or those with comorbidities such as diabetes and cardiovascular disease. A major complication of COVID-19 is the development of acute respiratory distress syndrome (ARDS), which presents with difficulty breathing and acute respiratory failure, requiring mechanical ventilation. Some infected people remain asymptomatic.

[0422] The treatment according to the methods disclosed herein can achieve one or more of the following: reducing the viral load level of type β coronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant) in the subject or the subject's tissue / organ (such as the lung), reducing the expression level of pro-inflammatory cytokines (such as IL-6, CCL2 and / or CXCL10) in the subject or the subject's tissue / organ (such as the lung), increasing the expression level of IFNγ in the subject or the subject's tissue / organ (such as the lung), reducing type β coronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant) RS-CoV-2 variants), inhibit the occurrence / progression of diseases / symptoms caused by infection with type B coronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variants), such as COVID-19, reduce the severity of diseases / symptoms caused by infection with type B coronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variants), such as COVID-19, inhibit the occurrence / progression of acute respiratory distress syndrome (ARDS) in subjects, and improve the survival rate of subjects.

[0423] In certain embodiments, a subject is selected for treatment as described herein based on an assay result for infection by a betacoronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant), e.g., by detecting a betacoronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant) in a sample taken from the subject. In certain embodiments, a subject is selected for treatment as described herein based on an assay result that the subject is at risk of being infected by a betacoronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant). For example, the subject can have been in close contact with a subject infected by a betacoronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant).

[0424] The articles as described in the present disclosure are preferably administered in “therapeutically effective” or “prophylactically effective” amounts, which are sufficient to show a therapeutic or prophylactic benefit to the subject. The actual amount administered, and rate and time of administration, will depend on the nature and severity of the disease / disorder and on the subject’s individual characteristics like age, weight, health, and the kind of pharmaceutical product given. Prescription of treatment, including decisions on dosages, lies within the responsibility of general practitioners and other medical doctors, who typically take into account the disease / disorder to be treated, the individual condition of the subject, the place and method of administration, and other factors known by them. Examples of the above techniques and protocols can be found in Remington’s The Science and Practice of Pharmacy (A. Adejare, ed.), 23rdedition (2020), Mack Publishing Company.

[0425] The administration of the articles as described in the present disclosure can be parenteral, systemic, intracavitary, intravenous, intraarterial, intramuscular, intrathecal, intraocular, intravitreal, intracorneal, subretinal, suprachoroidal, subcutaneous, intradermal, intrathecal, oral, nasal, topical, or transdermal. Administration can be by any suitable nasal administration means, such as nose drops, nasal spray, nebulizer, etc. Administration can be by injection or infusion.

[0426] Multiple doses of the antigen-binding molecules, polypeptides, nucleic acids (or multiple thereof), expression vectors (or multiple thereof), cells, combinations, or compositions as described herein can be provided. The multiple doses can be separated by a pre-determined time interval, which can be selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days, or 1, 2, 3, 4, 5, or 6 months. For example, the doses can be administered once every 7, 14, 21, or 28 days (plus or minus 3, 2, or 1 day).

[0427] The formulations as described herein can be administered alone or simultaneously / cyclically / sequentially with another prophylactic / therapeutic agent, depending upon the disease / condition to be treated, as described herein. The antigen binding molecules, cells, combinations or compositions described herein and other prophylactic / therapeutic agents can be administered simultaneously or sequentially.

[0428] Concurrent administration means that the antigen binding molecules, polypeptides, nucleic acids (or multiples thereof), expression vectors (or multiples thereof), cells, combinations or compositions as described herein and other prophylactic / therapeutic agents are administered simultaneously, e.g., as a pharmaceutical composition (combination preparation) containing both agents, or immediately sequentially and preferably by the same route, e.g., administration to the same artery, vein or other blood vessel. Sequential administration means that one of (i) the antigen binding molecules, polypeptides, nucleic acids (or multiples thereof), expression vectors (or multiples thereof), cells, combinations or compositions as described herein, or (ii) the other prophylactic / therapeutic agent, is administered first, and the other of (i) / (ii) is administered separately and at a time interval thereafter. It does not require that (i) and (ii) be administered by the same route, although in certain embodiments they are. The time interval can be any time interval.

[0429] The present disclosure further provides uses of the antigen binding molecules / combinations / compositions as described herein: inhibiting the interaction between a betacoronavirus spike protein (SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein) and ACE2; and / or inhibiting infection of an ACE2-expressing cell by SARS-CoV-2 / SARS-CoV-2 variant. The present disclosure further provides methods of using the antigen binding molecules / combinations / compositions as described herein to inhibit the interaction between a betacoronavirus spike protein (SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein) and ACE2, and / or to inhibit infection of an ACE2-expressing cell by SARS-CoV-2 / SARS-CoV-2 variant. These uses / methods can be performed in vitro, or in vivo.

[0430] Thus, the present disclosure provides methods of inhibiting the interaction between a betacoronavirus spike protein (SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein) and ACE2, and / or inhibiting infection of an ACE2-expressing cell by SARS-CoV-2 / SARS-CoV-2 variant, comprising administering to a subject an antigen binding molecule / combinations / compositions as described herein.

[0431] Detection method

[0432] The present disclosure also provides articles of manufacture as described herein for use in methods of detecting, localizing or imaging a betacoronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant) and / or a betacoronavirus spike protein (SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein), or a cell comprising a betacoronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant) and / or a betacoronavirus spike protein (SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein).

[0433] The antigen binding molecules, combinations and compositions described herein can be used in methods involving detecting an antigen binding molecule that binds to a betacoronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant) and / or a betacoronavirus spike protein (SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein). These methods can comprise detecting a binding complex of the antigen binding molecule and a betacoronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant) and / or a betacoronavirus spike protein (SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein). It will be appreciated that a betacoronavirus / betacoronavirus spike protein can be contained within a cell as a result of the cell being infected with a betacoronavirus.

[0434] Accordingly, there is provided a method comprising contacting a sample containing or suspected of containing a betacoronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant) and / or a betacoronavirus spike protein (SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein) with an antigen binding molecule / combination / composition as described herein, and detecting the formation of a complex of the antigen binding molecule and the betacoronavirus / betacoronavirus spike protein. There is also provided a method comprising contacting a sample containing or suspected of containing a cell comprising a betacoronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant) and / or a betacoronavirus spike protein (SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein) with an antigen binding molecule / combination / composition as described herein, and detecting the formation of a complex of the antigen binding molecule and the betacoronavirus / betacoronavirus spike protein.

[0435] Suitable methods known in the art include immunoassays, such as sandwich assays, i.e. ELISAs. The methods can comprise labelling the antigen binding molecule or the target or both with a detectable label, such as a fluorescent label, a phosphorescent label, a luminescent label, an immunodetectable label, a radioactive label, a chemical label, a nucleic acid label or an enzymatic label. The detection technique known to the skilled person can be chosen accordingly depending on the labelling agent.

[0436] Methods including methods of diagnosing / prognosing a disease / condition as described herein, comprising detecting a betacoronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant) and / or a betacoronavirus spike protein (SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein), or a cell comprising a betacoronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant) and / or a betacoronavirus spike protein (SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein).

[0437] Such methods can be performed in vitro on a patient sample, or after processing of a patient sample. Once the sample has been collected, the performance of the method in vitro does not require the patient to be present, and thus the method is one that does not require manipulation on a human or animal body. In certain embodiments, the method is performed in vivo.

[0438] The methods can comprise detecting or quantifying a betacoronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant) and / or a betacoronavirus spike protein (SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein), or a cell comprising a betacoronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant) and / or a betacoronavirus spike protein (SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein) in a patient sample. Where the method comprises quantifying the relevant factor, the method can further comprise comparing the determined value to a standard or reference value as part of the diagnostic or prognostic assessment. Other diagnostic / prognostic tests can be used in conjunction with the detection methods described herein to improve the accuracy of the diagnosis or prognosis, or to validate results obtained using the detection methods as described herein.

[0439] The sample detection can be used for the diagnosis of a disease / condition (COVID-19), for the assessment of the susceptibility to a disease / condition, or for providing a prognosis (prediction) of a disease / condition, the disease / condition being a disease / condition as described herein. The diagnosis or prognosis can be in relation to an existing (previously diagnosed) disease / condition.

[0440] The sample can be taken from any tissue or bodily fluid. The sample taken from the subject can be of any type. The biological sample can be taken from any tissue or bodily fluid, for example a blood sample, a blood-derived sample, a serum sample, a lymph sample, a semen sample, a saliva sample, a synovial fluid sample. The blood-derived sample can be a specific component of the patient's blood, for example a selected cellular fraction or a plasma or serum component. The sample can comprise a tissue sample or a biopsy; or cells isolated from the subject.

[0441] The subject can be selected for diagnostic / prognostic evaluation based on the presence of symptoms indicative of a disease / condition described herein, or based on the subject being considered to be at risk of developing a disease / condition described herein.

[0442] The present disclosure also provides methods of screening / stratifying a subject for treatment with a betacoronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant) targeted drug. In certain embodiments, a subject is screened for treatment / prevention according to the results of a cellular detection / quantification assay for betacoronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant) and / or betacoronavirus spike protein (SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein), or comprising betacoronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant) and / or betacoronavirus spike protein (SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein), performed on a sample taken from the individual, or determining that the subject is able to benefit from such treatment / prevention, performed according to the methods as described in the present disclosure.

[0443] Subjects

[0444] The subject as described in aspects of the present disclosure can be any animal or human. Therapeutic and prophylactic applications can be used in humans or animals (veterinary use).

[0445] The subject to which the article as described in the present disclosure (corresponding to a therapeutic or prophylactic intervention) is administered is a subject in need of such intervention. The subject is preferably a mammal, most preferably a human. The subject can be a non-human mammal, but is more preferably a human. The subject can be a male or a female. The subject can be a patient.

[0446] The subject can have (may have been diagnosed with) a disease or condition as described herein, can be suspected of having such a disease / condition, or can be at risk of developing / contracting such a disease / condition. In embodiments described in the present disclosure, the subject can be selected for treatment according to the described methods based on the characteristics of one or more markers of such a disease / condition.

[0447] In certain embodiments, a subject may be selected to receive a therapeutic or prophylactic intervention as described herein based on the results of a betacoronavirus (SARSr-CoV, SARS-CoV-2 / SARS-CoV-2 variant) test in a sample obtained from the subject and / or a betacoronavirus spike protein (SARS-CoV-2 spike protein / SARS-CoV-2 variant spike protein).

[0448] Reagent test kit

[0449] The present disclosure also provides kit assemblies.

[0450] In certain embodiments, the kit may comprise at least one container having a predetermined number of an antigen binding molecule, polypeptide, nucleic acid (or nucleic acids), expression vector (or expression vectors), cell, combination or composition as described herein.

[0451] In certain embodiments, the kit may include raw materials for preparing antigen binding molecules, polypeptides, nucleic acids (or multiple nucleic acids), expression vectors (or multiple expression vectors), cells, combinations or compositions as described herein. In certain embodiments, the kit components may include materials for configuring antigen binding molecules, polypeptides, nucleic acids (or multiple nucleic acids), expression vectors (or multiple expression vectors), cells, combinations or compositions as described herein into pharmaceutical compositions / medicaments, such as further including a pharmaceutically acceptable carrier, diluent, excipient or adjuvant in the combination.

[0452] The kits can provide antigen binding molecules, polypeptides, nucleic acids (or nucleic acids), expression vectors (or expression vectors), cells, combinations or compositions and instructions for administration to a patient for treating a particular disease / disorder (such as the diseases / disorders described herein).

[0453] In certain embodiments, the kit may further include at least one container having a predetermined amount of another therapeutic agent (as described herein). In this embodiment, the kit also contains a second agent or drug combination, so that the two agents or drug combinations can be administered simultaneously or separately to provide a combined treatment for a particular disease / condition.

[0454] The kits described herein may include instructions for use in the form of leaflets or booklets. The instructions may include a protocol for performing any one or more of the methods described herein.

[0455] Sequence identity

[0456] "Sequence identity" herein means the percentage of nucleotide / amino acid residues in a subject sequence that are identical with the reference sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as identity. To determine percent sequence identity between two or more sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first sequence for optimal alignment with a second sequence). Optimal alignment of sequences for comparison can be conducted, e.g., using publicly available computer software such as Clustal Omega (http: / / www.ebi.ac.uk / Tools / clustalo / ) (Notredame et al., 2000, J. Mol. Biol. 302:205- 217), T-coffee (Notredame et al., 2000, J. Mol. Biol. 302:205-217), Kalign (Lassmann and Sonnhammer 2005, BMC Bioinformatics 6:298), and MAFFT (Katoh and Standley 2013, Molecular Biology and Evolution 30:4 772-780), using the default parameters, e.g., gap penalties and extension penalties.

[0457] J.2005, Bioinformatics 21:951-960), T-coffee (Notredame et al., 2000, J. Mol. Biol. 302:205-217), Kalign (Lassmann and Sonnhammer 2005, BMC Bioinformatics 6:298), and MAFFT (Katoh and Standley 2013, Molecular Biology and Evolution 30:4 772-780). When using such software, it is preferred to use the default parameters, e.g., gap penalties and extension penalties.

[0458] Sequence Listing

[0459]

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[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520] Table A

[0521]

[0522]

[0523]

[0524] Table B

[0525]

[0526]

[0527]

[0528]

[0529] Table C

[0530]

[0531]

[0532] Table D

[0533]

[0534]

[0535] Other aspects and embodiments of the present disclosure

[0536] The following sections describe other aspects, embodiments, and technical features as described in the present disclosure.

[0537] It is envisaged that a broad spectrum of protein antigen binding molecules, such as neutralizing antibodies, are suitable for treating or preventing coronavirus, in particular SARS-CoV-2 variant infection.

[0538] Accordingly, one aspect of the present disclosure relates to an antigen binding molecule that binds to and neutralizes SARS-CoV-2 variants BQ.1.1 and XBB at a lower concentration than required for E7 to bind to and neutralize SARS-CoV-2 variants BQ.1.1 and XBB, the antigen binding molecule comprising: (i) a heavy chain having amino acids with at least 95% sequence identity to SEQ ID NO: 822 or SEQ ID NO: 36 or SEQ ID NO: 52; and (ii) a light chain having amino acids with at least 95% sequence identity to SEQ ID NO: 823 or SEQ ID NO: 44 or SEQ ID NO: 59.

[0539] In another aspect of the present disclosure, an antigen binding molecule that binds and neutralizes SARS-CoV-2 variant BQ.1.1 at a lower concentration than required to bind and neutralize SARS-CoV-2 variant BQ.1.1; binds and neutralizes at least one other SARS-CoV-2 variant and other betacoronaviruses, the antigen binding molecule comprises: (i) a heavy chain having at least 95% sequence identity to any one of the amino acid sequences selected from the group consisting of SEQ ID NO: 822, SEQ ID NO: 36, SEQ ID NO: 52, SEQ ID NO: 67, SEQ ID NO: 83, SEQ ID NO: 96, SEQ ID NO: 105, SEQ ID NO: 120, SEQ ID NO: 136, SEQ ID NO: 149, SEQ ID NO: 179, SEQ ID NO: 193, SEQ ID NO: 206, SEQ ID NO: 220, SEQ ID NO: 285, SEQ ID NO: 299, SEQ ID NO: 312, SEQ ID NO: 325, SEQ ID NO: 336, SEQ ID NO: 362, SEQ ID NO: 368, SEQ ID NO: 381, SEQ ID NO: 393, SEQ ID NO: 436, SEQ ID NO: 464, SEQ ID NO: 496, SEQ ID NO: 508, SEQ ID NO: 522, SEQ ID NO: 535, SEQ ID NO: 547, SEQ ID NO: 559, SEQ ID NO: 584, SEQ ID NO: 592, SEQ ID NO: 600, SEQ ID NO: 614, SEQ ID NO: 627, SEQ ID NO: 643, and SEQ ID NO: 656;and (ii) a light chain having at least 95% sequence identity to any of the amino acid sequences selected from the group consisting of SEQ ID NO:823, SEQ ID NO:44, SEQ ID NO:59, SEQ ID NO:75, SEQ ID NO:89, SEQ ID NO:102, SEQ ID NO:113, SEQ ID NO:128, SEQ ID NO:144, SEQ ID NO:157, SEQ ID NO:187, SEQ ID NO:200, SEQ ID NO:213, SEQ ID NO:228, SEQ ID NO:291, SEQ ID NO:305, SEQ ID NO:318, SEQ ID NO:331, SEQ ID NO:343, SEQ ID NO:366, SEQ ID NO:374, SEQ ID NO:388, SEQ ID NO:400, SEQ ID NO:443, SEQ ID NO:471, SEQ ID NO:502, SEQ ID NO:515, SEQ ID NO:529, SEQ ID NO:542, SEQ ID NO:554, SEQ ID NO:567, SEQ ID NO:587, SEQ ID NO:596, SEQ ID NO:607, SEQ ID NO:621, SEQ ID NO:635, SEQ ID NO:651, and SEQ ID NO:663.

[0540] In another aspect of the present disclosure, it relates to a combination of any of the above antigen binding molecules and Bamlanivimab LY-CoV555, Regeneron, Casirivimab and Imdevimab REGN-COV3, Etesevimab LY-CoV2164, Atexakin alfa, LY-CoV1404, and E7.

[0541] In another aspect of the present disclosure, it relates to a method of treating a coronavirus infection, comprising administering to a patient in need thereof a therapeutically effective amount of any of the above antigen binding molecules or combinations.

[0542] In another aspect of the present disclosure, it relates to a therapeutically effective amount of any of the above antigen binding molecules or combinations for use in treating a coronavirus infection.

[0543] According to embodiments, there is an antigen binding molecule that binds and neutralizes SARS-CoV-2 variants BQ.1.1 and XBB at a lower concentration than is required for E7 to bind and neutralize SARS-CoV-2 variants BQ.1.1 and XBB, the antigen binding molecule comprising: (i) a heavy chain of amino acids having at least 95% sequence identity to SEQ ID NO: 822 or SEQ ID NO: 36, SEQ ID NO: 52, or SEQ ID NO: 96; and (ii) a light chain of amino acids having at least 95% sequence identity to SEQ ID NO: 823 or SEQ ID NO: 44, SEQ ID NO: 59, or SEQ ID NO: 102.

[0544] In embodiments: (i) the VH region comprises the following CDRs: HC-CDR1 of amino acids having at least 85% sequence identity to SEQ ID NO: 37; HC-CDR2 of amino acids having at least 85% sequence identity to SEQ ID NO: 38 or SEQ ID NO: 53; HC-CDR3 of amino acids having at least 85% sequence identity to SEQ ID NO: 39 or SEQ ID NO: 54; and (ii) the VL region comprises the following CDRs: LC-CDR1 of amino acids having at least 85% sequence identity to SEQ ID NO: 45 or SEQ ID NO: 60; LC-CDR2 of amino acids having at least 85% sequence identity to SEQ ID NO: 46 or SEQ ID NO: 61; LC-CDR3 of amino acids having at least 85% sequence identity to SEQ ID NO: 47 or SEQ ID NO: 62.

[0545] The advantage is the ability to neutralize BQ.1.1 and XBB variants and can be used to treat those in need of treatment. Antibody 1, Antibody 2, and Antibody 5 are all able to neutralize SARS-CoV-2 variants BQ.1.1 and XBB at an IC50 of 200 or less. 50 SARS-CoV-2 variants BQ.1.1 and XBB at a concentration of 200 or less, see Figure 1 E], Figure 1 F], Figure 2 A], and Figure 3This is a great improvement over the E7 antibody, which requires a much higher concentration to inhibit BQ.1.1 and XBB variants, and is currently much needed since the Balovapimab (LY-CoV1404) antibody does not bind to these variants. In various embodiments, the concentration of E7 that is lower than the concentration required to bind and neutralize SARS-CoV-2 variants BQ.1.1 and XBB is at least 2-fold lower than the concentration of E7, or at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 15, 20, 29, 30, 34, 35, or 40-fold lower than the concentration of E7.

[0546] In various embodiments, Antibody 1 comprises a VH region comprising a HC-CDR1 comprising the amino acids of SEQ ID NO: 37; a HC-CDR2 comprising the amino acids of SEQ ID NO: 38; a HC-CDR3 comprising the amino acids of SEQ ID NO: 39; and a VL region comprising a LC-CDR1 comprising the amino acids of SEQ ID NO: 45; a LC-CDR2 comprising the amino acids of SEQ ID NO: 46; a LC-CDR3 comprising the amino acids of SEQ ID NO: 47. In various embodiments, Antibody 1 comprises a heavy chain comprising the amino acids of SEQ ID NO: 36; and a light chain comprising the amino acids of SEQ ID NO: 44. Antibody 1 effectively neutralizes SARS-CoV-2 variant BQ.1.1 at only 16.5 ng / ml, which is about 34 to 35-fold lower than the concentration required for E7 to bind and neutralize SARS-CoV-2 variant BQ.1.1. Antibody 1 effectively neutralizes SARS-CoV-2 variant XBB at only 11.6 ng / ml, which is about 29 to 30-fold lower than the concentration required for E7 to bind and neutralize SARS-CoV-2 variant XBB.

[0547] In embodiments, antibody 2 comprises a VH region comprising HC-CDR1 comprising the amino acids of SEQ ID NO: 37; HC-CDR2 comprising the amino acids of SEQ ID NO: 53; HC- CDR3 comprising the amino acids of SEQ ID NO: 54; and a VL region comprising LC-CDR1 comprising the amino acids of SEQ ID NO: 60; LC-CDR2 comprising the amino acids of SEQ ID NO: 61; LC-CDR3 comprising the amino acids of SEQ ID NO: 62. In various embodiments, antibody 2 comprises a heavy chain comprising the amino acids of SEQ ID NO: 52; and a light chain comprising the amino acids of SEQ ID NO: 59. Antibody 2 effectively neutralizes SARS-CoV-2 variant BQ.1.1 at only 16.6 ng / ml, which is about 34 to 35-fold lower than the concentration required for E7 to bind to and neutralize SARS-CoV-2 variant BQ.1.1. Antibody 2 effectively neutralizes SARS-CoV-2 variant XBB at only 8.5 ng / ml, which is about 40-fold lower than the concentration required for E7 to bind to and neutralize SARS-CoV-2 variant XBB.

[0548] In embodiments, antibody 5 comprises a heavy chain comprising the amino acids of SEQ ID NO: 96; and a light chain comprising the amino acids of SEQ ID NO: 102. Antibody 5 effectively neutralizes SARS-CoV-2 variant BQ.1.1 at only 57.5 ng / ml, which is about 10-fold lower than the concentration required for E7 to bind to and neutralize SARS-CoV-2 variant BQ.1.1. Antibody 5 effectively neutralizes SARS-CoV-2 variant XBB at only 40.8 ng / ml, which is about 8-fold lower than the concentration required for E7 to bind to and neutralize SARS-CoV-2 variant XBB.

[0549] The amino acids of SEQ ID NO: 822 comprise a sequence comprising the heavy chain amino acids of SEQ ID NO: 36 and SEQ ID NO: 52 and the CDRs of SEQ ID NOs: 107, 108, 109, 113, 114, and 115. The amino acids of SEQ ID NO: 823 comprise a sequence comprising the light chain amino acids of SEQ ID NO: 44 and SEQ ID NO: 59 and the CDRs of SEQ ID NOs: 110, 111, 112, 116, 117, and 118.

[0550] In embodiments, the E7 antibody includes a heavy chain including the amino acid sequence of SEQ ID NO: 824 and a light chain including the amino acid sequence of SEQ ID NO: 830. Any inhibition assay known in the art that can determine the inhibition of binding of the variant strains to ACE2, such as the 50% inhibitory concentration (IC50) of the monoclonal antibody to block cell entry using a pseudovirus neutralization assay format, can be used to determine antibodies that can be used at a concentration lower than the concentration required for E7 to bind to and neutralize SARS-CoV-2 variant BQ.1.1 and XBB. 50 ; ng / ml) can be used to determine antibodies that can be used at a concentration lower than the concentration required for E7 to bind to and neutralize SARS-CoV-2 variant BQ.1.1 and XBB.

[0551] The higher neutralization potency of the antibodies of the present disclosure can allow for the use of lower doses of antigen binding molecules in the clinic, which can be used as a single antigen binding molecule or as a mixture with two or more antigen binding molecules or as an antigen binding molecule with two or more different antigen binding domains.

[0552] In embodiments, the Antibody 1 includes the following VH region: HC-FR1 - SEQ ID NO: 40; HC-CDR1 - SEQ ID NO: 37; HC-FR2 - SEQ ID NO: 41; HC-CDR2 - SEQ ID NO: 38; HC-FR3 - SEQ ID NO: 42; HC-CDR3 - SEQ ID NO: 39; HC-FR4 - SEQ ID NO: 43; and the following VL region: LC-FR1 - SEQ ID NO: 48; LC-CDR1 - SEQ ID NO: 45; LC-FR2 - SEQ ID NO: 49; LC-CDR2 - SEQ ID NO: 46; LC-FR3 - SEQ ID NO: 50; LC-CDR3 - SEQ ID NO: 47; LC-FR4 - SEQ ID NO: 51.

[0553] In embodiments, the Antibody 2 includes the following VH region: HC-FR1 - SEQ ID NO: 55; HC-CDR1 - SEQ ID NO: 37; HC-FR2 - SEQ ID NO: 56; HC-CDR2 - SEQ ID NO: 53; HC-FR3 - SEQ ID NO: 57; HC-CDR3 - SEQ ID NO: 54; HC-FR4 - SEQ ID NO: 58; and the following VL region: LC-FR1 - SEQ ID NO: 63; LC-CDR1 - SEQ ID NO: 60; LC-FR2 - SEQ ID NO: 64; LC-CDR2 - SEQ ID NO: 61; LC-FR3 - SEQ ID NO: 65; LC-CDR3 - SEQ ID NO: 62; LC-FR4 - SEQ ID NO: 66.

[0554] In embodiments, the term, inhibits or neutralizes can include inhibiting or neutralizing binding between 50% or more of the SARS-CoV-2 spike protein and ACE2. In embodiments, the inhibition or neutralization of binding between 50% or more of the SARS-CoV-2 spike protein and ACE2 can be selected from one of at least 50%, 55%, 60%, 61%, 62%, 63%, 64%, 65%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 95%, 99%, or greater.

[0555] In embodiments, the heavy chain has at least 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acids of SEQ ID NO: 822 or SEQ ID NO: 36 or SEQ ID NO: 52 or SEQ ID NO: 96; and the light chain has at least 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acids of SEQ ID NO: 823 or SEQ ID NO: 44 or SEQ ID NO: 59 or SEQ ID NO: 102.

[0556] According to embodiments, there is an antigen binding molecule that can bind and neutralize SARS-CoV-2 variant B.1.1.1 at a lower concentration than that required for E7 binding and neutralization of SARS-CoV-2 variant B.1.1.1; and at least one other SARS-CoV2 variant and another non-SARS-CoV-2 betacoronavirus, the antigen binding molecule comprising: (i) a heavy chain having at least 95% sequence identity to the amino acid sequence of any one of SEQ ID NO: 822, SEQ ID NO: 36, SEQ ID NO: 52, SEQ ID NO: 67, SEQ ID NO: 83, SEQ ID NO: 96, SEQ ID NO: 105, SEQ ID NO: 120, SEQ ID NO: 136, SEQ ID NO: 149, SEQ ID NO: 179, SEQ ID NO: 193, SE ID NO: 206, SEQ ID NO: 220, SEQ ID NO: 285, SEQ ID NO: 299, SEQ NO: 312, SEQ ID NO: 325, SEQ ID NO: 336, SEQ ID NO: 362, SEQ ID NO: 368, SEQ ID NO: 381, SEQ ID NO: 393, SEQ ID NO: 436, SEQ ID NO: 464, SEQ ID NO: 496, SEQ ID NO: 508, SEQ ID NO: 522, SEQ ID NO: 535, SEQ ID NO: 547, SEQ ID NO: 559, SEQ ID NO: 584, SEQ ID NO: 592, SEQ ID NO: 600, SEQ ID NO: 614, SEQ ID NO: 627, SEQ ID NO: 643, and SEQ ID NO: 656;and (ii) a light chain having at least 95% sequence identity to an amino acid sequence selected from any one of SEQ ID NO:823, SEQ ID NO:44, SEQ ID NO:59, SEQ ID NO:75, SEQ ID NO:89, SEQ ID:102, SEQ ID NO:113, SEQ ID NO:128, SEQ ID NO:144, SEQ ID NO 157, SEQ ID NO:187, SEQ ID NO:200, SEQ ID NO:213, SEQ ID NO:228, SEQ ID NO:291, SEQ ID NO:305, SEQ ID NO:318, SEQ ID NO:331, SEQ ID NO:343, SEQ ID NO:366, SEQ ID NO:374, SEQ ID NO:388, SEQ ID NO:400, SEQ ID NO:443, SEQ ID NO:471, SEQ ID NO:502, SE ID NO:515, SEQ ID NO:529, SEQ ID NO:542, SEQ ID NO:554, SEQ NO:567, SEQ ID NO:587, SEQ ID NO:596, SEQ ID NO:607, SEQ ID NO:621, SEQ ID NO:635, SEQ ID NO:651, and SEQ ID NO:663.

[0557] The advantage is that it is able to neutralize the currently circulating variant strain BQ.1.1 and is suitable for use at an appropriate concentration to treat a human in need (see, e.g., Figure 1 E], Figure 2 A], Figure 3 ) Antibodies 1-5 include Antibody 1, Antibody 2, Antibody 3, Antibody 4, and Antibody 5, all of which are able to neutralize SARS-CoV-2 variant strain BQ.1.1 at an IC 50 at a concentration of 300 ng / ml or less, see Figure 3 This is a significant improvement over the E7 antibody, which requires a higher concentration to inhibit this variant strain, and is currently highly desirable due to the Betulovir (LY-CoV1404) antibody not binding to the variant strain BQ.1.1. However, it also has the potential advantage of being useful in managing another zoonotic Betacoronavirus infection in the future, such as the infection currently observed in bats or pangolins (see Figure 3 ).

[0558] In various embodiments, a concentration lower than the concentration required for E7 to bind and neutralize the SARS-CoV-2 variant BQ.1.1 refers to a concentration that is at least 1.1-fold lower than the concentration of E7 or at least 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 15, 20, 29, 30, 34, 35, or 40-fold lower than the concentration of E7. Antibody 1 requires only 16.5 ng / ml to effectively neutralize the SARS-CoV-2 variant BQ.1.1, which is approximately 34-35-fold lower than the concentration required for E7 to bind and neutralize the SARS-CoV-2 variant BQ.1.1. Antibody 2 requires only 16.6 ng / ml to effectively neutralize the SARS-CoV-2 variant BQ.1.1, which is approximately 34-35-fold lower than the concentration required for E7 to bind and neutralize the SARS-CoV-2 variant BQ.1.1. Antibody 3 only requires 270.6ng / ml to effectively neutralize the SARS-CoV-2 variant BQ.1.1, which is about 2 times lower than the concentration required for E7 to bind to and neutralize the SARS-CoV-2 variant BQ.1.1. Antibody 4 only requires 48.4ng / ml to effectively neutralize the SARS-CoV-2 variant BQ.1.1, which is about 11 times lower than the concentration required for E7 to bind to and neutralize the SARS-CoV-2 variant BQ.1.1. Antibody 5 only requires 57.5ng / ml to effectively neutralize the SARS-CoV-2 variant BQ.1.1, which is about 10 times lower than the concentration required for E7 to bind to and neutralize the SARS-CoV-2 variant BQ.1.1. Antibodies 6-9, 11-14, 19-23, 25-28, 32, 35, 39-44 and 46-52 can also be effectively neutralized at IC 50 It effectively neutralizes SARS-CoV-2 variant BQ.1.1 at concentrations of 550ng / ml or lower.

[0559] In each embodiment, the above sequences refer to antibodies 1-5, 6-9, 11-14, 19-23, 25-28, 32, 35, 39-44, and 46-52 listed in Table C herein. In contrast, although antibodies 10, 15-18, 24, 29-31, 33, 34, 36-38, and 45 were able to bind to and neutralize SARS-CoV-2 variant BQ.1.1 in some cases, each was less effective than the E7 antibody and therefore required a higher concentration than E7 to bind to and neutralize SARS-CoV-2 variant BQ.1.1 (see [ Figure 3 ]).

[0560] In embodiments, the at least one other SARS-CoV-2 variant includes Alpha COVID-19 variant SARS-CoV-2 B.1.1.7; Beta COVID-19 variant SARS-CoV-2 B.1.351, also known as 20H / 501Y.V2, or 501Y.V2 variant; Gamma variant P.1; Delta SARS-CoV-2 B.1.617.2; and Omicron variant SARS-CoV-2 B.1.1.529 BA.1, BA.2, BA.5, BA.2.75, BA.2.75.2, BA.4.6.1, BF.7, BQ.1.1, and XBB. In embodiments, the at least one other SARS-CoV-2 variant can include 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, or 7 or more of Alpha COVID-19 variant SARS-CoV-2 B.1.1.7; Beta COVID-19 variant SARS-CoV-2 B.1.351, also known as 20H / 501Y.V2, or 501Y.V2 variant; Gamma variant P.1; Delta SARS-CoV-2 B.1.617.2; and Omicron variant SARS-CoV-2 B.1.1.529 BA.1, BA.2, BA.5, BA.2.75, BA.2.75.2, BA.4.6.1, BF.7, BQ.1.1, and XBB.

[0561] Another betacoronavirus as described herein refers to a betacoronavirus other than SARS-CoV-2. In embodiments, another betacoronavirus includes SARS-CoV, BANAL-52, WIV-1, SC2r-CoV RaTG13, SC2r-CoVGX-P5L, SC2r-CoV GD-1, SC2r-CoVRmYN02, RacCS203, or other unknown betacoronavirus. In embodiments, another betacoronavirus includes any betacoronavirus that utilizes ACE2 receptor to enter cells that is not SARS-CoV-2 or is a betacoronavirus other than SARS-CoV-2. Broad spectrum antigen binding molecules have the advantage of being able to effectively block most betacoronaviruses, helping to prevent infection of known and unknown betacoronaviruses. In embodiments, the antigen binding molecules include monoclonal antibodies (mAbs). mAbs can be one of the most effective and powerful tools to be rapidly developed and deployed against future emerging zoonotic viruses, particularly betacoronaviruses.

[0562] According to embodiments, there is a composition of any one of the antigen binding molecules described above in combination with Bamlanivimab LY-CoV555 and Etesevimab LY-CoV 539. In embodiments, the Bamlanivimab LY-CoV555 antibody includes the antibody described in WO / 2020 / 25667. In embodiments, the Etesevimab LY-CoV539 antibody includes the antibody described in WO / 2020 / 25667. In embodiments, such a composition or cocktail has the advantage of increasing the range of SARS-CoV-2 variants and other betacoronaviruses that the antigen binding molecules can bind and neutralize (see Examples Figure 3 ]) In embodiments, the composition includes:

[0563] a first antigen binding molecule including: (i) a VH region including CDRs: an HC-CDR1 having amino acids with at least 85% sequence identity to SEQ ID NO: 37; an HC-CDR2 having amino acids with at least 85% sequence identity to SEQ ID NO: 38 or SEQ ID NO: 53; and an HC-CDR3 having amino acids with at least 85% sequence identity to SEQ ID NO: 39 or SEQ ID NO: 54; and (ii) a VL region including CDRs: an LC-CDR1 having amino acids with at least 85% sequence identity to SEQ ID NO: 45 or SEQ ID NO: 60; an LC-CDR2 having amino acids with at least 85% sequence identity to SEQ ID NO: 46 or SEQ ID NO: 61; and an LC-CDR3 having amino acids with at least 85% sequence identity to SEQ ID NO: 47 or SEQ ID NO: 62; and

[0564] a second antigen binding molecule including: (iii) a heavy chain having amino acids with at least 95% sequence identity to SEQ ID NO: 824; and (iv) a light chain having amino acids with at least 95% sequence identity to SEQ ID NO: 830.

[0565] In embodiments, the composition includes an antigen binding molecule selected from any one of antibodies 1-52 in combination with the antibody Bamlanivimab LY-CoV555 or the antibody Etesevimab LY-CoV539.

[0566] According to embodiments, there is a method of treating a coronavirus infection comprising administering to a patient in need thereof a therapeutically effective amount of an antigen binding molecule or composition described above. In embodiments, the therapeutically effective amount of the antigen binding molecule or composition refers to an amount sufficient to neutralize or inhibit a coronavirus infection, thereby preventing, mitigating, or halting symptoms of the coronavirus infection. According to embodiments, there is a method of treating a coronavirus infection comprising administering to a patient in need thereof a therapeutically effective amount of an antigen binding molecule that binds to and neutralizes SARS-CoV-2 variant BQ.1.1 and XBB at a concentration lower than that required for E7 to bind to and neutralize SARS-CoV-2 variant BQ.1.1 and XBB, the antigen binding molecule comprising: (i) a VH region comprising the following CDRs: HC-CDR1 comprising amino acids having at least 85% sequence identity to SEQ ID NO: 37; HC-CDR2 comprising amino acids having at least 85% sequence identity to SEQ ID NO: 38 or SEQ ID NO: 53; HC-CDR3 comprising amino acids having at least 85% sequence identity to SEQ ID NO: 39 or SEQ ID NO: 54; and (ii) a VL region comprising the following CDRs: LC-CDR1 comprising amino acids having at least 85% sequence identity to SEQ ID NO: 45 or SEQ ID NO: 60; LC-CDR2 comprising amino acids having at least 85% sequence identity to SEQ ID NO: 46 or SEQ ID NO: 61; LC-CDR3 comprising amino acids having at least 85% sequence identity to SEQ ID NO: 47 or SEQ ID NO: 62.

[0567] According to embodiments, there is a method of treating a coronavirus infection comprising administering to a patient in need thereof a therapeutically effective amount of an antigen binding molecule that binds to and neutralizes SARS-CoV-2 variant BQ.1.1 and XBB at a concentration lower than that required for E7 to bind to and neutralize SARS-CoV-2 variant BQ.1.1 and XBB, the antigen binding molecule comprising: (i) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 822, SEQ ID NO: 36, SEQ ID NO: 52, or SEQ ID NO: 96; and (ii) a light chain comprising an amino acid having at least 95% sequence identity to SEQ ID NO: 823, SEQ ID NO: 44, SEQ ID NO: 59, or SEQ ID NO: 102.

[0568] According to embodiments, there is an antigen binding molecule that can bind and neutralize SARS-CoV-2 variant B.1.1.1 at a lower concentration than that required for E7 binding and neutralization of SARS-CoV-2 variant B.1.1.1; and at least one other SARS-CoV2 variant and another betacoronavirus, the antigen binding molecule comprising: (i) a heavy chain having at least 95% sequence identity to the amino acid sequence of any one of SEQ ID NO: 822, SEQ ID NO: 36, SEQ ID NO: 52, SEQ ID NO: 67, SEQ ID NO: 83, SEQ ID NO: 96, SEQ ID NO: 105, SEQ ID NO: 120, SEQ ID NO: 136, SEQ ID NO: 149, SEQ ID NO: 179, SEQ ID NO: 193, SE ID NO: 206, SEQ ID NO: 220, SEQ ID NO: 285, SEQ ID NO: 299, SEQ NO: 312, SEQ ID NO: 325, SEQ ID NO: 336, SEQ ID NO: 362, SEQ ID NO: 368, SEQ ID NO: 381, SEQ ID NO: 393, SEQ ID NO: 436, SEQ ID NO: 464, SEQ ID NO: 496, SEQ ID NO: 508, SEQ ID NO: 522, SEQ ID NO: 535, SEQ ID NO: 547, SEQ ID NO: 559, SEQ ID NO: 584, SEQ ID NO: 592, SEQ ID NO: 600, SEQ ID NO: 614, SEQ ID NO: 627, SEQ ID NO: 643, and SEQ ID NO: 656;and (ii) a light chain having at least 95% sequence identity to an amino acid sequence selected from any one of SEQ ID NO:823, SEQ ID NO:44, SEQ ID NO:59, SEQ ID NO:75, SEQ ID NO:89, SEQ ID:102, SEQ ID NO:113, SEQ ID NO:128, SEQ ID NO:144, SEQ ID NO 157, SEQ ID NO:187, SEQ ID NO:200, SEQ ID NO:213, SEQ ID NO:228, SEQ ID NO:291, SEQ ID NO:305, SEQ ID NO:318, SEQ ID NO:331, SEQ ID NO:343, SEQ ID NO:366, SEQ ID NO:374, SEQ ID NO:388, SEQ ID NO:400, SEQ ID NO:443, SEQ ID NO:471, SEQ ID NO:502, SE ID NO:515, SEQ ID NO:529, SEQ ID NO:542, SEQ ID NO:554, SEQ NO:567, SEQ ID NO:587, SEQ ID NO:596, SEQ ID NO:607, SEQ ID NO:621, SEQ ID NO:635, SEQ ID NO:651, and SEQ ID NO:663.

[0569] According to various embodiments, a method of treating a betacoronavirus infection is provided, the method comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising any of the antigen binding molecules described above, and either of Bamlanivimab LY-CoV 1404 and E7. Compositions combining Antibody 1 and Antibody E7 are able to improve inhibition capacity and effectively inhibit all tested SARS-CoV-2 variants and all tested betacoronaviruses. Likewise, compositions combining Antibody 2 and Antibody E7 are able to improve inhibition capacity and effectively inhibit all tested SARS-CoV-2 variants and all tested betacoronaviruses.

[0570] In embodiments, the patient in need can be an individual who has been diagnosed with infection by a betacoronavirus. In embodiments, the patient in need can be an individual who has been diagnosed with infection by a SARS-CoV-2 variant. In embodiments, the method comprises determining that the infection is caused by a betacoronavirus, such as a SARS-CoV-2 variant. In embodiments, the patient in need can be an individual who has been diagnosed with COVID-19 caused by a betacoronavirus, such as a SARS-CoV-2 variant. In embodiments, the patient in need can be an individual who has been diagnosed with COVID-19 caused by one of SARS-CoV-2 variants BQ.1.1 and XBB.

[0571] According to embodiments, there is provided a therapeutically effective amount of an antigen binding molecule or composition described above for use in the treatment of a betacoronavirus infection. In embodiments, the betacoronavirus infection can be caused by a non-SARS-CoV-2, such as an earlier known betacoronavirus that can infect bats or pangolins or any currently unknown betacoronavirus. In embodiments, the betacoronavirus infection can be caused by a SARS-CoV-2 variant. In embodiments, the betacoronavirus infection can be caused by one of SARS-CoV-2 variants BQ.1.1 and XBB. In embodiments, the antigen binding molecule as described above is suitable for use in the treatment of an individual who has been diagnosed with a betacoronavirus infection.

[0572] The following numbered paragraphs describe particular aspects and embodiments of the present disclosure:

[0573] 1. An antigen binding molecule that binds and neutralizes SARS-CoV-2 variants BQ.1.1 and XBB at a lower concentration than required to bind and neutralize SARS-CoV-2 variants B.1.1 and XBB, the antigen binding molecule comprising: a heavy chain comprising amino acids having at least 95% sequence identity to SEQ ID NO: 822 or SEQ ID NO: 36 or SEQ ID NO: 52 or SEQ ID NO: 96; and a light chain comprising amino acids having at least 95% sequence identity to SEQ ID NO: 823 or SEQ ID NO: 44 or SEQ ID NO: 59 or SEQ ID NO: 102.

[0574] NO:52 or SEQ ID NO: 96; and a light chain comprising amino acids having at least 95% sequence identity to SEQ ID NO: 823 or SEQ ID NO: 44 or SEQ ID NO: 59 or SEQ ID NO: 102.

[0575] 2. The antigen binding molecule of paragraph 1, wherein (i) the heavy chain variable (VH) region comprises the following CDRs: HC-CDR1 comprising amino acids having at least 85% sequence identity to SEQ ID NO: 37; HC-CDR2 comprising amino acids having at least 85% sequence identity to SEQ ID NO: 38 or SEQ ID NO: 53; HC-CDR3 comprising amino acids having at least 85% sequence identity to SEQ ID NO: 39 or SEQ ID NO: 54; and (ii) the light chain variable (VL) region comprises the following CDRs: LC-CDR1 comprising amino acids having at least 85% sequence identity to SEQ ID NO: 45 or SEQ ID NO: 60; LC-CDR2 comprising amino acids having at least 85% sequence identity to SEQ ID NO: 46 or SEQ ID NO: 61; LC-CDR3 comprising amino acids having at least 85% sequence identity to SEQ ID NO: 47 or SEQ ID NO: 62.

[0576] 3. An antigen binding molecule that binds and neutralizes SARS-CoV-2 variant B.1.1.1 at a lower concentration than that required for E7 to bind and neutralize SARS-CoV-2 variant B.1.1.1; and at least one other SARS-CoV2 variant and another betacoronavirus, the antigen binding molecule comprising: (i) a heavy chain having at least 95% sequence identity to the amino acid of any one of SEQ ID NO: 822, SEQ ID NO: 36, SEQ ID NO: 52, SEQ ID NO: 67, SEQ ID NO: 83, SEQ ID NO: 96, SEQ ID NO: 105, SEQ ID NO: 120, SEQ ID NO: 136, SEQ ID NO: 149, SEQ ID NO: 179, SEQ ID NO: 193, SE ID NO: 206, SEQ ID NO: 220, SEQ ID NO: 285, SEQ ID NO: 299, SEQ NO: 312, SEQ ID NO: 325, SEQ ID NO: 336, SEQ ID NO: 362, SEQ ID NO: 368, SEQ ID NO: 381, SEQ ID NO: 393, SEQ ID NO: 436, SEQ ID NO: 464, SEQ ID NO: 496, SEQ ID NO: 508, SEQ ID NO: 522, SEQ ID NO: 535, SEQ ID NO: 547, SEQ ID NO: 559, SEQ ID NO: 584, SEQ ID NO: 592, SEQ ID NO: 600, SEQ ID NO: 614, SEQ ID NO: 627, SEQ ID NO: 643, and SEQ ID NO: 656;and (ii) a light chain having at least 95% sequence identity of the amino acid of any one selected from the group consisting of SEQ ID NO:823, SEQ ID NO:44, SEQ ID NO:59, SEQ ID NO:75, SEQ ID NO:89, SEQ ID:102, SEQ ID NO:113, SEQ ID NO:128, SEQ ID NO:144, SEQ ID NO 157, SEQ ID NO:187, SEQ ID NO:200, SEQ ID NO:213, SEQ ID NO:228, SEQ ID NO:291, SEQ ID NO:305, SEQ ID NO:318, SEQ ID NO:331, SEQ ID NO:343, SEQ ID NO:366, SEQ ID NO:374, SEQ ID NO:388, SEQ ID NO:400, SEQ ID NO:443, SEQ ID NO:471, SEQ ID NO:502, SE ID NO:515, SEQ ID NO:529, SEQ ID NO:542, SEQ ID NO:554, SEQ NO:567, SEQ ID NO:587, SEQ ID NO:596, SEQ ID NO:607, SEQ ID NO:621, SEQ ID NO:635, SEQ ID NO:651, and SEQ ID NO:663.

[0577] 4. A composition comprising any one of the antigen binding molecules of paragraphs 1-3 and any one of the following: Bamlanivimab LY-CoV 1404 and E7.

[0578] 5. The composition of paragraph 4, wherein the antigen binding molecule comprises: (i) a heavy chain variable (VH) region comprising the following CDRs: HC-CDR1 comprising amino acids having at least 85% sequence identity to SEQ ID NO: 37; HC-CDR2 comprising amino acids having at least 85% sequence identity to SEQ ID NO: 38 or SEQ ID NO: 53; HC-CDR3 comprising amino acids having at least 85% sequence identity to SEQ ID NO: 39 or SEQ ID NO: 54; and (ii) a light chain variable (VL) region comprising the following CDRs: LC-CDR1 comprising amino acids having at least 85% sequence identity to SEQ ID NO: 45 or SEQ ID NO: 60; LC-CDR2 comprising amino acids having at least 85% sequence identity to SEQ ID NO: 46 or SEQ ID NO: 61; LC-CDR3 comprising amino acids having at least 85% sequence identity to SEQ ID NO: 47 or SEQ ID NO: 62; and

[0579] wherein E7 comprises a second antigen binding molecule comprising: (iii) a heavy chain comprising amino acids having at least 95% sequence identity to the sequence set forth in SEQ ID NO: 824; and (iv) a light chain comprising amino acids having at least 95% sequence identity to the sequence set forth in SEQ ID NO: 830.

[0580] 6. A composition that binds to and neutralizes SARS-CoV-2 variant BQ.1.1, at least three other SARS-CoV-2 variants, and another betacoronavirus, wherein the composition comprises an antigen binding molecule comprising: (i) a heavy chain that binds to an antigen selected from the group consisting of SEQ ID NO: 822, SEQ ID NO: 36, SEQ ID NO: 52, SEQ ID NO: 67, SEQ ID NO: 83, SEQ ID NO: 96, SEQ ID NO: 105, SEQ ID NO: 120, SEQ ID NO: 136, SEQ ID NO: 149, SEQ ID NO: 179, SEQ ID NO: 193, SEQ ID NO: 206, SEQ ID NO: 220, SEQ ID NO: 235, SEQ ID NO: 249, SEQ ID NO: 262, SEQ ID NO: 274, SEQ ID NO: 285, SEQ ID NO: 299, SEQ ID NO: 312, SEQ ID NO: 325, SEQ ID NO: 336, SEQ ID NO: : The amino acid sequence of any one of SEQ ID NO:350, SEQ ID NO:362, SEQ ID NO:368, SEQ ID NO:381, SEQ ID NO:393, SEQ ID NO:405, SEQ ID NO:416, SEQ ID NO:427, SEQ ID NO:436, SEQ ID NO:449, SEQ ID NO:453, SEQ ID NO:464, SEQ ID NO:475, SEQ ID NO:487, SEQ ID NO:496, SEQ ID NO:508, SEQ ID NO:522, SEQ ID NO:535, SEQ ID NO:547, SEQ ID NO:559, SEQ ID NO:572, SEQ ID NO:584, SEQ ID NO:592, SEQ ID NO:600, SEQ ID NO:614, SEQ ID NO:627, SEQ ID NO:643, and SEQ ID NO:656 has at least 95% sequence identity;and (ii) a light chain selected from the group consisting of SEQ ID NO:823, SEQ ID NO:44, SEQ ID NO:59, SEQ ID NO:75, SEQ ID NO:89, SEQ ID:102, SEQ ID NO:113, SEQ ID NO:128, SEQ ID NO:144, SEQ ID NO157, SEQ ID NO:171, SEQ ID NO:187, SEQ ID NO:200, SEQ ID NO:213, SEQ ID NO:228, SEQ ID NO:242, SEQ ID NO:256, SEQ ID NO:270, SEQ ID NO:280, SEQ ID NO:291, SEQ ID NO:305, SEQ ID NO:318, SEQ ID NO:331, SEQ ID NO:343, SEQ ID NO:355, SEQ ID NO:366, SEQ ID NO:374, SEQ ID NO:388, SEQ ID NO:400, SEQ ID NO:411, SEQ ID NO:423, SEQ ID NO:432, SEQ ID NO:443, SEQ ID NO:451, SEQ ID NO:460, SEQ ID NO:471, SEQ ID NO:481, SEQ ID NO:491, SEQ ID NO:502, SEQ ID NO:515, SEQ ID NO:529, SEQ ID NO:542, SEQ ID NO:554, SEQ ID NO:567, SEQ ID NO:579, SEQ ID NO:587, SEQ ID NO:596, SEQ ID NO:607, SEQ ID NO:621, SEQ ID NO:635, SEQ ID NO:651, and SEQ ID NO:663; and a second antigen-binding molecule comprising any one of beteclovir monoclonal antibodies LY-CoV1404 and E7. ;

[0581] 6. A method of treating a betacoronavirus infection comprising administering to a patient in need thereof a therapeutically effective amount of an antigen binding molecule that binds and neutralizes SARS-CoV-2 variants BQ.1.1 and XBB at a lower concentration than is required for E7 to bind and neutralize SARS-CoV-2 variants B.1.1 and XBB, wherein the antigen binding molecule comprises: (i) a heavy chain variable (VH) region comprising the following CDRs: an HC-CDR1 comprising amino acids having at least 85% sequence identity to SEQ ID NO: 37; an HC-CDR2 comprising amino acids having at least 85% sequence identity to SEQ ID NO: 38 or SEQ ID NO: 53; an HC-CDR3 comprising amino acids having at least 85% sequence identity to SEQ ID NO: 39 or SEQ ID NO: 54; and

[0582] (ii) a light chain variable (VL) region comprising the following CDRs: an LC-CDR1 comprising amino acids having at least 85% sequence identity to SEQ ID NO: 45 or SEQ ID NO: 60; an LC-CDR2 comprising amino acids having at least 85% sequence identity to SEQ ID NO: 46 or SEQ ID NO: 61; an LC-CDR3 comprising amino acids having at least 85% sequence identity to SEQ ID NO: 47 or SEQ ID NO: 62.

[0583] 7. A method of treating a betacoronavirus infection comprising administering to a patient in need thereof a therapeutically effective amount of an antigen binding molecule that binds and neutralizes SARS-CoV-2 variants BQ.1.1 and XBB at a lower concentration than is required for E7 to bind and neutralize SARS-CoV-2 variants B.1.1 and XBB, wherein the antigen binding molecule comprises:

[0584] (i) a heavy chain comprising amino acids having at least 95% sequence identity to SEQ ID NO: 822 or SEQ ID NO: 36 or SEQ ID NO: 52 or SEQ ID NO: 96; and (ii) a light chain comprising amino acids having at least 95% sequence identity to SEQ ID NO: 823 or SEQ ID NO: 44 or SEQ ID NO: 59 or SEQ ID NO: 102.

[0585] 8. A method for treating a betacoronavirus infection, comprising administering to a patient in need thereof a therapeutically effective amount of an antigen binding molecule that binds to and neutralizes SARS-CoV-2 variant BQ.1.1, as well as at least one other SARS-CoV-2 variant and another betacoronavirus at a concentration lower than that required for E7 to bind to and neutralize SARS-CoV-2 variant B.1.1, the antigen binding molecule comprising: (i) a heavy chain that binds to an antigen selected from the group consisting of SEQ ID NO: 822, SEQ ID NO: 36, SEQ ID NO: 52, SEQ ID NO: 67, SEQ ID NO: 83, SEQ ID NO: 96, SEQ ID NO: 105, SEQ ID NO: 120, SEQ ID NO: 136, SEQ ID NO: 149, SEQ ID NO: 179, SEQ ID NO: 193, SEQ ID NO: 206, SEQ ID NO: 220, SEQ ID NO: 285, SEQ ID NO: 299, SEQ ID NO: 312, SEQ ID NO: 325, SEQ ID NO: the amino acid sequence of any one of SEQ ID NO:336, SEQ ID NO:362, SEQ ID NO:368, SEQ ID NO:381, SEQ ID NO:393, SEQ ID NO:436, SEQ ID NO:464, SEQ ID NO:496, SEQ ID NO:508, SEQ ID NO:522, SEQ ID NO:535, SEQ ID NO:547, SEQ ID NO:559, SEQ ID NO:584, SEQ ID NO:592, SEQ ID NO:600, SEQ ID NO:614, SEQ ID NO:627, SEQ ID NO:643, and SEQ ID NO:656, having at least 95% sequence identity;and (ii) a light chain having at least 95% sequence identity to an amino acid sequence selected from any one of SEQ ID NO:823, SEQ ID NO:44, SEQ ID NO:59, SEQ ID NO:75, SEQ ID NO:89, SEQ ID:102, SEQ ID NO:113, SEQ ID NO:128, SEQ ID NO:144, SEQ ID NO 157, SEQ ID NO:187, SEQ ID NO:200, SEQ ID NO:213, SEQ ID NO:228, SEQ ID NO:291, SEQ ID NO:305, SEQ ID NO:318, SEQ ID NO:331, SEQ ID NO:343, SEQ ID NO:366, SEQ ID NO:374, SEQ ID NO:388, SEQ ID NO:400, SEQ ID NO:443, SEQ ID NO:471, SEQ ID NO:502, SE ID NO:515, SEQ ID NO:529, SEQ ID NO:542, SEQ ID NO:554, SEQ NO:567, SEQ ID NO:587, SEQ ID NO:596, SEQ ID NO:607, SEQ ID NO:621, SEQ ID NO:635, SEQ ID NO:651, and SEQ ID NO:663.

[0586] 9. A method of treating a betacoronavirus infection comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising the antigen binding molecule of paragraphs 1-3 and any one of batelovimab LY-CoV1404 and E7.

[0587] 10. A therapeutically effective amount of any one of the antigen binding molecules of paragraphs 1-3 or the composition of paragraphs 4 or 5 for use in treating a betacoronavirus infection.

[0588] 11. The antigen binding molecule or composition for use of paragraph 10, wherein the betacoronavirus infection is caused by a SARS-CoV-2 variant comprising BQ.1.1.

[0589] 12. The therapeutically effective amount of the antigen binding molecule or composition for use of paragraph 10, wherein the betacoronavirus infection is caused by a SARS-CoV-2 variant comprising BQ.1.1 or XBB.

[0590] ***

[0591] The present disclosure includes combinations of the described aspects and preferred features unless such combinations are clearly impractical or otherwise clearly excluded.

[0592] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0593] Aspects and embodiments of the present disclosure will be described with reference to the accompanying drawings. Further aspects and embodiments will be apparent to those of ordinary skill in the art. All documents mentioned herein are hereby incorporated by reference.

[0594] Throughout this specification, including in the claims, the term "comprise" and variations thereof such as "comprising" and "comprises" are not intended to exclude other additives, components, integers or steps. Throughout this specification, including in the claims, the term "comprise" and variations thereof such as "comprising" and "comprises" are not intended to exclude other additives, components, integers or steps.

[0595] As used herein, a stretch of amino acid sequence or polypeptide region "corresponds to" a particular reference amino acid sequence or polypeptide region, i.e. it has at least 60% sequence identity, such as at least one of 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%, to the amino acid sequence of the reference amino acid sequence / polypeptide / region.

[0596] Amino acid sequences / regions / sites of a polypeptide / amino acid sequence corresponding to amino acid sequences / regions / sites of a particular reference polypeptide / amino acid sequence can be determined by performing a sequence alignment of the sequence to be tested and the reference sequence using sequence alignment software such as Clustal Omega (http: / / www.ebi.ac.uk / Tools / clustalo / ) (Cuchillo et al. 2005, Bioinformatics 21 951-960). J. 2005, Bioinformatics 21 951-960).

[0597] It must be noted that as used herein the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Ranges can be expressed herein as from "about" one particular value, and / or to "about" another particular value. In another embodiment, a range can be expressed as from a particular value and / or to a particular value. In this instance, particularly with respect to values that are approximations, the term "about" can be understood as an approximation to a particular value.

[0598] The reverse complement of any nucleic acid sequence disclosed herein is expressly included.

[0599] The methods described herein can preferably be performed in vitro. The term "in vitro" is meant to include procedures performed with cultured cells, while "in vivo" is meant to include procedures performed with / in intact multicellular organisms. BRIEF DESCRIPTION OF DRAWINGS

[0600] Figure 1 A to IF: Plots of the inhibition rate (%) of each antibody on pseudovirus infection of ACE2-expressing cells expressing (1A) SARS-CoV-2, (1B) BA.2.75.2, (1C) BF.7, (1D) BA.4.6.1, (1E) BQ.1.1, and (1F) XBB.1 spike proteins, as determined by the pseudovirus neutralization test (pVNT).

[0601] Figure 2 A to 2C: Tables summarizing the IC 50 values of the specified antibodies / antibody combinations on pseudovirus infection of ACE2-expressing cells expressing specific betacoronavirus spike proteins, as determined by the pVNT.

[0602] Figure 3 : Plots showing the IC 50 values of the specified antibodies on pseudovirus infection of ACE2-expressing cells expressing specific betacoronavirus spike proteins, as determined by the pVNT.

[0603] Figure 4 : Plots showing the IC 50 values of the specified antibodies / antibody combinations on pseudovirus infection of ACE2-expressing cells expressing specific betacoronavirus spike proteins, as determined by the pVNT in the presence of human serum.

[0604] Figure 5 : Plots showing the IC 50 values of the specified antibodies / antibody combinations inhibiting the interaction of human ACE2 with the RBD of specific betacoronavirus spike proteins, as determined by the surrogate virus neutralization test (sVNT).

[0605] Example

[0606] Example 1 - Materials and Methods

[0607] 1.1 Pseudovirus preparation

[0608] Vesicular stomatitis virus (VSV) pseudoviruses carrying SARS-CoV-2 Wuhan-Hu-1 (original strain), Omicron BA.1, BA.2, BA.5, BA.2.75, BA.2.75.2, BA.4.6.1, BF.7, BQ.1.1, XBB.1, XBB.1.16, XBB.2.3, EG.5, EG.5.1, BANAL-52, GD-1, GX-P5L, WIV-1 or SARS-CoV-1 full-length spike proteins were prepared and packaged using a slightly modified method described by Tan et al., Nat. Biotechnol. 2020 38:1073-1078. Briefly, 5 million HEK293T cells were transfected with 20 pg of pCAGGS plasmid encoding the respective spike protein using FuGENE6 transfection reagent (Promega). Twenty-four hours after transfection, cells were incubated with VSVAG-luc for 2 hours at an MOI of 5. After two phosphate-buffered saline (PBS) washes, cells were infected with complete growth medium containing 1:5000 diluted anti-VSV-G mAb (8GF11 clone, Cell Biolabs). Twenty-four hours after infection, pseudoviruses were collected by centrifugation at 2000 x g for 5 minutes.

[0609] 1.2 Pseudovirus neutralization test (pVNT)

[0610] For pVNT, 3 x 106RLU pseudoviruses were pre-incubated with serially diluted monoclonal antibodies in PBS buffer. For serum-added pVNT, human serum was supplemented at 1:20 dilution to mimic the ex vivo environment. Monoclonal antibodies were started at 20 pg / ml, serially diluted 4-fold to a final reaction volume of 50 mΐ, and incubated for 1 hour at 37°C. Pseudovirus-monoclonal antibody mixtures were used to infect A549 cells stably expressing human ACE2. Twenty to twenty-four hours after infection, an equal volume of ONE-Glo luciferase substrate (Promega) was added, and the fluorescent signal was measured using a Cytation 5 microplate reader (Biotek) with Gen5 software version 3.10.

[0611] 1.3 Multiplexed surrogate virus neutralization test (sVNT)

[0612] Multisubstituted virus neutralization tests (sVNTs) were performed essentially as described in Tan et al., Nat. biotechnology 2020 38 1073-1078 using receptor binding domain (RBD) proteins from 11 different betacoronaviruses: SARS-CoV-2; SARS-CoV-2 B.1.351 (Beta); SARS-CoV-2 B.1.617.2 (Delta); SARS-CoV-2 B.1.1.529.1 (BA.1); SARS-CoV-2 B.1.1.529.5 (BA.5); SARS-CoV-2 XBB.1; SC1 r-CoV Rs2018B; SC1 r-CoV RsSHC014; SARS-CoV and Bat CoV Khosta-2.

[0613] Briefly, aViTag biotinylated RBDs of different betacoronaviruses were coated on MagPlex Avidin microspheres (Luminex) at 5 pg per 1 million beads. RDB coated microspheres (600 beads per antigen) were pre-incubated with test monoclonal antibodies at an initial concentration of 10 pg / ml, serially diluted 4-fold and incubated for 15 minutes at 37°C with 250 rpm agitation. After 15 minutes of incubation, 50 mΐ of 2 pg / ml phycoerythrin (PE) conjugated hACE2 (Kisstech) was added to the wells and incubated for 15 minutes at 37°C with agitation, followed by two PBS-1% bovine serum albumin washes. Data were collected using a MAGPIX (Luminex) system.

[0614] Example 2 - Antibodies neutralize ACE2 expression in pseudo-betacoronaviruses expressing betacoronavirus spike protein Cell competency analysis

[0615] Antibodies capable of binding to SARS-CoV-2 spike protein were obtained, the sequence features of which are summarized in Tables A to C.

[0616] Different antibodies were analyzed for their ability to neutralize pseudovirus infection of ACE2 expressing cells expressing SARS-CoV-2 and 6 SARS-CoV-2 variants (BA.2.75.2, BA.4.6.1, BF.7, BQ.1.1 and XBB) spike proteins using a pseudovirus neutralization test (pVNT). 51 different antibodies were shown to be able to bind to and neutralize infection of BQ.1.1 and / or other SARS-CoV-2 variants.

[0617] Figure 1Figures A to IF show the results of pVNT for two known SARS-CoV-2 spike protein antibodies (LyCoV-1404 and E7) and Ab1, Ab2, Ab3, Ab4 and Ab38. Ab1, Ab2, Ab3 and Ab4 were found to be able to inhibit infection of ACE2-expressing cells by pseudoviruses expressing SARS-CoV-2 and all tested SARS-CoV-2 variant spike proteins.

[0618] Ab1, Ab2, Ab3, Ab4 and Ab38 were able to neutralise infection of ACE2-expressing cells by pseudoviruses expressing BQ.1.1 spike protein, whereas LyCoV-1404 did not inhibit infection of ACE2-expressing cells by pseudoviruses expressing BQ.1.1 spike protein Figure 1 E) Ab1, Ab2, Ab3 and Ab4 were more efficient than E7 at inhibiting infection of ACE2-expressing cells by pseudoviruses expressing BQ.1.1 spike protein.

[0619] Ab1, Ab2 and Ab3 were able to neutralise infection of ACE2-expressing cells by pseudoviruses expressing XBB.1 spike protein, whereas LyCoV-1404 did not inhibit infection of ACE2-expressing cells by pseudoviruses expressing XBB.1 spike protein Figure 1 F) Ab1 and Ab2 were more efficient than E7 at inhibiting infection of ACE2-expressing cells by pseudoviruses expressing XBB.1 spike protein.

[0620] Ab1 and Ab2 were also able to inhibit infection of ACE2-expressing cells by pseudoviruses expressing SARS-CoV-2, BA2.75.2, BF.7 or BA.4.6.1 spike protein with similar and higher efficiency than LyCoV-1404 and E7.

[0621] The antibodies were then evaluated in pVNT against pseudoviruses expressing spike proteins derived from a wider range of sarbecov-2, including SARS-CoV-2, SARS-CoV-2 variants BA.1, BA.2, BA.2.75, BA.2.75.2, BA.4.6.1, BF.7, BQ.1.1 and XBB, the 1b branch sarbecovirus BANAL-20-52 (BANAL-52), GD-1, GX-P5L, and the 1a branch sarbecoviruses WIV-1 and SARS-CoV-1. The inventors also investigated the performance of certain antibody combinations (E7 + LyCoV-1404, E7 + Ab1, E7 + H12.2) at a 1:1 ratio. IC 50 values were derived from % inhibition response curves fitted to the neutralisation data as Figure 2 A to 2C.

[0622] The effect of antibodies on pseudoviruses expressing spike proteins derived from a broad spectrum of betacoronaviruses including SARS-CoV-2, SARS-CoV-2 variants BA.1, BA.2, BA.2.75, BA.2.75.2, BA.4.6.1, BF.7, BQ.1.1 and XBB, betacoronavirus 1b clade BANAL-20-52 (BANAL-52), GD-1, GX-P5L, and betacoronavirus 1a clade WIV-1 and SARS-CoV-1 was assessed by pVNT. The inventors also investigated the ability of certain antibody combinations at a 1:1 ratio (E7 + LyCoV-1404, E7 + Ab1, E7 + H12.2). IC 50 values as Figure 2 shown in Figures A to 2C.

[0623] A variety of antibodies were tested for their ability to neutralize infection of ACE2-expressing cells by pseudoviruses expressing betacoronavirus spike proteins that were not inhibited by LyCoV-1404. A variety of antibodies inhibited infection of ACE2-expressing cells by pseudoviruses expressing betacoronavirus spike proteins with higher potency than E7.

[0624] Ab1 (B11.2) and Ab2 (H12.2) showed very strong neutralization of 13 and 14 out of 15 test pseudobetacoronaviruses (i.e. pseudoviruses expressing spike proteins of all 1b clade betacoronaviruses investigated), respectively, with IC 50 values of 1.1 to 30.4 ng / mL for Ab1 and 0.3 to 16.6 ng / mL for Ab2 (as Figure 2 shown in Figure A). Formulations containing E7 + Ab1 or E7 + Ab2 were able to neutralize all pseudobetacoronaviruses tested (i.e. pseudoviruses expressing spike proteins of all 1a and 1b clade betacoronaviruses investigated) with IC 50 values of 0.9-69.2 ng / mL.

[0625] Control antibody LyCoV-1404 showed potent activity against 10 out of 15 test betacoronaviruses, but was inactive against the remaining 6 including SARS-CoV-2 variants BQ.1.1 or XBB.

[0626] Control antibody E7 showed neutralization against all test variants, but was less potent against most of the SARS-CoV-2 variants tested including BQ.1.1 and XBB compared to Ab1 and Ab2.

[0627] These data demonstrate that the newly developed antibodies Ab1 and Ab2 are broad and highly potent, including their ability to neutralize beta coronaviruses of clade 1 including SARS-CoV-2 variants BQ.1.1 and XBB.1, which are not efficiently neutralized by the known antibodies E7 and LyCoV-1404.

[0628] Example 3 - Antibodies neutralize ACE2 expressing cells expressing SARS-CoV-2 variants XBB.1.16, XBB.2.3, Analysis of the ability of pseudo-betacoronaviruses to infect with EG.5 or EG5.1 spike proteins

[0629] The inventors subsequently investigated the ability of Ab2 (H12.2) to inhibit infection of ACE2-expressing cells by pseudobetacoronaviruses expressing SARS-CoV-2 variants XBB.1.16, XBB.2.3, EG.5 or EG5.1 spike proteins by a more advanced pVNT. The inhibitory effect of E7 and LyCoV1404 on these pseudobetacoronaviruses was also investigated.

[0630] The results are shown in Figure 2. LyCoV1404 was unable to neutralize the pseudoviruses corresponding to these SARS-CoV-2 variants. Ab2 exhibited similar or higher ability to neutralize the pseudoviruses corresponding to these SARS-CoV-2 variants compared to E7. In particular, Ab2 inhibited infection of ACE2-expressing cells by the pseudovirus expressing SARS-CoV-2 variant XBB.1.16 spike protein with very high potency. Figure 3

[0631] Example 4 - serum-added pvnt The inventors subsequently investigated the ability of Ab2 (H12.2), E7 and the combination of Ab2 + E7 (at a 1 : 1 ratio) to neutralize infection of ACE2-expressing cells by pseudoviruses expressing different betacoronavirus spike proteins by an advanced pVNT with the addition of human serum in the reaction buffer (see Example 1.2).

[0632] The results are shown in Figure 3, which are consistent with the results described in Examples 2 and 3. Ab2 exhibited similar or higher ability to neutralize infection of ACE2-expressing cells by all pseudobetacoronaviruses expressing clade 1b betacoronavirus spike proteins compared to E7. Ab2 also exhibited similar ability to neutralize infection of ACE2-expressing cells by the pseudobetacoronavirus expressing clade 1a betacoronavirus WIV-1 spike protein compared to E7. The combination of Ab2 + E7 efficiently neutralized infection of ACE2-expressing cells by all tested pseudobetacoronaviruses, including those expressing clade 1a betacoronavirus (WIV-1 and SARS-CoV-1) spike proteins.

[0633] Figure 4

[0634] Example 5 - Ab 2 exhibits neutralization against clade 3 betacoronaviruses ​​

[0635] The inventors then investigated the ability of Ab2 and E7 to inhibit the interaction of ACE2 with a peptide consisting primarily of the RBDs of multiple different betacoronavirus spike proteins using a multiple surrogate virus neutralization test (sVNT; see Example 1.3).

[0636] The experiments investigated the ability of antibodies to inhibit the interaction of the RBD of Khosta-2 with ACE2. Khosta-2 is a clade 3 betacoronavirus that binds to human ACE2 and is resistant to current SARS-CoV-2 vaccines, posing a potential threat to future human infections (see Seifert et al., PLoS Pathog. 2022, Vol. 18, No. 9, e1010828).

[0637] The results are as follows Figure 5 As shown. Both Ab 2 and E7 inhibited the interaction of Khosta-2 RBD with human ACE2. E7 inhibited the interaction between ACE2 and all tested betacoronavirus RBDs, while Ab 2 only inhibited the interaction between ACE2 and all 1b and 3 clade betacoronavirus RBDs.

Claims

1. An optionally isolated antigen-binding molecule that binds to a betacoronavirus spike protein, wherein: The antigen-binding molecule comprises: (i) a heavy chain variable (VH) region comprising the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 37 HC-CDR2 having the amino acid sequence of SEQ ID NO: 53 an HC-CDR3 having the amino acid sequence of SEQ ID NO: 54; and (ii) a light chain variable (LH) region comprising the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 60 LC-CDR2 having the amino acid sequence of SEQ ID NO: 61 LC-CDR3 having the amino acid sequence of SEQ ID NO:

62.

2. The antigen-binding molecule according to claim 1, wherein The antigen-binding molecule comprises: a VH region having an amino acid sequence that has at least 70% amino acid sequence identity to SEQ ID NO: 52; and A VL region having an amino acid sequence that has at least 70% amino acid sequence identity to SEQ ID NO:

59.

3. The antigen-binding molecule according to claim 1 or claim 2, wherein The antigen-binding molecule is a multispecific antigen-binding molecule, and wherein the antigen-binding molecule further comprises an antigen-binding domain that binds to an antigen other than the beta coronavirus spike protein.

4. A chimeric antigen receptor (CAR) comprising the antigen-binding molecule according to any one of claims 1 to 3.

5. An optionally isolated nucleic acid or nucleic acids encoding the antigen binding molecule of any one of claims 1 to 3 or the CAR of claim 4.

6. An expression vector or multiple expression vectors comprising the nucleic acid or multiple nucleic acids according to claim 5.

7. A cell comprising the antigen binding molecule of any one of claims 1 to 3, the CAR of claim 4, the nucleic acid or nucleic acids of claim 5, or the expression vector or expression vectors of claim 6.

8. A method comprising culturing the cell of claim 7 under conditions suitable for the cell to express an antigen-binding molecule or CAR.

9. A composition comprising the antigen binding molecule of any one of claims 1 to 3, the CAR of claim 4, the nucleic acid or nucleic acids of claim 5, the expression vector or expression vectors of claim 6, or the cell of claim 7, and a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

10. The composition according to claim 9, wherein The composition further includes: an antigen binding molecule that binds to the type B coronavirus spike protein, comprising a VH region having an amino acid sequence with at least 70% amino acid sequence identity to SEQ ID NO: 824, and a VL region having an amino acid sequence with at least 70% amino acid sequence identity to SEQ ID NO:

830.

11. A combination comprising: (i) the antigen-binding molecule of any one of claims 1 to 3, and (ii) an antigen-binding molecule that binds to the betacoronavirus spike protein, comprising a VH region having an amino acid sequence that has at least 70% amino acid sequence identity to SEQ ID NO: 824, and a VL region having an amino acid sequence that has at least 70% amino acid sequence identity to SEQ ID NO:

830.

12. The antigen binding molecule of any one of claims 1 to 3, the CAR of claim 4, the nucleic acid or nucleic acids of claim 5, the expression vector or expression vectors of claim 6, the cell of claim 7, the composition of claim 9 or 10, or the combination of claim 11, for use in a medical treatment or prevention method.

13. The antigen binding molecule of any one of claims 1 to 3, the CAR of claim 4, the nucleic acid or nucleic acids of claim 5, the expression vector or expression vectors of claim 6, the cell of claim 7, the composition of claim 9 or 10, or the combination of claim 11, for treating or preventing a disease or symptom characterized by betacoronavirus infection, optionally wherein the disease or condition characterized by infection with betacoronavirus is COVID-19.

14. Use of the antigen binding molecule of any one of claims 1 to 3, the CAR of claim 4, the nucleic acid or nucleic acids of claim 5, the expression vector or expression vectors of claim 6, the cell of claim 7, the composition of claim 9 or 10, or the combination of claim 11 in the preparation of a medicament for treating or preventing a disease or symptom characterized by betacoronavirus infection, optionally wherein the disease or condition characterized by infection with betacoronavirus is COVID-19.

15. A method for treating or preventing a disease or symptom characterized by betacoronavirus infection in a subject, comprising administering to the subject a therapeutically or prophylactically effective amount of an antigen binding molecule as described in any one of claims 1 to 3, a CAR as described in claim 4, a nucleic acid or multiple nucleic acids as described in claim 5, an expression vector or multiple expression vectors as described in claim 6, a cell as described in claim 7, a composition as described in claim 9 or 10, or a combination as described in claim 11, optionally, wherein the disease or condition characterized by infection with betacoronavirus is COVID-19.

16. An optionally isolated in vitro complex comprising an antigen binding molecule as claimed in any one of claims 1 to 3 that binds to a betacoronavirus or a betacoronavirus spike protein.

17. A method for detecting betacoronavirus or betacoronavirus spike protein in a sample, comprising contacting a sample containing or suspected of containing betacoronavirus or betacoronavirus spike protein with an antigen-binding molecule according to any one of claims 1 to 3, and detecting formation of a complex between the antigen-binding molecule and the betacoronavirus or betacoronavirus spike protein.

18. A method for selecting and stratifying subjects for treatment with a betacoronavirus targeted drug, the method comprising contacting a sample from a subject in vitro with an antigen-binding molecule as described in any one of claims 1 to 3, and detecting the formation of a complex between the antigen-binding molecule and the betacoronavirus or the betacoronavirus spike protein.

19. Use of the antigen-binding molecule according to any one of claims 1 to 3 as an in vitro or in vivo diagnostic or prognostic agent.

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