WO2022112392A1

WO2022112392A1 - Anti-sars-cov-2 antibody molecules

Info

Publication number: WO2022112392A1
Application number: PCT/EP2021/082948
Authority: WO
Inventors: Christoph Esslinger; Simone SCHMITT; Marcel Weber; Matthias Hillenbrand; Karsten Fischer
Original assignee: Memo Therapeutics Ag
Priority date: 2020-11-26
Filing date: 2021-11-25
Publication date: 2022-06-02

Abstract

Anti-SARS-CoV-2 antibody molecules or binding fragments thereof are disclosed. These anti-SARS-CoV-2 antibody molecules or binding fragments can be used in the treatment or prevention of SARS-CoV-2 infection and/or SARS-CoV-2 associated disorder.

Description

Anti-SARS-CoV-2 antibody molecules

FIELD

The present disclosure relates to anti-SARS-CoV-2 antibody molecules or binding fragments thereof. The present disclosure further relates to nucleic acids encoding the antibody molecules or binding fragments thereof, expression vectors, host cells and methods for making the antibody molecules or binding fragments thereof. Pharmaceutical compositions comprising the antibody molecules or binding fragments thereof are also provided. The anti-SARS-CoV-2 antibody molecules or binding fragments thereof of the present disclosure can be used (alone or in combination with other agents or therapeutic modalities) to treat or prevent a SARS- CoV-2 infection and/or a SARS-CoV-2 associated disorder. Thus, the present disclosure further relates to anti-SARS-CoV-2 antibody molecules or binding fragments thereof, or pharmaceutical compositions comprising anti-SARS-CoV-2 antibody molecules or binding fragments thereof, for use in treatment or prevention of a SARS-CoV-2 infection and/or a SARS-CoV-2 associated disorder. Diagnostic compositions comprising the antibody molecules or binding fragments thereof are also provided.

BACKGROUND

Coronavirus disease 2019 (COVID-19) is caused by a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is spreading as a pandemic and is causing a major distress to the health care systems worldwide. Infection with SARS-CoV-2 is associated with a relatively high hospitalisation and mortality rate. As of now no effective disease modifying therapy or vaccine is available.

In view of the ongoing need for improved strategies for a prophylactic or curative therapy, new compositions for neutralizing SARS-CoV-2 activity are highly desirable. SUMMARY

In one aspect, the present disclosure relates to an anti-SARS-CoV-2 antibody molecule or an anti-SARS-CoV-2 binding fragment thereof.

Structural properties

In some embodiments, the present disclosure relates to an anti-SARS-CoV-2 antibody molecule or an anti-SARS-CoV-2 binding fragment thereof, wherein the antibody molecule or binding fragment comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all of the CDRs) from a heavy chain variable region (VH) and/or a light chain variable region (VL) comprising an amino acid sequence shown in Table 6, wherein one or more of the CDRs (or collectively all of the CDRs) may have one, two, three, four, five, six or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions), insertions or deletions, relative to an amino acid sequence shown in Table 6.

In some embodiments, the present disclosure relates to an anti-SARS-CoV-2 antibody molecule or an anti-SARS-CoV-2 binding fragment thereof, comprising: a heavy chain variable region (VH) comprising one, two, or three of: a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 17 or a sequence having one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions or deletions, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 18 or a sequence having one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions or deletions, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 19 or a sequence having one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions or deletions; and/or a light chain variable region (VL) comprising one, two, or three of: a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 20 or a sequence having one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions or deletions, a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 21 or a sequence having one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions or deletions, and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 22 or a sequence having one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), insertions or deletions.

In some embodiments, the present disclosure relates to an anti-SARS-CoV-2 antibody molecule or an anti-SARS-CoV-2 binding fragment thereof comprising: a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 19, or a sequence having one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions); and/or a light chain variable region (VL) comprising a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 22, or a sequence having one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions).

In some embodiments, the present disclosure relates to an anti-SARS-CoV-2 antibody molecule or an anti-SARS-CoV-2 binding fragment thereof, comprising: a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 17 or a sequence having one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 18 or a sequence having one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 19 or a sequence having one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions); and/or a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 20 or a sequence having one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 21 or a sequence having one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions), and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 22 or a sequence having one, two, three, or four amino acid substitutions (e.g., conservative amino acid substitutions).

In some embodiments, the present disclosure relates to an anti-SARS-CoV-2 antibody molecule or an anti-SARS-CoV-2 binding fragment thereof, comprising: a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1 ) amino acid sequence of SEQ ID NO: 17 or a sequence having one or two amino acid substitutions, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 18 or a sequence having one or two amino acid substitutions, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 19 or a sequence having one or two amino acid substitutions; and a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 20 or a sequence having one or two amino acid substitutions, a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 21 or a sequence having one or two amino acid substitutions, and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 22 or a sequence having one or two amino acid substitutions.

In some embodiments, the anti-SARS-CoV-2 antibody molecule or an anti- SARS-CoV-2 binding fragment thereof comprises: a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 17, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 18, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 19; and a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 20, a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 21, and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 22, wherein one, two, three, four, five or six amino acids within a CDR have been inserted, deleted or substituted.

In some embodiments, the anti-SARS-CoV-2 antibody molecule or an anti- SARS-CoV-2 binding fragment thereof comprises: a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 17, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 18, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 19; and a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 20, a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 21, and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 22, wherein one, two, three, or four amino acids within a CDR have been inserted, deleted or substituted.

In some embodiments, the anti-SARS-CoV-2 antibody molecule or an anti- SARS-CoV-2 binding fragment thereof comprises: a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 17, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 18, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 19; and a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 20, a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 21, and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 22, wherein one or two amino acids within a CDR have been inserted, deleted or substituted.

In some embodiments, the anti-SARS-CoV-2 antibody molecule or an anti- SARS-CoV-2 binding fragment thereof comprises: a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 17, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 18, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 19; and a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 20, a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 21, and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 22.

In some embodiments, the anti-SARS-CoV-2 antibody molecule or an anti- SARS-CoV-2 binding fragment thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 23, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 23.

In some embodiments, the anti-SARS-CoV-2 antibody molecule or an anti- SARS-CoV-2 binding fragment thereof comprises a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 24, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 24. In some embodiments, the anti-SARS-CoV-2 antibody molecule or an anti- SARS-CoV-2 binding fragment thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 23, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 23; and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 24, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 24.

In some embodiments, the anti-SARS-CoV-2 antibody molecule or an anti- SARS-CoV-2 binding fragment thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 23, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 24.

Functional properties

In some embodiments, the anti-SARS-CoV-2 antibody molecule or an anti- SARS-CoV-2 binding fragment thereof comprises one or more (e.g., 2, 3, 4, 5 or 6) of the following properties:

(i) binds to SARS-CoV-2 Spike RBD with a EC50 of less than about 10 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.19 nM, 0.18 nM, 0.17 nM, 0.16 nM, 0.15 nM, 0.14 nM, 0.13 nM, 0.12 nM, 0.11 nM, 0.10 nM, 0.09 nM, 0.08 nM, 0.07 nM, 0.06 nM, or 0.05 nM, e.g., when the antibody molecule or binding fragment thereof is tested as a bivalent molecule using ELISA, e.g., as described in Example 2;

(ii) does not bind to SARS-CoV-1 Spike RBD;

(iii) does not bind to MERS-CoV-1 Spike RBD;

(iv) neutralizes D614G variant of SARS-CoV-2 Wuhan strain in pseudovirus assay, e.g., as described in Example 5;

(v) blocks huACE2 receptor binding to SARS-CoV-2 Spike RBD;

(vi) neutralizes D614G variant of SARS-CoV-2 Wuhan strain in pseudovirus assay after nebulization, e.g., as described in Example 9.

In one aspect, the present disclosure relates to an antibody molecule or a binding fragment thereof that competes for binding to SARS-CoV-2 Spike RBD with an antibody molecule or a binding fragment thereof described herein. In some embodiments, the present disclosure relates to an antibody molecule or a binding fragment thereof that competes for binding to SARS-CoV-2 Spike RBD with an antibody molecule or a binding fragment thereof that comprises a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 17, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 18, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 19; and a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 20, a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 21 , and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 22.

In some embodiments, the present disclosure relates to an antibody molecule or a binding fragment thereof that competes for binding to SARS-CoV-2 Spike RBD with an antibody molecule or a binding fragment thereof that comprises (i) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 23, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 24.

In one aspect, the present disclosure relates to a pharmaceutical composition comprising the antibody molecule or binding fragment thereof described herein and a pharmaceutically acceptable carrier, excipient or stabilizer. In some embodiments, the pharmaceutical composition is an inhalable pharmaceutical composition.

In one aspect, the present disclosure relates to anti-SARS-CoV-2 antibody molecules or binding fragments thereof described herein, or pharmaceutical compositions comprising anti-SARS-CoV-2 antibody molecules or binding fragments thereof described herein, for use in the treatment or prevention of a SARS-CoV-2 infection and/or a SARS-CoV-2 associated disorder. In some embodiments, the present disclosure relates to anti-SARS-CoV-2 antibody molecules or binding fragments thereof described herein, or pharmaceutical compositions comprising anti-SARS-CoV-2 antibody molecules or binding fragments thereof described herein, for use in the treatment or prevention of a SARS-CoV-2 infection and/or a SARS-CoV-2 associated disorder by inhalation. In some embodiments, the SARS- CoV-2 associated disorder is selected from the group consisting of respiratory illnesses, such as sore throat, cough, shortness of breath, and chest pain; high temperature including fever; pneumonia; headache; gastrointestinal illnesses such as nausea, diarrhea, vomiting, and muscle pain; fatigue; and neurological manifestations such as sudden loss of sense of smell and/or taste, encephalitis, other encephalopathias, and Guillain-Barre syndrome. In one aspect, the present disclosure relates to a nucleic acid encoding the antibody heavy and/or light chain variable region of the antibody molecule or binding fragment thereof described herein.

In one aspect, the present disclosure relates to an expression vector comprising the nucleic acid described herein.

In one aspect, the present disclosure relates to a host cell comprising the nucleic acid described herein or the expression vector described herein.

In one aspect, the present disclosure relates to a method of producing an antibody molecule, the method comprising culturing the host cell described herein under conditions suitable for gene expression.

In one aspect, the present disclosure relates to a diagnostic composition comprising the antibody molecule or binding fragment thereof described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1. Binding of anti-SARS-CoV-2 antibody to SARS-CoV-2 Spike RBD in ELISA. These Data were used to determine the EC50_E values by three-parameter analysis in GraphPad Prism Software.

Figure 2. Binding of anti-SARS-CoV-2 antibody was tested in three concentrations to SARS-CoV-2-RBD and to closely related SARS-CoV-1-RBD and MERS-CoV-1-RBD. Additionally, binding to irrelevant antigens such as Siglec-9 (S9), BK Virus VP1 (BKV-VP1), CMV pentameric complex (CMV) and Tetanus Toxoid (TT) or to no coated antigen (PBS) was evaluated. SARS-CoV-2 antibody selectively binds to SARS-CoV-2-RBD but not to other proteins. CR3022 on the other hand binds strongly to SARS-CoV-1-RBD but less strong to SARS-CoV-2- RBD. Control antibody 24C03 binds selectively to TT but not to the other antigens including SARS-CoV-2-RBD.

Figure 3. Binding of SARS-CoV-2 RBD and huACE2 to beads saturated with the antibodies (IgG) under evaluation. Presence of IgG, RBD and huACE2 on the beads was analysed by analytic flow cytometry. The location of the bead population indicates, if antibody and huACE2 are competing for the binding to RBD (lower, right quadrant; see anti-SARS-CoV-2 antibody), bind simultaneously (upper, right quadrant; see 13A09) or if antibody is not binding to RBD at all (lower, left quadrant; see unrelated control 24C03). CR3022 shows a partial competition. Bead populations shown correspond to single IgG-positive beads.

Figure 4. Anti-SARS-CoV-2 antibody and control antibodies were tested against two SARS-CoV-2 spike protein variants, i.e. the Wuhan wild-type variant and the more recent and dominant D614G variant. SARS-CoPsV-2 pseudoparticles (luciferase) displaying the Wuhan or D614G spike variant were used in neutralization assays on HEK293T cells stably expressing huACE2. No neutralization was observed for CR3022 and unrelated control 24C03. The anti- SARS-CoV-2 antibody shows superior neutralization over the positive control MM57. Data are graphed as percent neutralization relative to virus only (100%) and no virus (0%) infection controls. Data were analysed and IC50 values were determined using the “[Inhibitor] vs. normalized response -- Variable slope” fitting model of GraphPad Prism 8. Symbols shown are mean of triplicates and error bars are SD.

Figure 5. Anti-SARS-CoV-2 antibody and control antibody were tested for capability to neutralize SARS-CoV-2 virus in plaque assay. Data are depicted as percent neutralization relative to average amount of plaques in negative control (100%) and no plaques visible (0%). Data were analysed and IC50 values were determined using the “[Inhibitor] vs. response -- Variable slope” fitting model of GraphPad Prism 8. Symbols shown are mean of triplicates and error bars are SD.

Figure 6. 42C06 in vivo efficacy was tested in treatment and prophylaxis of SARS-CoV-2 infection in the golden Syrian hamster model. Animals were dosed with antibody either one day before (Prophylactic) or one day after (Therapy) challenge with SARS-CoV-2. Impact of 42C06 on weight loss as a clinical marker for disease burden in the prophylaxis and treatment settings are shown over time.

Figure 7. 42C06 antiviral activity as determined by SARS-CoV-2 pseudovirus neutralization after nebulization of the antibody using a mesh nebulizer (after) compared to an aliquot of the antibody prior to nebulization (prior) and a reference aliquot (GMP1). 24C03 is an irrelevant antibody used as negative control for the neutralization assay.

DETAILED DESCRIPTION

The present invention as illustratively described in the following may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. The present invention will be described with respect to particular embodiments and with reference to certain figures but the invention is not limited thereto but only by the claims.

Where the term “comprising” is used in the present description and claims, it does not exclude other elements. For the purposes of the present invention, the term “consisting of is considered to be a preferred embodiment of the term “comprising of. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also to be understood to disclose a group, which preferably consists only of these embodiments.

Where an indefinite or definite article is used when referring to a singular noun, e.g. “a”, “an” or “the”, this includes a plural of that noun unless something else is specifically stated. The terms “about” or “approximately” in the context of the present invention denote an interval of accuracy that the person skilled in the art will understand to still ensure the technical effect of the feature in question. The term indicates deviation from the indicated numerical value of ±20%, preferably ±10%, and more preferably of ±5%.

Technical terms are used in their common meaning. If a specific meaning is conveyed to certain terms, definitions of terms will be given in the following in the context of which the terms are used.

Certain aspects of the present disclosure are based, at least in part, on the identification of anti-SARS-CoV-2 antibody molecules or binding fragments thereof that bind to and neutralize SARS-CoV-2.

Administration of SARS-CoV-2-neutralising recombinant monoclonal antibodies as a prophylactic or curative therapy may be an avenue to meet the medical need in the current pandemic and the post pandemic era. For instance, it was found recently that blood plasma from convalescent donors may have a beneficial clinical effect in COVID-19 patients (Duan et al., Proc Natl Acad Sci U S A 2020, 117(17):9490- 9496; and Shen et al., JAMA 2020, 323(16): 1582-1589).

In a preferred embodiment, the anti-SARS-CoV-2 antibody molecules or binding fragments thereof neutralize SARS-CoV-2.

As mentioned above, the present disclosure considers anti-SARS-CoV-2 antibody molecules or binding fragments thereof. A full-length antibody includes a constant domain and a variable domain. The constant region need not be present in an antigen-binding fragment of an antibody.

Binding fragments may thus include portions of an intact full-length antibody, such as an antigen binding or variable region of the complete antibody. Examples of antibody fragments include Fab, F(ab')2, Id and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv); multispecific antibody fragments such as bispecific, trispecific, and multispecific antibodies (e.g., diabodies, triabodies, tetrabodies); minibodies; chelating recombinant antibodies; tribodies or bibodies; intrabodies; nanobodies; small modular immunopharmaceuticals (SMIP), binding-domain immunoglobulin fusion proteins; camelized antibodies; VH H containing antibodies; and any other polypeptides formed from antibody fragments. The skilled person is aware that the antigen binding function of an antibody can be performed by fragments of a full-length antibody.

Disclosed herein are polypeptides having the sequences specified, or sequences substantially identical or similar thereto, e.g. sequences having at least about 85%, 90%, 95%, or 99% sequence identity to the sequence specified.

The determination of percent identity between two sequences is preferably accomplished using the mathematical algorithm of Karlin and Altschul (1993) Proc. Natl. Acad. Sci USA 90: 5873-5877. Such an algorithm is incorporated into the BLASTp (Protein BLAST) program of Altschul et al. (1990) J. Mol. Biol. 215: 403- 410 available at NCBI (https://blast.ncbi.nlm.nih.gov/). The determination of percent identity may be performed with the standard parameters of the BLASTp program.

For the general parameters, the “Max Target Sequences” box may be set to 100, the “Short queries” box may be ticked, the “Expect threshold” box may be set to 10, the “Word Size” box may be set to “3” and the “Max matches in a query range” may be set to “0”. For the scoring parameters the “Matrix” box may be set to “BLOSUM62”, the “Gap Costs” Box may be set to “Existence: 11 Extension: 1”, the “Compositional adjustments” box may be set to “Conditional compositional score matrix adjustment”. For the Filters and Masking parameters the “Low complexity regions” box may not be ticked, the “Mask for lookup table only” box may not be ticked and the “Mask lower case letters” box may not be ticked.

According to the disclosure, a "conservative amino acid substitution" is an amino acid substitution in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g. , lysine, arginine, histidine), acidic side chains (e.g. , aspartic acid, glutamic acid), uncharged polar side chains (e.g. , glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g. , alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta- branched side chains (e.g. , threonine, valine, isoleucine) and aromatic side chains (e.g. , tyrosine, phenylalanine, tryptophan, histidine).

As mentioned, the disclosure also relates in some embodiments to a nucleic acid encoding antibody molecules or binding fragments thereof, vectors comprising such nucleic acids and host cells comprising such nucleic acids or vectors.

The antibody molecules or binding fragments thereof may be encoded by a single nucleic acid (e.g., a single nucleic acid comprising nucleotide sequences that encode the light and heavy chain polypeptides of the antibody), or by two or more separate nucleic acids, each of which encode a different part of the antibody molecule or antibody fragment. The nucleic acids may be DNA, cDNA, RNA and the like.

The nucleic acids described herein can be inserted into vectors. A “vector” is any molecule or composition that has the ability to carry a nucleic acid sequence into a suitable cell where synthesis of the encoded polypeptide can take place.

The present disclosure in some aspects further provides a host cell (e.g., an isolated or purified cell) comprising a nucleic acid or vector of the invention. The host cell can be any type of cell capable of being transformed with the nucleic acid or vector of the invention so as to produce a polypeptide encoded thereby.

The anti-SARS-CoV-2 antibody molecules or anti-SARS-CoV-2 binding fragments thereof can be formulated in compositions, especially pharmaceutical compositions. Such compositions comprise a therapeutically effective amount of an antibody or binding fragment thereof in admixture with a pharmaceutically acceptable carrier, excipient or stabilizer.

Further, the anti-SARS-CoV-2 antibody molecules or anti-SARS-CoV-2 binding fragments thereof and the pharmaceutical compositions as described herein can be administered in methods of treating or preventing a SARS-CoV-2 infection and/or a SARS-CoV-2 associated disorder. EXAMPLES

Introductory comments

SARS-CoV-2 Spike RBD (NCBI Reference Sequence: YP_009724390, Arg319- Phe541) has the following amino acid sequence (SEQ ID NO: 27):

RVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSA SFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDD FTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVE GFNCYFPLQSYGFQPTNGVGYQPYRWVLSFELLHAPATVCGPKKSTNLVKN KCV NF

SARS-CoV-1 Spike RBD (NCBI Reference Sequence: AAX16192.1, Arg306- Phe527) has the following amino acid sequence (SEQ ID NO: 28):

RVVPSGDVVRFPNITNLCPFGEVFNATKFPSVYAWERKKISNCVADYSVLYNS

TFFSTFKCYGVSATKLNDLCFSNVYADSFVVKGDDVRQIAPGQTGVIADYNYKLPD

DFMGCVLAWNTRNIDATSTGNYNYKYRYLRHGKLRPFERDISNVPFSPDGKPCTP

PALNCYWPLNDYGFYTTTGIGYQPYRWVLSFELLNAPATVCGPKLSTDLIKNQCV

NF

MERS-CoV-1 Spike RBD (NCBI Reference Sequence: AFS88936.1 , Glu367- Tyr606 ) has the following amino acid sequence (SEQ ID NO: 29):

EAKPSGSVVEQAEGVECDFSPLLSGTPPQVYNFKRLVFTNCNYNLTKLLSLFS

VNDFTCSQISPAAIASNCYSSLILDYFSYPLSMKSDLSVSSAGPISQFNYKQSFSNP

TCLILATVPHNLTTITKPLKYSYINKCSRLLSDDRTEVPQLVNANQYSPCVSIVPSTV

WEDGDYYRKQLSPLEGGGWLVASGSTVAMTEQLQMGFGITVQYGTDTNSVCPKL

EFANDTKIASQLGNCVEY huACE2 receptor (NCBI Reference Sequence: NP_001358344.1) has the following amino acid sequence (SEQ ID NO: 30):

MSSSSWLLLSLVAVTAAQSTIEEQAKTFLDKFNHEAEDLFYQSSLASWNYNTNITE

ENVQNMNNAGDKWSAFLKEQSTLAQMYPLQEIQNLTVKLQLQALQQNGSSVLSE

DKSKRLNTILNTMSTIYSTGKVCNPDNPQECLLLEPGLNEIMANSLDYNERLWAWE

SWRSEVGKQLRPLYEEYWLKNEMARANHYEDYGDYWRGDYEVNGVDGYDYSR

GQLIEDVEHTFEEIKPLYEHLHAYVRAKLMNAYPSYISPIGCLPAHLLGDMWGRFW

TNLYSLTVPFGQKPNIDVTDAMVDQAWDAQRIFKEAEKFFVSVGLPNMTQGFWEN

SMLTDPGNVQKAVCHPTAWDLGKGDFRILMCTKVTMDDFLTAHHEMGHIQYDMA

YAAQPFLLRNGANEGFHEAVGEIMSLSAATPKHLKSIGLLSPDFQEDNETEINFLLK

QALTIVGTLPFTYMLEKWRWMVFKGEIPKDQWMKKWWEMKREIVGVVEPVPHDE

TYCDPASLFHVSNDYSFIRYYTRTLYQFQFQEALCQAAKHEGPLHKCDISNSTEAG QKLFNMLRLGKSEPWTLALENWGAKNMNVRPLLNYFEPLFTWLKDQNKNSFVG WSTDWSPYADQSIKVRISLKSALGDKAYEWNDNEMYLFRSSVAYAM RQYFLKVKN QMILFGEEDVRVANLKPRISFNFFVTAPKNVSDIIPRTEVEKAIRMSRSRINDAFRLN DNSLEFLGIQPTLGPPNQPPVSIWLIVFGWMGVIVVGIVILIFTGIRDRKKKNKARSG ENPYASIDISKGENNPGFQNTDDVQTSF

Preparation of SARS-CoV-2 Spike RBD

SARS-CoV-2 Spike RBD (aa319-541 , linker and tag) was ordered as gene synthesis construct, cloned, expressed in 293F cells and purified in-house. If needed, it was labeled fluorescently or biotinylated for FACS or ELISA experiments using Lightning-link® kits (Lightning-Link® R-Phycoerythrin Conjugation Kit, Expedeon, #703-0030; Lightning-Link® Allophycocyanin (APC) Conjugation Kit, Expedeon, #705-0030; Lightning-link rapid biotin type A labelling kit, Expedeon, #370-0030). The sequence shown in Table 1 below was expressed using a signal peptide containing vector.

Table 1 - Amino acid sequence and DNA sequence of SARS-CoV-2 Spike RBD

Preparation of human ACE2 construct

The human ACE2 receptor was cloned as extracellular domain (aa1-742) with its original signal peptide and fused C-terminally to a rabbit Fc domain. The construct was ordered as gene synthesis, expressed and purified in FIEK293F cells. If needed, it was labeled fluorescently for FACS experiments using Lightning-link® kits (Lightning-link® Rapid Alexa Fluor® 647-R labelling kit, Expedeon, #336-0030). The amino acid sequence and DNA sequence of the human ACE2 construct are shown in Table 2 below.

Table 2 - Amino acid sequence and DNA sequence of human ACE2 construct

Preparation of Pseudotyped SARS-CoV-2 (SARS-CoPsV-2)

Lentivirus-based pseudo-typed virus particles with SARS-CoV-2 Spike protein or a Spike protein mutant, replacing the VSV-G gene, were cloned and produced in- house. In order to increase infection efficiency, the SARS-CoV-2 spike protein was modified by a deletion of the furin cleavage site and by a C-terminal truncation of 17 amino acids. As a reporter of infection, a transfer vector encoding a constitutively expressed, secreted luciferase was co-transfected during production of pseudo- typed virus batches. Luciferase secreted into the virus-containing supernatant during virus production was removed by precipitating and washing virus particles using PEG-it™ Virus Precipitation Solution (System Biosciences, #LV825A-1).

Two types of pseudovirus were produced: The Wuhan-wild-type variant and the more recent and dominant D614G variant. The amino acid sequence and DNA sequence of the SARS-CoPsV-2 Spike of the Wuhan-wild-type strain are shown in Table 3 below. The D614G variant is based on this construct.

Table 3 - Amino acid sequence and DNA sequences of SARS-CoPsV-2 Spike

Comparative antibodies

The antibody CR3022 (WO 2005/012360) was described as a neutralizer of SARS- CoV-1 . This antibody is cross-reactive with SARS-CoV-2 Spike protein (binds also to SARS-CoV-2 Spike) and thus was used as a positive control in binding studies (e.g. Example 3). CR3022 does not display neutralization of SARS-CoV-2 (e.g. Example 5). This antibody was produced in-house, the amino acid sequences for comparative antibody CR3022 are summarized in Table 4 below.

Table 4 - Amino acid sequences for comparative antibody CR3022 (WO 2005/012360)

The comparative antibodies REGN 10933 and REGN 10987 were described as neutralizers of SARS-CoV-2 (US 10 787 501 B1). The antibodies REGN 10933 and REGN 10987 were produced in-house, the amino acid sequences for antibodies REGN 10933 and REGN 10987 are summarized in Table 5 below. REGN-CoV-2 is a 1 :1 mixture of REGN 10933 and REGN 10987.

Table 5 - Amino acid sequences for comparative antibodies REGN 10933 and REGN 10987

Negative control 24C03 is an antibody derived from a healthy human donor and is directed against an unrelated antigen. The variable fragments were fused to the identical constant domains of IgG as described for CR3022.

As reference for pseudovirus neutralization assays a mouse monoclonal antibody MM57 was used. This antibody was purchased from Sino Biologicals (order number 40592-MM57). The sequence is not publicly available.

Antibody discovery

Example 1

Peripheral blood memory B cells from two human donors with positive SARS- CoV-2 test (either virus or serological) were pooled. The human donors were tested positive the first time in March, 2020 and April, 2020, respectively. Blood was drawn one month and 24 days later, respectively. Both human donors showed light symptoms and received no treatment. Both were symptom-free at blood-take.

Isolated memory B cells were used to prepare antibody repertoire expression libraries by cloning the immunoglobulin light chain and heavy chain variable regions into an expression cassette providing the human immunoglobulin constant heavy region combined with a transmembrane domain derived from human CD8 to allow for mammalian cell display of the antibodies. Screening of the antibody libraries was performed after transduction of the library in HEK 293T cells by antigen-specific sorting using fluorescently labelled SARS-CoV-2 Spike RBD. This sort yielded RBD- specific-antibody-expressing HEK cell clones. Clone specificity was confirmed in analytical FACS, testing for high-affinity binding of cell-membrane expressed antibodies to purified SARS-CoV-2 Spike RBD protein and simultaneously absence of RBD-binding to purified huACE2. It was speculated that blocking ACE2 binding by an antibody would increase the chance of finding neutralizing antibodies. Antibody clones positive for RBD binding and negative for huACE2 binding were sequenced and sub-cloned into expression vectors for soluble antibody expression and expressed after transient transfection in HEK 293F. Antibodies were then purified via Protein A for characterization in the various assays including SARS-CoPsV-2 and SARS CoV-2 neutralization. Table 6 - Amino acid sequences for anti-SARS-CoV-2 antibody 42C06:

Assays

Example 2 - Binding to SARS-CoV-2 Spike RBD in indirect ELISA Material and methods

The binding of anti-SARS-CoV-2 antibody to SARS-CoV-2 Spike RBD was analyzed by indirect ELISA. Briefly, Costar® Assay Plate 96 well, half-area, high binding plates (Corning Inc. #3690) were coated with 30pl/well 2pg/ml Streptavidin (Sigma Aldrich 85878-1 MG) in carbonate buffer (Sigma Aldrich C3041-100CAP) overnight at 4°C. Next morning, plate was blocked using 5% skim milk powder (Rapilait, Migros #7610200017598) diluted in PBS. After a wash step with PBS 0.05% Tween20 (AppliChem, A4974) plates were incubated with 30pl/well 2pg/ml RBD-biotin in PBS 0.5% skim milk powder. After 2.5 h plates were washed with PBS 0.05% Tween20 (AppliChem, A4974). Antibodies were serially diluted in PBS with 0.5% skim milk powder and allowed to bind Streptavidin/antigen-coated plates for 1 h. Plates were washed with PBS 0.05% Tween20 (AppliChem, A4974) and then incubated with secondary antibody (HRP-conjugated goat anti-human IgG, Jackson- Immuno #109-035-098) diluted 1 :10’OOO in PBS with 0.5% skim milk powder for 30min. Plates were washed three times with PBS 0.05% Tween20. Reaction was developed using 30pl/well TMB liquid substrate (Sigma-Aldrich, #T0440) and reaction was stopped after 3min by addition of 15pl/well H2SO4. Absorbance was detected at 450 nm (Tecan, CM INFINITE MONO 200). Data were fitted and apparent EC50 ELISA values (EC50_E) were determined by three-parameter analysis in GraphPad Prism (GraphPad Software).

Results

The antibody 42C06 showed strong and selective binding to SARS-CoV-2 Spike RBD (Figure 1, EC50_e: 0.046 nM (95% C: 0.03 nM - 0.06 nM)). Example 3 - Cross-reactivity with SARS-CoV-1 Spike RBD and MERS-CoV-1 Spike RBD in ELISA

Material and methods

Different antigens were coated directly to ELISA plate. A comparison was performed between MERS-CoV-1 Spike RBD (Sino Biological, catalog number 40071 -V08B1), SARS-CoV-1 Spike RBD (Sino Biological, catalog number 40150- V08B2), SARS-CoV-2 Spike RBD (in-house production) as well as four unrelated antigens. Assayed antibodies were added in three dilutions: 0.67 nM, 6.7 nM and 67 nM. Bound antibodies were detected with anti-human IgG.

Results

As illustrated in Figure 2, the antibody 42C06 binds specifically to SARS-CoV-2 Spike RBD. No cross-reactivity to other coronavirus spike proteins or unrelated antigens was detectable. As expected, CR3022 shows cross-reactivity and binds to SARS-CoV-1 Spike RBD and SARS CoV-2 Spike RBD. Negative control 24C03 binds to its antigen. Coating of all antigens was confirmed with control antibody (anti-his, data not shown).

Example 4 - Cytometer assay for huACE2 competition Material and methods

Antibodies under evaluation were immobilized on polystyrene anti-hu IgG (H&L) beads (Spherotech, #H UP-60-5). Next, SARS CoV-2 Spike RBD (in house produced and labelled with R-Phycoerythrin, PE) at 0.5 pg/ml (~20 nM), huACE2 (in house produced and labelled with AlexaFluor® 647) at 0.9 pg/ml (~8 nM) and Brilliant Violet 421 ™ anti-human IgG Fc Antibody (Biolegend, #410704) at 1 :200 dilution were added to the beads and amount of fluorescent signals of SARS-CoV-2 Spike RBD and huACE2 on the antibody-coated beads were analyzed in analytic FACS. If the antibody on the beads blocks binding of huACE2 to RBD, only RBD is detectable (shift to the right). If the antibody is not competing with huACE2 for binding to RBD, both signals will be detected (shift to the right and up). For the analysis of RBD- and huACE2- binding only single IgG-positive beads were used. Data was analysed and figure was prepared using FlowJo 10.7.1 (Becton Dickinson & Company).

Results

As illustrated in Figure 3, the antibody 42C06 fully competes with huACE2 for binding to SARS-CoV-2 Spike RBD. Negative control 24C03 does not bind RBD and thus binding of huACE2 is also absent. CR3022 only partially competes with huACE2 for binding to SARS-CoV-2 Spike RBD. 13A09 does not block huACE2 binding to RBD and thus both huACE2 and RBD are bound to the beads.

Example 5 - Neutralization of SARS-CoPsV-2 Wuhan strain and D614G in pseudovirus assay

Material and methods

In 96-well cell culture plates HEK293T cells stably expressing full length huACE2 (aa1-805) were seeded and left to adhere. Serial antibody dilutions were prepared and added to the adherent cells. Directly after, SARS-CoPsV-2 pseudoparticles carrying a secreted luciferase reporter gene was added and the mix was incubated for 3 days. After 3 days, the amount of secreted luciferase in the supernatant was determined by luciferase assay (NanoGlo® Luciferase Assay, Promega, #N1130). This allows for a qualitative analysis of infected cells and at which antibody concentration all viral particles could be neutralized. Two types of pseudovirus (wt- Wuhan-variant and the more recent and dominant D614G variant) were tested. Data were analysed and IC50 values were determined using the “[Inhibitor] vs. normalized response -- Variable slope” fitting model of GraphPad Prism 8.

Results

The antibody 42C06 neutralizes SARS-CoPsV-2 pseudoparticles (Wuhan and D614G variant) with an IC50 in the low pM range (Table 7 below) and reaches complete neutralization (Figure 4). Comparative antibody MM57 also reaches complete inhibition, but displays a one log higher IC50 (low nM). SARS-CoV-2 RBD binder CR3022 and negative control 24C03 do not display neutralization of SARS- CoPsV-2 pseudoparticles.

Table 7 - SARS-CoPsV-2 neutralization was assessed as described in Figure 4. IC50 (nM) values are shown for each mAb tested. No dose-dependent neutralization was observed for SARS-CoV-2 RBD binder CR3022 and negative control 24C03 (N/A).

Example 6 - Neutralization of SARS-CoV-2 (clinical isolate) in plaque assay Material and methods

At day 0, Vero E6 cells were seeded with a concentration of 1^*10⁵ cells/well in 300 pi medium. At day 1 , the antibodies were serially diluted using a 1:3.16 dilution starting with 1 or 10 pg/ml in a total volume of 300 mI/well. Subsequently, the antibodies were mixed with SARS-CoV-2 virus (1800 PFU/ml) and incubated for 1h at 37°C. Then, media from the Vero E6 cells was removed and the cells were incubated with the antibody-virus mix for 1h. Afterwards, the inoculum was aspirated and the cells were overlaid with 300 mI of 1.5% methyl-cellulose and incubated for 3 days. Then, the plates were fixed with 6% Formaldehyde for 1 h followed by a 1 h staining with 300 mI crystal violet/well. After 2-3 day, the plaques were counted manually under an inverted light microscope.

Results

Antibody 42C06 is able to completely neutralize SARS-CoV-2 infection of Vero E6 cells. This results in an IC50 value of 3.68E-11 M (95%CI: 2.84E-11 - 4.77E-11 M).

Example 7 - In vivo efficacy in the Syrian hamster model of SARS-CoV-2 infection

Material and methods

A total of 56 Golden Syrian hamsters, 36 male and 20 female, weighting between 80g and 130g were used in the study. Animals were weighed prior to the start of the study and randomly distributed in the different cohorts. Each of the 5 prophylactic cohorts contained 4 male and 4 female hamsters. Each of the four therapeutic cohort contained 4 male hamsters. The animals were monitored twice daily at least 6 hours apart during the study period. Body weights were measured once daily during the study period. Antibodies were diluted in PBS and dosed at the indicated concentrations in a constant volume of 500mI through intraperitoneal (IP) injection either one day before challenge with virus (“prophylaxis”) or one day after challenging with virus (“therapy”). Animals were challenged at day 0 with SARS- CoV-2 by administration of 0.05ml of a 1 :10 dilution of OWS stock (CAT#- NR- 53780), into each nostril.

Results

As a sign of infection, all animals showed weight-loss after challenge with SARS- CoV-2 (Figure 6). In the prophylactic treatment arm, injection of 42C06 one day before virus challenge completely prevented weight loss at all doses tested including the lowest dose of 1 mg/kg body weight. Weight gain over time was observed for the doses 5mg/kg, 10mg/kg and 25mg/kg. Weight gain was most pronounced for the two highest doses tested.

In the therapeutic setting, the antibody was injected 1 day after virus challenge. A stabilization of weight loss was observed 2days after antibody injection for the 10mg/kg and the 50mg/kg doses. 6 days after injection, all animals, including those treated with the lowest dose started to gain weight, whereas the placebo group continued to lose weight until day 7.

Compared with the efficacy of REGN-CoV-2 (i.e. REGN 10933 + REGN 10987; efficacy is described in Baum et al., Science. 2020 Nov 27;370(6520):1110-1115) a higher delta in the recovery from the weight loss was observed with 42C06: At the dose of 50mg/kg more than 10% of weight gain was observed under 42C06 treatment (Figure 6) whereas for REGN-CoV-2, less than 10% of weight gain was observed (see Figure 3B of Baum et al., Science. 2020 Nov 27;370(6520):1110- 1115).

Example 8 - Neutralization of D614G variant of SARS-CoPsV-2 Wuhan strain in pseudovirus assay (antibodies 42C06, REGN 10933 and REGN 10987)

Material and methods

In 96-well cell culture plates FIEK293T cells stably expressing full length huACE2 (aa1-805) were seeded and left to adhere. Serial antibody dilutions were prepared and added to the adherent cells (42C06 was used as a GMP-conform production batch). Directly after, SARS-CoPsV-2 pseudoparticles (D614G variant of SARS- CoPsV-2 Wuhan strain) carrying a secreted luciferase reporter gene was added and the mix was incubated for 3 days. After 3 days, the amount of secreted luciferase in the supernatant was determined by luciferase assay (NanoGlo® Luciferase Assay, Promega, #N1130). This allows for a qualitative analysis of infected cells and at which antibody concentration all viral particles could be neutralized. Data were analysed and IC50 values were determined using the “[Inhibitor] vs. normalized response -- Variable slope” fitting model of GraphPad Prism 8.

Results

The IC50 values are summarized in below Table 8. Table 8 - IC50 (nM) values are shown for each mAb tested.

Example 9 - Retention of neutralizing activity after nebulization of GMP1 material of antibody 42C06

Currently, all anti-infective antibodies are applied either intravenously or subcutaneously. The inhalation route would be more appropriate for therapeutic efficacy and for the ease of administration. However, for most antibodies stability and thus product integrity after nebulization is a major bottleneck (Mayor et al., Drug Deliv Transl Res. 2021 Aug; 11 (4): 1625-1633). As described below, antibody 42C06 can be readily nebulized and retains 100% of its efficacy.

Materials and Methods

Antibody 42C06 was used as GMP manufactured antibody at 50 mg/ml in 20 mM L- His, 82 mg/ml sucrose, 0.3 mg/ml polysorbate 20 pH 5.5. A post nebulization sample (“after”) was generated in a FOX® nebulizer (Vectura, Chippenham, UK) to determine the functional integrity after nebulization. Approximately 1 ml of formulation was nebulized and collected. An aliquot of the formulation was retained without nebulization (“prior”) as a control to measure any influence of the processes at the site of nebulization in comparison to a reference aliquot stored under controlled conditions at the site of the neutralization assay (“GMP1”). Pseudovirus neutralization experiments were performed with SARS-CoPsV-2 D614G strain as described in Example 5.

Results: 42C06 when used at its standard i.v. formulation can successfully be nebulized to over 90% using Vectura’s FOX® nebulizer platform (data not shown).

In addition, the nebulized antibody retains 100% of its protein integrity (data not shown) and 100% of its functionality in binding strength (data not shown). Moreover, the nebulized antibody retains 100% of its virus-neutralizing capacity (Table 9 and Figure 7). Table 9 - SARS-CoPsV-2 neutralization (SARS-CoPsV-2 D614G strain)

Claims

1. An anti-SARS-CoV-2 antibody molecule or an anti-SARS-CoV-2 binding fragment thereof comprising: a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 17 or a sequence having one or two amino acid substitutions, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 18 or a sequence having one or two amino acid substitutions, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 19 or a sequence having one or two amino acid substitutions; and a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 20 or a sequence having one or two amino acid substitutions, a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 21 or a sequence having one or two amino acid substitutions, and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 22 or a sequence having one or two amino acid substitutions.

2. The antibody molecule or binding fragment thereof of claim 1 , comprising: a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 17, a heavy chain complementarity determining region 2 (VHCDR2) amino acid sequence of SEQ ID NO: 18, and a heavy chain complementarity determining region 3 (VHCDR3) amino acid sequence of SEQ ID NO: 19; and a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 20, a light chain complementarity determining region 2 (VLCDR2) amino acid sequence of SEQ ID NO: 21 , and a light chain complementarity determining region 3 (VLCDR3) amino acid sequence of SEQ ID NO: 22.

3. The antibody molecule or binding fragment thereof of claims 1 or 2, comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 23, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 23, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 24, or an amino acid sequence having at least about 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO: 24.

4. The antibody molecule or binding fragment thereof of any one of claims 1 -3, comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 23, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 24.

5. The antibody molecule or binding fragment thereof of any one of claims 1 -4, comprising one or more one or more (e.g., 2, 3, 4, 5 or 6) of the following properties:

(ii) does not bind to SARS-CoV-1 Spike RBD;

(iii) does not bind to MERS-CoV-1 Spike RBD;

(v) blocks huACE2 receptor binding to SARS-CoV-2 Spike RBD;

6. An antibody molecule or a binding fragment thereof that competes for binding to SARS-CoV-2 Spike RBD with the antibody molecule or binding fragment thereof of any one of claims 1 -5.

7. A pharmaceutical composition comprising the antibody molecule or binding fragment thereof of any one of claims 1-6 and a pharmaceutically acceptable carrier, excipient or stabilizer.

8. An antibody molecule or binding fragment thereof according to any one of claims 1-6 or a pharmaceutical composition according to claim 7 for use in the treatment or prevention of a SARS-CoV-2 infection and/or a SARS-CoV-2 associated disorder.

9. A nucleic acid encoding the antibody heavy and/or light chain variable region of the antibody molecule or binding fragment thereof of any one of claims 1-6.

10. An expression vector comprising the nucleic acid of claim 9.

11. A host cell comprising the nucleic acid of claim 9 or the expression vector of claim 10.

12. A method of producing an antibody molecule, the method comprising culturing the host cell of claim 11 under conditions suitable for gene expression.

13. A diagnostic composition comprising the antibody molecule or binding fragment thereof of any one of claims 1 -6.