WO2022162012A2 - Anticorps ciblant sur un large spectre des coronavirus et leurs utilisations - Google Patents

Anticorps ciblant sur un large spectre des coronavirus et leurs utilisations Download PDF

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WO2022162012A2
WO2022162012A2 PCT/EP2022/051776 EP2022051776W WO2022162012A2 WO 2022162012 A2 WO2022162012 A2 WO 2022162012A2 EP 2022051776 W EP2022051776 W EP 2022051776W WO 2022162012 A2 WO2022162012 A2 WO 2022162012A2
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seq
cdr2
amino acid
chain cdr1
antibody
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WO2022162012A3 (fr
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Federica SALLUSTO
Antonio Lanzavecchia
Antonino Cassotta
Jun Siong LOW
Josipa JERAK
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Eidgenoessische Technische Hochschule Zurich ETHZ
Institute for Research in Biomedicine IRB
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Eidgenoessische Technische Hochschule Zurich ETHZ
Institute for Research in Biomedicine IRB
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C07K14/08—RNA viruses
    • C07K14/165—Coronaviridae, e.g. avian infectious bronchitis virus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—RNA viruses
    • C07K16/102—Coronaviridae (F)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—RNA viruses
    • C07K16/102—Coronaviridae (F)
    • C07K16/104—Severe acute respiratory syndrome coronavirus 2 [SARS‐CoV‐2]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/20011—Coronaviridae
    • C12N2770/20034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • the present invention relates to the field of antibodies against coronaviruses, in particular to antibodies binding to the spike (S) protein of coronaviruses, in particular of multiple alpha- and betacoronaviruses.
  • the present invention also relates to the use of such antibodies, e.g. in the treatment of coronavirus infection.
  • the present invention relates to recombinant (poly)peptides comprising the epitope to which the antibodies bind to, as well as its use, e.g. in vaccination.
  • Coronaviruses cause a number of pathological conditions in humans, including common cold, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease 2019 (COVID-19). Symptoms of coronavirus infections range from relatively harmless to severe symptoms. For example, infection with MERS CoV can kill more than 30% of infected humans. Major symptoms of coronavirus infection include symptoms of common cold, such as fever and a sore throat, as well as pneumonia and bronchitis. Other coronavirus-induced diseases have a unique pathogenesis, such as severe acute respiratory syndrome (SARS), including upper and lower respiratory tract infections.
  • SARS severe acute respiratory syndrome
  • MERS Middle East respiratory syndrome
  • COVID-19 coronavirus disease 2019
  • coronavirus SARS-CoV-2 spread rapidly around the world, leading to the COVID- 19 pandemic. Symptoms of COVID-19 are highly variable, ranging from none to severe illness and death. As of 8 January 2021 , more than 88 million cases have been confirmed, with more than 1 .89 million deaths attributed to COVID-19. The responses to the pandemic around the world have resulted in global social and economic disruption, including the largest global recession since the Great Depression. Recent reports of different variants of SARS-CoV-2 have raised concern about the impact and spreading of viral changes.
  • VOC- 202012/01 variant initially detected in the United Kingdom has meanwhile been detected in at least 40 other countries/territories/areas
  • the 501 Y.V2 variant initially detected in South African in at least six other countries/territories/areas.
  • human coronavirus OC43 HKU1
  • HKU1 human coronavirus HKU1
  • HKU-229E human coronavirus 229E
  • HoV-NL63 HoV-NL63
  • MERS-CoV Middle East respiratory syndrome-related coronavirus
  • SARS-CoV Severe acute respiratory syndrome coronavirus
  • SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2
  • coronavirus refers to any member of the subfamily Orthocoronavirinae of the family Coronaviridae, which includes the four genera, namely Alphacoronavirus, Betacoronavirus, Deltacoronavirus, and Gammacoronavirus.
  • human coronavirus 229E (HCoV-229E) and human coronavirus NL63 (HCoV-NL63) belong to alphacoronaviruses (a-CoV), human coronavirus OC43 (HCoV-OC43), human coronavirus HKU1 (HCoV-HKU1 ), Middle East respiratory syndrome- related coronavirus (MERS-CoV), Severe acute respiratory syndrome coronavirus (SARS-CoV) and Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belong to betacoronaviruses (P-CoV).
  • Coronaviruses are enveloped viruses having a viral envelope made up of a lipid bilayer in which the membrane (M), envelope (E) and spike (S) structural proteins are anchored.
  • the spike (S) proteins required for interaction with host cells. It forms trimers ("spikes") giving coronaviruses their characteristic shape.
  • the S protein mediates receptor binding and membrane fusion between the virus and host cell. Structurally, the S protein contains an S1 and S2 subunit, with the S1 subunit forming the "head” of the spike containing the receptor binding domain (RBD) and the S2 subunit forming the "stem", which anchors the spike in the viral envelope and which contains the fusion peptide (FP) for fusion with the host cell.
  • RBD receptor binding domain
  • Antibodies against coronaviruses such as SARS-CoV-2, represent a promising tool for combatting diseases caused by coronaviruses, such as COVID-19. They can be passively transferred into individuals before or after viral infection to prevent or treat disease.
  • casirivimab/imdevimab as well as the large majority of the anti-coronavirus antibodies currently in development bind to the receptor binding domain (RBD) of the spike protein, which is known to be more divergent.
  • RBD receptor binding domain
  • viral escape mutants can develop, which exhibit mutations in the RBD, thereby escaping the recognition of antibodies targeting the RBD (Greaney AJ, Starr TN, Gilchuk P, et al. Complete Mapping of Mutations to the SARS- CoV-2 Spike Receptor-Binding Domain that Escape Antibody Recognition [published online ahead of print, 2020 Nov 19], Cell Host Microbe. 2020; SI 931 -3128(20)30624-7.
  • the object of the present invention to provide antibodies that broadly target coronaviruses, in particular antibodies binding to different strains of coronaviruses, e.g. to various alpha- and betacoronaviruses.
  • composition “comprising” thus encompasses “including” as well as “consisting” e.g., a composition “comprising” X may consist exclusively of X or may include something additional e.g., X + Y.
  • the terms "a” and “an” and “the” and similar reference used in the context of describing the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
  • x means x + 10%, for example, x + 5%, or x + 7%, or x ⁇ 10%, or x ⁇ 12%, or x + 15%, or x ⁇ 20%.
  • disease as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
  • treatment of a subject or patient is intended to include prevention, prophylaxis, attenuation, amelioration and therapy.
  • subject or patient are used interchangeably herein to mean all mammals including humans. Examples of subjects include humans, cows, dogs, cats, horses, goats, sheep, pigs, and rabbits. In some embodiments, the patient is a human.
  • Doses are often expressed in relation to the bodyweight.
  • a dose which is expressed as [g, mg, or other unit]/kg (or g, mg etc.) usually refers to [g, mg, or other unit] "per kg (or g, mg etc.) bodyweight", even if the term “bodyweight” is not explicitly mentioned.
  • binding and similar reference usually means “specifically binding”, which does not encompass non-specific sticking.
  • the term "antibody” encompasses various forms of antibodies including, without being limited to, whole antibodies, antibody fragments (such as antigen binding fragments), human antibodies, chimeric antibodies, humanized antibodies, recombinant antibodies and genetically engineered antibodies (variant or mutant antibodies) as long as the characteristic properties according to the invention are retained.
  • the antibody is a human antibody.
  • the antibody is a monoclonal antibody.
  • the antibody may be a human monoclonal antibody.
  • antibody generally also includes antibody fragments. Fragments of the antibodies may retain the antigen-binding activity of the antibodies. Such fragments are referred to as "antigen-binding fragments". Antigen-binding fragments include, but are not limited to, single chain antibodies, Fab, Fab', F(ab')2 , Fv or scFv. Fragments of the antibodies can be obtained from the antibodies by methods that include digestion with enzymes, such as pepsin or papain, and/or by cleavage of disulfide bonds by chemical reduction.
  • enzymes such as pepsin or papain
  • fragments of the antibodies can be obtained by recombinant means, for example by cloning and expressing a part (fragment) of the sequences of the heavy and/or light chain.
  • the invention also encompasses single-chain Fv fragments (scFv) derived from the heavy and light chains of an antibody of the invention.
  • the invention includes a scFv comprising the CDRs from an antibody of the invention.
  • heavy or light chain monomers and dimers single domain heavy chain antibodies, single domain light chain antibodies, as well as single chain antibodies, e.g., single chain Fv in which the heavy and light chain variable domains are joined by a peptide linker.
  • Antibody fragments of the invention may be contained in a variety of structures known to the person skilled in the art.
  • the sequences of the invention may be a component of multispecific molecules in which the sequences of the invention target the epitopes of the invention and other regions of the molecule bind to other targets.
  • the specification, including the claims may, in some places, refer explicitly to antigen binding fragment(s), antibody fragment(s), variant(s) and/or derivative(s) of antibodies, it is understood that the term "antibody” includes all categories of antibodies, namely, antigen binding fragment(s), antibody fragment(s), variant(s) and derivative(s) of antibodies.
  • Human antibodies are well-known in the state of the art (van Dijk, M. A., and van de Winkel, J. G., Curr. Opin. Chem. Biol. 5 (2001 ) 368-374). Human antibodies can also be produced in transgenic animals (e.g., mice) that are capable, upon immunization, of producing a full repertoire or a selection of human antibodies in the absence of endogenous immunoglobulin production. Transfer of the human germ-line immunoglobulin gene array in such germ-line mutant mice will result in the production of human antibodies upon antigen challenge (see, e.g., Jakobovits, A., et al., Proc. Natl. Acad. Sci.
  • human monoclonal antibodies are also available for the preparation of human monoclonal antibodies (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); and Boerner, P., et al., J. Immunol. 147 (1991 ) 86-95).
  • human monoclonal antibodies are prepared by using improved EBV-B cell immortalization as described in Traggiai E, Becker S, Subbarao K, Kolesnikova L, Uematsu Y, Gismondo MR, Murphy BR, Rappuoli R, Lanzavecchia A. (2004): An efficient method to make human monoclonal antibodies from memory B cells: potent neutralization of SARS coronavirus. Nat Med.
  • variable region denotes each of the pair of light and heavy chains which is involved directly in binding the antibody to the antigen.
  • a human antibody comprises human variable region (VH/VL) sequences as well as human constant region sequences. It is understood that a human antibody may carry one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) mutations (mutated amino acids), in comparison to a corresponding human reference antibody occurring in nature. Such mutations may be introduced, for example, by site-directed mutagenesis known in the art.
  • one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) mutations may be introduced into the Fc region of the antibody, e.g. to modify its half-life, complement and/or Fc receptor binding functionalities.
  • one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) mutations may be introduced in the VH and/or VL sequences, e.g. to modify the antibody's binding to the antigen.
  • Antibodies of the invention can be of any isotype (e.g., IgA, IgG, IgM i.e. an a, y or p heavy chain).
  • the antibody is of the IgG type.
  • antibodies may be IgGI , lgG2, lgG3 or lgG4 subclass, for example IgGI .
  • Antibodies of the invention may have a K or a X light chain. In some embodiments, the antibody is of IgGI type and has a K light chain.
  • Antibodies according to the present invention may be provided in purified form. Typically, the antibody will be present in a composition that is substantially free of other polypeptides e.g., where less than 90% (by weight), usually less than 60% and more usually less than 50% of the composition is made up of other polypeptides.
  • Antibodies according to the present invention may be immunogenic in human and/or in non-human (or heterologous) hosts e.g., in mice.
  • the antibodies may have an idiotope that is immunogenic in non-human hosts, but not in a human host.
  • Antibodies of the invention for human use include those that cannot be easily isolated from hosts such as mice, goats, rabbits, rats, non-primate mammals, etc. and cannot generally be obtained by humanization or from xeno-mice.
  • neutralizing antibody is one that can neutralize, i.e., prevent, inhibit, reduce, impede or interfere with, the ability of a pathogen to initiate and/or perpetuate an infection in a host.
  • neutralizing antibody and “an antibody that neutralizes” or “antibodies that neutralize” are used interchangeably herein. These antibodies can be used alone, or in combination, as prophylactic or therapeutic agents upon appropriate formulation, in association with active vaccination, as a diagnostic tool, or as a production tool as described herein.
  • mutation relates to a change in the nucleic acid sequence and/or in the amino acid sequence in comparison to a reference sequence, e.g. a corresponding genomic sequence.
  • a mutation e.g. in comparison to a genomic sequence, may be, for example, a (naturally occurring) somatic mutation, a spontaneous mutation, an induced mutation, e.g. induced by enzymes, chemicals or radiation, or a mutation obtained by site- directed mutagenesis (molecular biology methods for making specific and intentional changes in the nucleic acid sequence and/or in the amino acid sequence).
  • mutation or “mutating” shall be understood to also include physically making a mutation, e.g.
  • a mutation includes substitution, deletion and insertion of one or more nucleotides or amino acids as well as inversion of several successive nucleotides or amino acids.
  • a mutation may be introduced into the nucleotide sequence encoding said amino acid sequence in order to express a (recombinant) mutated polypeptide.
  • a mutation may be achieved e.g., by altering, e.g., by site-directed mutagenesis, a codon of a nucleic acid molecule encoding one amino acid to result in a codon encoding a different amino acid, or by synthesizing a sequence variant, e.g., by knowing the nucleotide sequence of a nucleic acid molecule encoding a polypeptide and by designing the synthesis of a nucleic acid molecule comprising a nucleotide sequence encoding a variant of the polypeptide without the need for mutating one or more nucleotides of a nucleic acid molecule.
  • the present invention provides an (isolated) antibody, or an antigen-binding fragment thereof, which (specifically) binds to the spike (S) protein of different sarbecoviruses.
  • coronavirus refers to viruses of the subfamily Orthocoronavirinae, which belongs to the family Coronaviridae, a family of enveloped, positive-strand RNA viruses.
  • the subfamily Orthocoronavirinae includes four genera, namely, alphacoronavirus, betacoronavirus, gammacoronavirus and deltacoronavirus.
  • human coronavirus 229E also referred to herein as “229E”
  • human coronavirus NL63 also referred to herein as "NL63”
  • the genus of betacoronaviruses includes the subgenus of sarbecoviruses, which comprises the species severe acute respiratory syndrome (SARS)-related coronavirus.
  • SARS severe acute respiratory syndrome
  • This species includes the human infecting strains SARS-CoV-1 (also referred to herein as "SARS-CoV”) and SARS-CoV-2 (with its variants), as well as bat SARS-like coronavirus WIV-1 (also referred to as whether needWIV-1" or participatWIV1").
  • human infecting betacoronaviruses belong to the subgenus embecovirus, which includes, among others, the species human coronavirus HKU1 (also referred to herein as “F1KU1”) and the species betacoronavirus 1 including the humaninfecting strain human coronavirus OC43 (also referred to herein as "OC43”).
  • Another human infecting betacoronavirus is the species Middle East respiratory syndrome (MERS)-related coronavirus (also referred to herein as "MERS” or "MERS CoV”), which belong to the subgenus merbecovirus of betacoronaviruses.
  • MERS Middle East respiratory syndrome
  • the genus gammacoronavirus includes the subgenus igacovirus with the species avian coronavirus, also referred to as avian infectious bronchitis virus ("IBV").
  • the genus deltacoronavirus includes, for example, the subgenus buldecovirus with the species porcine deltacoronavirus (also referred to as "PdCV” or "(porcine) coronvirus HKU15").
  • the antibody, or antigen-binding fragment thereof, binding to the spike protein of different sarbecoviruses may bind, for example, to at least two different viruses of the group SARS- CoV-1 , SARS-CoV-2 and WIV-1 .
  • the antibody, or the antigen-binding fragment thereof binds to the spike (S) protein of SARS-CoV-1 and a SARS-CoV-2 virus.
  • the antibody, or the antigen-binding fragment thereof binds to the spike (S) protein of SARS-CoV-1 and WIV-1.
  • the antibody, or the antigenbinding fragment thereof binds to the spike (S) protein of SARS-CoV-2 and WIV-1.
  • the antibody, or the antigen-binding fragment thereof may bind to the spike (S) protein of SARS-CoV-1 , a SARS-CoV-2 virus and WIV-1.
  • S spike
  • SARS-CoV-1 spike protein of SARS-CoV-1
  • SARS-CoV-2 virus virus
  • WIV-1 WIV-1
  • pan-sarbecovirus antibodies target epitopes conserved among sarbecoviruses. Such antibodies targeting conserved epitopes are very likely to bind to different variants of sarbecoviruses, e.g. different variants of SARS-CoV-2.
  • the exemplified antibodies of the present invention CLM20_A7, CLM20_B8, CLM20_C9, CLM20_B8_UCA, CLM99_G12,
  • E7, CSC3_H1 , E371_F8, E2418_G12, E2121_B7, E1373__G3 and CSC3_H1_UCA bind to the spike protein of at least two different sarbecoviruses, in particular to SARS-CoV-1 and SARS-CoV-2.
  • the antibody, or the antigen-binding fragment thereof, binding to the spike (S) protein of different sarbecoviruses may comprise (i) heavy chain CDR1 , CDR2, and CDR3 sequences having at least 70% sequence identity with the amino acid sequences of SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 1 1 , respectively, and light chain CDR1 , CDR2, and CDR3 sequences having at least 70% sequence identity with the amino acid sequences of SEQ ID NO: 12, SEQ ID NO: 13 or 14, and SEQ ID NO: 15, respectively; or (ii) heavy chain CDR1 , CDR2, and CDR3 sequences having at least 70% sequence identity with the amino acid sequences of SEQ ID NO: 20, SEQ ID NO: 21 , and SEQ ID NO: 22, respectively, and light chain CDR1 , CDR2, and CDR3 sequences having at least 70% sequence identity with the
  • the antibody, or the antigen-binding fragment thereof, binding to the spike (S) protein of different sarbecovi ruses, such as to the spike (S) protein of SARS-CoV-1 and a SARS- CoV-2 virus may comprise (i) heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11 , respectively, and light chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 12, SEQ ID NO: 13 or 14, and SEQ ID NO: 15, respectively; or (ii) heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 20, SEQ ID NO: 21 , and SEQ ID NO: 22, respectively, and light chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 12, SEQ ID NO: 23 or 24, and SEQ ID NO: 25, respectively; or (iii) heavy chain CDR1 , CDR2, and C
  • the antibody, or the antigen-binding fragment thereof binds to the spike (S) protein of sarbecovi ruses and non-sarbecovirus betacoronaviruses.
  • the antibody, or the antigen-binding fragment thereof may bind to the spike (S) protein of sarbecoviruses and human-infecting non-sarbecovirus betacoronaviruses.
  • examples of human infecting non-sarbecovirus betacoronaviruses include HKU1 , OC43 and MERS coronavirus.
  • the antibody, or the antigen-binding fragment thereof binds to the spike (S) protein of HKU1 coronavirus, SARS-CoV-1 and SARS-CoV-2.
  • the exemplified antibodies of the present invention CLM20_A7, CLM20_B8, CLM20JZ9, CLM20_B8 pharmaceuticalUCA, CLM99_G12, CLM99_D10, CLM99_E3, CLM2O_Bis_B3, ISR42_E7, CSC3_H1 , E371 _F8, E2418_G12, E1373_G3 and CSC3_H1 JJCA bind to the spike protein of sarbecoviruses and (human-infecting) non-sarbecovirus betacoronaviruses, in particular to HKU1 , SARS-CoV-1 and SARS-CoV-2.
  • the antibody, or the antigen-binding fragment thereof, binding to the spike (S) protein of sarbecoviruses and (human-infecting) non-sarbecovirus betacoronaviruses, such as to the spike (S) protein of HKU1 , SARS-CoV-1 and a SARS-CoV-2 virus may comprise (i) heavy chain CDR1 , CDR2, and CDR3 sequences having at least 70% sequence identity with the amino acid sequences of SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11 , respectively, and light chain CDR1 , CDR2, and CDR3 sequences having at least 70% sequence identity with the amino acid sequences of SEQ ID NO: 12, SEQ ID NO: 13 or 14, and SEQ ID NO: 15, respectively; or (ii) heavy chain CDR1 , CDR2, and CDR3 sequences having at least 70% sequence identity with the amino acid sequences of SEQ ID NO: 20, SEQ ID NO: 21 , and SEQ ID NO: 22, respectively,
  • the antibody, or the antigen-binding fragment thereof, binding to the spike (S) protein of sarbecovi ruses and (human-infecting) non-sarbecovirus betacoronaviruses, such as to the spike (S) protein of HKU1 , SARS-CoV-1 and a SARS-CoV-2 virus may comprise (i) heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11 , respectively, and light chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 12, SEQ ID NO: 13 or 14, and SEQ ID NO: 15, respectively; or (ii) heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 20, SEQ ID NO: 21 , and SEQ ID NO: 22, respectively, and light chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 12, SEQ ID NO:
  • the antibody, or the antigen-binding fragment thereof binds to the spike (S) protein of HKU1 coronavirus, OC43 coronavirus, SARS-CoV-1 and SARS-CoV-2.
  • S spike
  • the exemplified antibodies of the present invention CLM20_A7, CLM20J38, CLM20_C9, CLM20_B8_UCA, CLM99_G12, CLM99_D10, CLM99_E3, CLM20_Bis_B3, ISR42_E7, CSC3_H1, E371_F8, E2418_G12 and
  • CSC3__H1_UCA bind to the spike protein of sarbecovi ruses and (human-infecting) non- sarbecovirus betacoronaviruses, in particular to HKU1 , OC43, SARS-CoV-1 and SARS-CoV- 2.
  • the antibody, or the antigen-binding fragment thereof, binding to the spike (S) protein of sarbecovi ruses and (human-infecting) non-sarbecovirus betacoronaviruses may comprise (i) heavy chain CDR1 , CDR2, and CDR3 sequences having at least 70% sequence identity with the amino acid sequences of SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11 , respectively, and light chain CDR1 , CDR2, and CDR3 sequences having at least 70% sequence identity with the amino acid sequences of SEQ ID NO: 12, SEQ ID NO: 13 or 14, and SEQ ID NO: 15, respectively; or (ii) heavy chain CDR1 , CDR2, and CDR3 sequences having at least 70% sequence identity with the amino acid sequences of SEQ ID NO: 20, SEQ ID NO: 21 , and SEQ
  • the antibody, or the antigen-binding fragment thereof, binding to the spike (S) protein of sarbecovi ruses and (human-infecting) non-sarbecovirus betacoronaviruses may comprise (i) heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 1 1, respectively, and light chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 12, SEQ ID NO: 13 or 14, and SEQ ID NO: 15, respectively; or (ii) heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 20, SEQ ID NO: 21 , and SEQ ID NO: 22, respectively, and light chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 12, SEQ
  • the antibody, or the antigen-binding fragment thereof binds to the spike (S) protein of HKU1 coronavirus, OC43 coronavirus, MERS coronavirus, SARS-CoV-1 and SARS-CoV-2 (i.e., to all known human infecting betacoronaviruses).
  • the exemplified antibodies of the present invention CLM20_A7, CLM20_B8, CLM20_C9, CLM20_B8_UCA, CLM99_G12, CLM99_D10, CLM99_E3, ISR42_E7, CSC3_H1 , E371 __F8, E2418_G12 and CSC3_H1_UCA bind to the spike protein of sarbecoviruses and (human-infecting) non-sarbecovirus betacoronaviruses, in particular to HKU1 , OC43, MERS- CoV, SARS-CoV-1 and SARS-CoV-2.
  • the antibody, or the antigen-binding fragment thereof, binding to the spike (S) protein of sarbecoviruses and (human-infecting) non-sarbecovirus betacoronaviruses may comprise (i) heavy chain CDR1 , CDR2, and CDR3 sequences having at least 70% sequence identity with the amino acid sequences of SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11 , respectively, and light chain CDR1 , CDR2, and CDR3 sequences having at least 70% sequence identity with the amino acid sequences of SEQ ID NO: 12, SEQ ID NO: 13 or 14, and SEQ ID NO: 15, respectively; or (ii) heavy chain CDR1 , CDR2, and CDR3 sequences having at least 70% sequence identity with the amino acid sequences of SEQ ID NO: 20, SEQ ID NO: 21
  • the antibody, or the antigen-binding fragment thereof, binding to the spike (S) protein of sarbecovi ruses and (human-infecting) non-sarbecovirus betacoronaviruses may comprise (i) heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 1 1 , respectively, and light chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 12, SEQ ID NO: 13 or 14, and SEQ ID NO: 15, respectively; or (ii) heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 20, SEQ ID NO: 21 , and SEQ ID NO: 22, respectively, and light chain CDR1, CDR2, and CDR3 sequences according to SEQ
  • the antibody, or the antigen-binding fragment thereof binds to the spike (S) protein of an alphacoronavirus and to the spike (S) protein of a betacoronavirus.
  • spike (S) protein of an alphacoronavirus and to the spike (S) protein of a betacoronavirus.
  • Such broad binding activity across different genera of coronaviruses typically requires binding to an epitope, which is strongly conserved, even across different genera of coronaviruses.
  • An example of a strongly conserved region in the spike protein of different coronavirus genera is the fusion peptide. Without being bound to any theory, it is assumed that such a strong conservation implies that mutations in the strongly conserved regions can easily abolish or reduce important functionalities, such that mutations in those strongly conserved regions are not well tolerated.
  • the antibody, or the antigen-binding fragment thereof, binding to the spike (S) protein of an alphacoronavirus and to the spike (S) protein of a betacoronavirus binds to the spike (S) protein of 229E coronavirus, NL63 coronavirus, HKU1 coronavirus, OC43 coronavirus, MERS coronavirus, SARS-CoV-1 and SARS-CoV-2 (i.e., to the spike protein of all known human infecting coronaviruses).
  • the exemplified antibodies of the present invention CLM20__A7, CLM20_B8, CLM20_C9, CLM20_B8_UCA, ISR42_E7, CSC3.H1, E371_F8, E2418J312 and CSC3_H1 JJCA bind to the spike protein of an alphacoronavirus and to the spike (S) protein of a betacoronavirus, in particular to HKU1 , OC43, MERS-CoV, SARS-CoV-1, SARS-CoV-2, 229E and NL63.
  • the antibody, or the antigen-binding fragment thereof, binding to the spike (S) protein of an alphacoronavirus and to the spike (S) protein of a betacoronavirus may comprise (i) heavy chain CDR1 , CDR2, and CDR3 sequences having at least 70% sequence identity with the amino acid sequences of SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 1 1 , respectively, and light chain CDR1 , CDR2, and CDR3 sequences having at least 70% sequence identity with the amino acid sequences of SEQ ID NO: 12, SEQ ID NO: 13 or 14, and SEQ ID NO: 15, respectively; or (ii) heavy chain CDR1 , CDR2, and CDR3 sequences having at least 70% sequence identity with the amino acid sequence
  • the antibody, or the antigen-binding fragment thereof, binding to the spike (S) protein of an alphacoronavirus and to the spike (S) protein of a betacoronavirus, such as to the spike (S) protein of 229E coronavirus, NL63 coronavirus, HKU1 coronavirus, OC43 coronavirus, MERS coronavirus, SARS-CoV-1 and SARS-CoV-2 may comprise (i) heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 1 1 , respectively, and light chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 12, SEQ ID NO: 13 or 14, and SEQ ID NO: 15, respectively; or (ii) heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO: 22, respectively, and light chain CDR1 , C
  • the antibody, or the antigen-binding fragment thereof, as described herein does not bind to the receptor binding domain (RBD) of the coronavirus spike protein.
  • the antibody, or the antigen-binding fragment thereof, as described above binds to the fusion peptide of the coronavirus spike (S) protein.
  • the antibody, or the antigen-binding fragment thereof also binds to the spike (S) protein of SARS-like coronavirus WIV-1 .
  • S spike protein of SARS-like coronavirus WIV-1 .
  • at least the exemplified antibodies of the present invention CSC3_H1 and E2418_G12 also bind to the spike protein of WIV-1.
  • the antibody, or the antigen-binding fragment thereof also binds to the spike (S) protein of SARS-like coronavirus WIV-1 may comprise (i) heavy chain CDR1 , CDR2, and CDR3 sequences having at least 70% sequence identity with the amino acid sequences of SEQ ID NO: 216, SEQ ID NO: 217, and SEQ ID NO: 218, respectively, and light chain CDR1 , CDR2, and CDR3 sequences having at least 70% sequence identity with the amino acid sequences of SEQ ID NO: 219, SEQ ID NO: 220 or 221 , and SEQ ID NO: 222, respectively; or (ii) heavy chain CDR1 , CDR2, and CDR3 sequences having at least 70% sequence identity with the amino acid sequences of SEQ ID NO: 234, SEQ ID NO: 235, and SEQ ID NO: 236, respectively, and light chain CDR1 , CDR2, and CDR3 sequences having at least 70% sequence identity with the amino acid sequences of SEQ ID NO: 2
  • the antibody, or the antigen-binding fragment thereof, also binds to the spike (S) protein of SARS-like coronavirus WIV-1 may comprise (i) heavy chain CDR1, CDR2, and CDR3 sequences according to SEQ ID NO: 216, SEQ ID NO: 217, and SEQ ID NO: 218, respectively, and light chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 219, SEQ ID NO: 220 or 221 , and SEQ ID NO: 222, respectively; or (ii) heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 234, SEQ ID NO: 235, and SEQ ID NO: 236, respectively, and light chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 237, SEQ ID NO: 21 1 or 238, and SEQ ID NO: 239, respectively.
  • the antibody, or the antigen-binding fragment thereof binds to the spike (S) protein of coronaviruses of all four genera.
  • the antibody, or the antigen-binding fragment thereof may bind to the spike (S) protein of an alphacoronavirus, to the spike (S) protein of a betacoronavirus, to the spike (S) protein of a gammacoronavirus, and to the spike (S) protein of a deltacoronavirus.
  • the antibody, or the antigenbinding fragment thereof, as described above may additionally bind to the spike (S) protein of infectious bronchitis virus (IBV) and porcine deltacoronavirus (PdCV).
  • the antibody, or the antigen-binding fragment thereof may bind to the spike (S) protein of 229E coronavirus, NL63 coronavirus, HKU1 coronavirus, OC43 coronavirus, MERS coronavirus, SARS-CoV-1 , SARS-CoV-2, infectious bronchitis virus (IBV) and porcine deltacoronavirus (PdCV).
  • S spike
  • NL63 coronavirus NL63 coronavirus
  • HKU1 coronavirus HKU1 coronavirus
  • OC43 coronavirus OC43 coronavirus
  • MERS coronavirus coronavirus
  • SARS-CoV-1 SARS-CoV-2
  • infectious bronchitis virus IBV
  • porcine deltacoronavirus PdCV
  • the antibody, or the antigen-binding fragment thereof, binding to the spike (S) protein of an alphacoronavirus, to the spike (S) protein of a betacoronavirus, to the spike (S) protein of a gammacoronavirus, and to the spike (S) protein of a deltacoronavirus, in particular binding to the spike (S) protein of 229E coronavirus, NL63 coronavirus, HKU1 coronavirus, OC43 coronavirus, MERS coronavirus, SARS-CoV-1 , SARS-CoV-2, infectious bronchitis virus (IBV) and porcine deltacoronavirus (PdCV), may comprise heavy chain CDR1 , CDR2, and CDR3 sequences having at least 70% sequence identity with the amino acid sequences of SEQ ID NO: 216, SEQ ID NO: 217, and SEQ ID NO: 218, respectively, and light chain CDR1 , CDR2, and CDR3 sequences having at least 70% sequence identity with the
  • the antibody, or the antigen-binding fragment thereof, binding to the spike (S) protein of an alphacoronavirus, to the spike (S) protein of a betacoronavirus, to the spike (S) protein of a gammacoronavirus, and to the spike (S) protein of a deltacoronavirus, in particular binding to the spike (S) protein of 229E coronavirus, NL63 coronavirus, HKU1 coronavirus, OC43 coronavirus, MERS coronavirus, SARS-CoV-1 , SARS-CoV-2, infectious bronchitis virus (IBV) and porcine deltacoronavirus (PdCV), may comprise heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 216, SEQ ID NO: 217, and SEQ ID NO: 218, respectively, and light chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 219, SEQ ID NO: 220 or
  • the antibody, or the antigen-binding fragment thereof binds to an amino acid sequence according to any one of SEQ ID NOs 1 - 8 and 264 - 269.
  • SEQ ID NOs 1 - 8 and 264 - 269 show exemplified sequences of (fusion peptide) epitopes of different coronaviruses.
  • isolates for each coronavirus (species), there are usually different isolates (variants).
  • HKU1 includes isolates N1 , N2 and N5
  • SARS-CoV-2 includes alpha, delta, gamma, and omicron variants.
  • the antibody, or the antigen-binding fragment thereof binds to an amino acid sequence having at least 73%, preferably at least 80%, more preferably at least 86% and even more preferably at least 93% sequence identity to any one of SEQ ID NOs 1 - 7 and 268 - 269.
  • the antibody, or the antigen-binding fragment thereof binds to an amino acid sequence having at least 70%, preferably at least 80%, more preferably at least 90% sequence identity to SEQ ID NO: 8.
  • the antibody, or the antigenbinding fragment thereof binds to an amino acid sequence having at least 62%, preferably at least 75%, more preferably at least 87% sequence identity to SEQ ID NO: 264. In some embodiments, the antibody, or the antigen-binding fragment thereof, binds to an amino acid sequence having at least 72%, preferably at least 81 %, more preferably at least 90% sequence identity to SEQ ID NO: 265. In some embodiments, the antibody, or the antigen-binding fragment thereof, binds to an amino acid sequence having at least 75%, preferably at least 83%, more preferably at least 91 % sequence identity to SEQ ID NO: 267.
  • the antibody, or the antigen-binding fragment thereof binds to an amino acid sequence having at least 75%, preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, still more preferably at least 95% sequence identity to SEQ ID NO: 266.
  • the changes (mutations) occur preferably at positions X lz X 2 and/or X 3 of general formulae I, la or II, as described below. Preferred mutations for each of those positions are also described below.
  • the antibody, or the antigen-binding fragment thereof binds to an amino acid sequence according to each of SEQ ID NOs 1 - 7; and, optionally, additionally to an amino acid sequence according to SEQ ID NO: 268 and to an amino acid sequence according to SEQ ID NO: 269.
  • SEQ ID NOs 1 - 8 and 264 - 269 relate to amino acid sequences of (fragments/epitopes of) the fusion peptide of the spike protein of different coronaviruses.
  • SEQ ID NO: 266 is the amino acid sequence of the fusion peptide of SARS-CoV-2.
  • antibodies, or antigen-binding fragments, as described herein to bind to the (fusion peptide of the) spike protein of SARS-CoV-2 may bind to an amino acid sequence according to SEQ ID NO: 266.
  • SEQ ID NO: 1 is a fragment of the spike protein (fusion peptide) of SARS-CoV-2.
  • antibodies, or antigen-binding fragments, as described herein to bind to the (fusion peptide of the) spike protein of SARS-CoV-2 may bind to an amino acid sequence according to SEQ ID NO: 1.
  • SEQ ID NO: 2 is a fragment of the spike protein (fusion peptide) of SARS-CoV-1 .
  • antibodies, or antigen-binding fragments, as described herein to bind to the (fusion peptide of the) spike protein of SARS-CoV-1 may bind to an amino acid sequence according to SEQ ID NO: 2.
  • SEQ ID NO: 3 is a fragment of the spike protein (fusion peptide) of MERS-CoV.
  • antibodies, or antigen-binding fragments, as described herein to bind to the (fusion peptide of the) spike protein of MERS-CoV may bind to an amino acid sequence according to SEQ ID NO: 3.
  • SEQ ID NO: 4 is a fragment of the spike protein (fusion peptide) of OC43 coronavirus.
  • antibodies, or antigen-binding fragments, as described herein to bind to the (fusion peptide of the) spike protein of OC43 coronavirus may bind to an amino acid sequence according to SEQ ID NO: 4.
  • SEQ ID NO: 5 is a fragment of the spike protein (fusion peptide) of HKU1 coronavirus.
  • antibodies, or antigen-binding fragments, as described herein to bind to the (fusion peptide of the) spike protein of HKU1 coronavirus may bind to an amino acid sequence according to SEQ ID NO: 5.
  • SEQ ID NO: 6 is a fragment of the spike protein (fusion peptide) of NL63 coronavirus.
  • antibodies, or antigen-binding fragments, as described herein to bind to the (fusion peptide of the) spike protein of NL63 coronavirus may bind to an amino acid sequence according to SEQ ID NO: 6.
  • SEQ ID NO: 7 is a fragment of the spike protein (fusion peptide) of 229E coronavirus.
  • antibodies, or antigen-binding fragments, as described herein to bind to the (fusion peptide of the) spike protein of 229E coronavirus may bind to an amino acid sequence according to SEQ ID NO: 7.
  • SEQ ID NO: 268 is a fragment of the spike protein (fusion peptide) of IBV.
  • antibodies, or antigen-binding fragments, as described herein to bind to the (fusion peptide of the) spike protein of IBV may bind to an amino acid sequence according to SEQ ID NO: 268.
  • SEQ ID NO: 269 is a fragment of the spike protein (fusion peptide) of PdCV. Accordingly, antibodies, or antigen-binding fragments, as described herein to bind to the (fusion peptide of the) spike protein of PdCV may bind to an amino acid sequence according to SEQ ID NO: 269.
  • SEQ ID NO: 8, SEQ ID NO: 264 and SEQ ID NO: 265 are fragments of the spike protein (fusion peptide) shared by SARS-CoV-1 , SARS-CoV-2 and HKU1 coronavirus. Accordingly, antibodies, or antigen-binding fragments, as described herein to bind to the (fusion peptide of the) spike protein of SARS-CoV-1 , SARS- CoV-2 and HKU1 coronavirus may bind to an amino acid sequence according to SEQ ID NO: 8, SEQ ID NO: 264 and SEQ ID NO: 265.
  • SEQ ID NO: 267 is a fragment of the spike protein (fusion peptide) shared by SARS-CoV-1 and SARS-CoV-2.
  • antibodies, or antigen-binding fragments, as described herein to bind to the (fusion peptide of the) spike protein of SARS-CoV-1 and SARS-CoV-2 may bind to an amino acid sequence according to SEQ ID NO: 267.
  • the present invention provides an (isolated) antibody, or an antigenbinding fragment thereof, which (specifically) binds to the fusion peptide (FP) of the coronavirus spike (S) protein.
  • the antibody, or the antigen-binding fragment thereof may bind to the fusion peptide of the spike protein of different coronaviruses as described above.
  • Coronaviruses typically enter host cells with their spike (S) glycoprotein.
  • the coronavirus S protein (schematically shown in Figure 2) contains two functional subunits, the N-terminal 51 subunit and the C-terminal 52 subunit.
  • the fusion peptide (FP) is located in the 52 subunit of the 5 protein.
  • the fusion peptide is usually involved in the fusion of the virus and the host cell (Madu I.G., Roth S.L., Belouzard 5., Whittaker G.R. Characterization of a highly conserved domain within the severe acute respiratory syndrome coronavirus spike protein S2 domain with characteristics of a viral fusion peptide. J. Virol. 2009;83:7411 -7421 . doi: 10.1 128/JVI.00079-09).
  • the present inventors identified antibodies broadly targeting the spike protein of different coronaviruses, in particular targeting the spike protein of various alpha- and betacoronaviruses.
  • Epitope mapping revealed that these antibodies bind to the fusion peptide (FP) of the spike protein.
  • FP fusion peptide
  • antibodies binding to the fusion peptide of the coronavirus S protein can target various distinct coronaviruses. Therefore, antibodies targeting the fusion peptide of the coronavirus S protein represent a group of broadly targeting anticoronavirus antibodies.
  • the antibody, or the antigen-binding fragment thereof binds to an amino acid sequence according to general formula I or la:
  • the antibody, or the antigen-binding fragment thereof binds to an amino acid sequence according to general formula II:
  • X may be a non-polar and/or neutral amino acid, such as an amino acid selected from A, C, G, I, L, M, F, P, W and V; preferably X 1 is selected from A, C, G, I, L, M, F, P, W and V; more preferably X 1 is A, L or F; even more preferably X 1 is Y, V, L, I or E. In some embodiments, X 1 is not P. Preferably, X 1 is F.
  • X 2 is preferably an aliphatic, non-polar and/or neutral amino acid, such as an amino acid selected from A, G, I, L, and V. In some embodiments, X 2 is I, L, F, S or V. More preferably X 2 is I or L. Even more preferably X 2 is I.
  • X 3 is preferably a polar amino acid, such as an amino acid selected from R, N, D, Q, E, H, K, S, T or Y; more preferably X 3 is N, H, K, S, T or D; even more preferably X 3 is N, S, T or D; still more preferably X 3 is N, S or D. In some embodiments, X 3 is N or D.
  • the antibody, or the antigen-binding fragment thereof binds to an amino acid sequence according to general formula I or II, wherein X 1 is A, L or F; X 2 is I or L; and X 3 is N, S, T or D, preferably wherein X 1 is A, L or F; X 2 is I or L; and X 3 is N, S or D.
  • the antibody, or the antigen-binding fragment thereof binds to an epitope in the fusion peptide of the coronavirus spike (S) protein (in particular of SARS-CoV- 2 S protein), which is exposed in an intermediate (transient) conformation of the S protein, in particular following receptor (in particular ACE2) binding, and/or which is more/better accessible upon receptor (in particular ACE2) binding (as compared to without receptor binding).
  • S coronavirus spike
  • ACE2 coronavirus spike
  • the antibody, or the antigen-binding fragment thereof binds to a (cryptic) epitope in the fusion peptide (region) of the spike protein (e.g., sarbecovirus, such as SARS-CoV-2, spike protein) that becomes exposed (accessible for antibodies) in the prefusion conformation upon ACE2 binding.
  • the spike protein e.g., sarbecovirus, such as SARS-CoV-2, spike protein
  • the antibody, or the antigen-binding fragment thereof binds to an amino acid sequence according to SEQ ID NO: 264 or to a sequence variant thereof which includes 1 , 2, 3 or 4 mutations in comparison to SEQ ID NO: 264.
  • the sequence variant includes three or four mutations in comparison to SEQ ID NO: 264. Preferred positions of these mutations are positions 11 , L4, N7 and/or K8 in SEQ ID NO: 264.
  • the sequence variant has at least 75% sequence identity, preferably at least 87% sequence identity to SEQ ID NO: 264. Accordingly, it is preferred that SEQ ID NO: 264 includes no more than one or two mutation(s).
  • these mutations may preferably occur at any one of positions 11 , L4, N7 and/or K8 in SEQ ID NO: 264. More preferred positions of these mutations are those of X 2 and X 3 in general formula la above (corresponding to positions 11 and N7 in SEQ ID NO: 264, respectively). Accordingly, an amino acid sequence with at least 75% sequence identity to SEQ ID NO: 264 is preferably mutated at positions X 2 and X 3 of general formula la. An amino acid sequence with at least 87% sequence identity to SEQ ID NO: 264 is preferably mutated either at position X 2 or at position X 3 (but not at both) of general formula la. Even more preferably, the antibody, or the antigen-binding fragment thereof, binds to an amino acid sequence according to SEQ ID NO: 264.
  • the antibody, or the antigen-binding fragment thereof binds to an amino acid sequence according to SEQ ID NO: 8 or to a sequence variant thereof having at least 70% sequence identity, preferably at least 80% sequence identity and more preferably at least 90% sequence identity.
  • SEQ ID NO: 8 may include one or more (e.g., 1 , 2, 3, 4 or 5) mutations, preferably at any one of positions F2, I3, L6, N9 and/or K10 of SEQ ID NO: 8.
  • SEQ ID NO: 8 may include up to three (1 , 2 or 3) mutations.
  • Preferred positions of these mutations are those ofX 1 , X 2 and X 3 in general formula I above (corresponding to F2, 13 and N9, respectively, in SEQ ID NO: 8).
  • the above-mentioned preferred mutations for each of those positions in general formula I likewise apply to SEQ ID NO: 8. Accordingly, an amino acid sequence with at least 70% sequence identity to SEQ ID NO: 8 is preferably mutated at positions X 1 , X 2 and X 3 of general formula I.
  • An amino acid sequence with at least 80% sequence identity to SEQ ID NO: 8 is preferably mutated at positions X, and X 3 of general formula I or at positions X 2 and X 3 of general formula I.
  • amino acid sequence with at least 90% sequence identity to SEQ ID NO: 8 is preferably mutated at positionX 1 , X 2 or X 3 of general formula I. Even more preferably, the antibody, or the antigen-binding fragment thereof, binds to an amino acid sequence according to SEQ ID NO: 8.
  • the antibody, or the antigen-binding fragment thereof binds to an amino acid sequence according to SEQ ID NO: 265 or a sequence variant thereof having at least 70% sequence identity, preferably at least 80% sequence identity and more preferably at least 90% sequence identity.
  • SEQ ID NO: 265 may include one or more (e.g., 1 , 2, 3, 4 or 5) mutations, preferably at any one of positions F3, I4, L7, N10 and/or K1 1 of SEQ ID NO: 265.
  • SEQ ID NO: 265 may include up to three (1, 2 or 3) mutations.
  • Preferred positions of these mutations are those of X, X 1 2 and X 3 in general formula II above (corresponding to F3, 14 and N10, respectively, in SEQ ID NO: 265).
  • the above- mentioned preferred mutations for each of those positions in general formula II likewise apply to SEQ ID NO: 265.
  • an amino acid sequence with at least 70% sequence identity to SEQ ID NO: 265 is preferably mutated at positions X 1 , X 2 and X 3 of general formula II.
  • An amino acid sequence with at least 80% sequence identity to SEQ ID NO: 265 is preferably mutated at positions X 1 and X 3 of general formula II or at positions X 2 and X 3 of general formula II.
  • amino acid sequence with at least 90% sequence identity to SEQ ID NO: 265 is preferably mutated at position X 1 , X 2 or X 3 of general formula II. Even more preferably, the antibody, or the antigen-binding fragment thereof, binds to an amino acid sequence according to SEQ ID NO: 265.
  • the antibody, or the antigen-binding fragment thereof binds to an amino acid sequence according to SEQ ID NO: 265 or a sequence variant thereof, wherein Ri, E 5 and F 9 of SEQ ID NO: 265 are maintained. In some embodiments, the antibody, or the antigen-binding fragment thereof, binds to an amino acid sequence according to SEQ ID NO: 265 or a sequence variant thereof, wherein R lz E s and F 9 of SEQ ID NO: 265 may be maintained and wherein
  • S 2 is substituted with V, R, M, G, E or A, preferably with G;
  • F 3 is substituted with Y, V, T, S, R, M, L, K, I, E, D or A, preferably with Y, V, L, I, or E;
  • l 4 is substituted with Y, V or L, preferably with L;
  • D 6 is substituted with Y, W, V, T, S, M, L, I, F, C or A, preferably with Y, T, S or F;
  • L 7 is substituted with Y, V, T, M, I, or F, preferably with Y, V, I or F;
  • Kn is substituted with V, T, S, M, I, G, F, E or A, preferably with T, S, M, G, E or A.
  • the antibody, or the antigen-binding fragment thereof binds to an amino acid sequence according to SEQ ID NO: 265 or a sequence variant thereof, wherein Ri, E 5 , La and F 9 of SEQ ID NO: 265 may be maintained and wherein
  • S 2 is substituted with V, T, R, Q, P, M, K, G, E, D or A, preferably with E, D or A;
  • F 3 is substituted with any amino acid, preferably with V, I, M, E, D or A;
  • l 4 is substituted with Y, V, L or F;
  • L? is substituted with Y, V, T, S, M, I, F or A, preferably with V, I or F;
  • Nio is substituted with any amino acid except P, preferably with Y, W, V, T, S, R, Q, M,
  • Kn with V, T, S, M, G, E or A, preferably with T, S, G, E or A.
  • the antibody, or the antigen-binding fragment thereof binds to an amino acid sequence according to SEQ ID NO: 267 or a sequence variant thereof having at least 70% sequence identity, preferably at least 80% sequence identity and more preferably at least 90% sequence identity.
  • SEQ ID NO: 267 may include one or more (e.g., 1 , 2, 3, 4 or 5) mutations, preferably at any one of positions F4, I5, L8, Ni l and/or K12 of SEQ ID NO: 267. Even more preferably, the antibody, or the antigen-binding fragment thereof, binds to an amino acid sequence according to SEQ ID NO: 267.
  • the antibody, or the antigen-binding fragment thereof binds to an amino acid sequence according to SEQ ID NO: 266 or a sequence variant thereof having at least 70% or 75% sequence identity, preferably at least 80% or 85% sequence identity and more preferably at least 90% or 95% sequence identity.
  • SEQ ID NO: 266 may include one or more (e.g., 1 , 2, 3, 4 or 5) mutations, preferably at any one of positions F7, I8, L1 1 , N14 and/or K15 of SEQ ID NO: 266.
  • the antibody, or the antigen-binding fragment thereof binds to an amino acid sequence according to one or more of SEQ ID NOs 1 - 7, 268 and 269; or to a sequence variant thereof, as described herein, having at least 66%, preferably at least 73%, more preferably at least 80%, even more preferably at least 86% and still more preferably at least 93% sequence identity.
  • the sequence variant of SEQ ID NOs 1 - 7, 268 and 269 may include one or more (e.g., 1 , 2, 3, 4 or 5) mutations, preferably at any one of positions corresponding to F7, I8, L1 1 , N14 and/or KI 5 of SEQ ID NO: 1 .
  • the antibody, or the antigen-binding fragment thereof binds to an amino acid sequence according to any one of SEQ ID NOs 1 - 7.
  • An alignment of SEQ ID NOs 1 - 7 is shown in Fig. 3.
  • the antibody, or the antigen-binding fragment thereof may bind to an amino acid sequence according to SEQ ID NO: 1 or to a sequence variant thereof having at least 70% sequence identity, preferably at least 80% sequence identity and more preferably at least 90% sequence identity. More preferably, the antibody, or the antigenbinding fragment thereof, binds to an amino acid sequence according to SEQ ID NO: 1 .
  • the antibody, or the antigen-binding fragment thereof binds to an amino acid sequence according to SEQ ID NO: 1 and to an amino acid sequence according to SEQ ID NO: 2.
  • the antibody, or the antigen-binding fragment thereof binds to amino acid sequences according to SEQ ID NOs 1 , 2, 4 and 5. More preferably, the antibody, or the antigen-binding fragment thereof, binds to amino acid sequences according to according to SEQ ID NOs 1 , 2, 3, 4 and 5. Even more preferably, the antibody, or the antigenbinding fragment thereof, binds to each of the amino acid sequences according to SEQ ID NOs 1 - 7.
  • the antibody, or the antigen-binding fragment thereof (additionally) binds to an amino acid sequence according to SEQ ID NO: 268 and/or to an amino acid sequence according to SEQ ID NO: 269.
  • the antibody, or an antigen-binding fragment thereof, according to the present invention may comprise (at least) three complementarity determining regions (CDRs) on a heavy chain and (at least) three CDRs on a light chain.
  • complementarity determining regions (CDRs) are the hypervariable regions present in heavy chain variable domains and light chain variable domains.
  • the CDRs of a heavy chain and the connected light chain of an antibody together form the antigen receptor.
  • the three CDRs (CDR1 , CDR2, and CDR3) are arranged non-consecutively in the variable domain. Since antigen receptors are typically composed of two variable domains (on two different polypeptide chains, i.e.
  • heavy and light chain heavy chain variable region (VH) and light chain variable region (VL)
  • CDRs for each antigen receptor
  • a classical IgG antibody molecule usually has two antigen receptors and therefore contains twelve CDRs.
  • the CDRs on the heavy and/or light chain may be separated by framework regions, whereby a framework region (FR) is a region in the variable domain which is less "variable" than the CDR.
  • FR framework region
  • a variable region or each variable region, respectively
  • the sequences of the heavy chains and light chains of exemplary antibodies of the invention, comprising three different CDRs on the heavy chain and three different CDRs on the light chain were determined.
  • the position of the CDR amino acids are defined according to the IMGT numbering system (IMGT: http://www.imgt.org/; cf. Lefranc, M.-P. et al. (2009) Nucleic Acids Res. 37, D1006-D1012).
  • the antibody or the antigen-binding fragment thereof comprises (i) heavy chain CDR1 , CDR2, and CDR3 sequences having at least 70% or 75% sequence identity with the amino acid sequences of SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 1 1 , respectively, and light chain CDR1 , CDR2, and CDR3 sequences having at least 70% or 75% sequence identity with the amino acid sequences of SEQ ID NO: 12, SEQ ID NO: 13 (or 14), and SEQ ID NO: 15, respectively; or (ii) heavy chain CDR1 , CDR2, and CDR3 sequences having at least 70% or 75% sequence identity with the amino acid sequences of SEQ ID NO: 20, SEQ ID NO: 21 , and SEQ ID NO: 22, respectively, and light chain CDR1 , CDR2, and CDR3 sequences having at least 70% or 75% sequence identity with the amino acid sequences of SEQ ID NO: 12, SEQ ID NO: 23 (or 24), and SEQ ID NO: 25, respectively; or (i) heavy chain C
  • the present invention also provides an antibody, or an antigen-binding fragment thereof, which binds to the coronavirus spike (S) protein, wherein the antibody or the antigen-binding fragment thereof comprises (i) heavy chain CDR1 , CDR2, and CDR3 sequences having at least 70% or 75% sequence identity with the amino acid sequences of SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 1 1 , respectively, and light chain CDR1 , CDR2, and CDR3 sequences having at least 70% or 75% sequence identity with the amino acid sequences of SEQ ID NO: 12, SEQ ID NO: 13 (or 14), and SEQ ID NO: 15, respectively; or (ii) heavy chain CDR1 , CDR2, and CDR3 sequences having at least 70% or 75% sequence identity with the amino acid sequences of SEQ ID NO: 20, SEQ ID NO: 21 , and SEQ ID NO: 22, respectively, and light chain CDR1 , CDR2, and CDR3 sequences having at least 70% or 75% sequence identity with the amino
  • the antibody or the antigen-binding fragment thereof comprises (i) heavy chain CDR1 , CDR2, and CDR3 sequences having at least 80% or 85% sequence identity with the amino acid sequences of SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 1 1 , respectively, and light chain CDR1 , CDR2, and CDR3 sequences having at least 80% or 85% sequence identity with the amino acid sequences of SEQ ID NO: 12, SEQ ID NO: 13 (or 14), and SEQ ID NO: 15, respectively; or (ii) heavy chain CDR1 , CDR2, and CDR3 sequences having at least 80% or 85% sequence identity with the amino acid sequences of SEQ ID NO: 20, SEQ ID NO: 21 , and SEQ ID NO: 22, respectively, and light chain CDR1 , CDR2, and CDR3 sequences having at least 80% or 85% sequence identity with the amino acid sequences of SEQ ID NO: 12, SEQ ID NO: 23 (or 24), and SEQ ID NO: 25, respectively
  • amino acid sequence variant has an altered sequence in which one or more of the amino acids (or nucleotides) as compared to the respective reference sequence is/are deleted or substituted, and/or one or more amino acids (or nucleotides) is/are inserted into the sequence of the reference amino acid sequence.
  • the amino acid sequence variant has an amino acid sequence which is at least 70% identical to the reference sequence.
  • Variant sequences which are at least 70% identical have no more than 30 alterations, i.e. any combination of deletions, insertions or substitutions, per 100 amino acids of the reference sequence.
  • a (nucleic acid or amino acid) "sequence variant” may have at least 70%, preferably at least 75%, more preferably at least 80%, even more preferably at least 85%, still more preferably at least 90% and particularly preferably at least 95% (such as at least 97% or 98%) sequence identity in comparison to the respective reference sequence (e.g., the sequences according to SEQ ID NOs 1 to 269 as described herein).
  • the functionality of the reference sequence e.g., in the present case binding to the coronavirus spike protein, for example of various distinct coronaviruses, e.g. alpha- and betacoronaviruses
  • the reference sequence e.g., in the present case binding to the coronavirus spike protein, for example of various distinct coronaviruses, e.g. alpha- and betacoronaviruses
  • conservative amino acid substitutions involve substitution of one aliphatic or hydrophobic amino acids, e.g. alanine, valine, leucine and isoleucine, with another; substitution of one hydoxyl-containing amino acid, e.g. serine and threonine, with another; substitution of one acidic residue, e.g. glutamic acid or aspartic acid, with another; replacement of one amide-containing residue, e.g.
  • asparagine and glutamine with another; replacement of one aromatic residue, e.g. phenylalanine and tyrosine, with another; replacement of one basic residue, e.g. lysine, arginine and histidine, with another; and replacement of one small amino acid, e.g., alanine, serine, threonine, cysteine, and glycine, with another.
  • one aromatic residue e.g. phenylalanine and tyrosine
  • basic residue e.g. lysine, arginine and histidine
  • replacement of one small amino acid e.g., alanine, serine, threonine, cysteine, and glycine
  • Amino acid sequence insertions include amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues.
  • terminal insertions include the fusion to the N- or C-terminus of an amino acid sequence to a reporter molecule or an enzyme.
  • the antibody, or an antigen-binding fragment thereof, of the present invention may comprise (i) heavy chain CDR1 , CDR2, and CDR3 sequences having at least 90% sequence identity (e.g., 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) with the amino acid sequences of SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11 , respectively, and light chain CDR1 , CDR2, and CDR3 sequences having at least 90% sequence identity (e.g., 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) with the amino acid sequences of SEQ ID NO: 12, SEQ ID NO: 13 (or 14), and SEQ ID NO: 15, respectively; or (ii) heavy chain CDR1 , CDR2, and CDR3 sequences having at least 90% sequence identity (e.g., 91 %, 92%, 93%, 94%,
  • the antibody or the antigen-binding fragment thereof comprises (i) heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 1 1 , respectively, and light chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 12, SEQ ID NO: 13 (or 14), and SEQ ID NO: 15, respectively; or (ii) heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 20, SEQ ID NO: 21 , and SEQ ID NO: 22, respectively, and light chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 12, SEQ ID NO: 23 (or 24), and SEQ ID NO: 25, respectively; or (iii) heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively, and light chain CDR1 , CDR2, and CDR3
  • the antibody or the antigen-binding fragment thereof comprises heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 9 (CDRH1 ), SEQ ID NO: 10 (CDRH2), and SEQ ID NO: 11 (CDRH3), respectively, and light chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 12 (CDRL1 ), SEQ ID NO: 13 or 14 (CDRL2), and SEQ ID NO: 15 (CDRL3), respectively.
  • the antibody or the antigen-binding fragment thereof comprises heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 20 (CDRH1 ), SEQ ID NO: 21 (CDRH2), and SEQ ID NO: 22 (CDRH3), respectively, and light chain CDR1, CDR2, and CDR3 sequences according to SEQ ID NO: 12 (CDRL1 ), SEQ ID NO: 23 or 24 (CDRL2), and SEQ ID NO: 25 (CDRL3), respectively.
  • the antibody or the antigen-binding fragment thereof comprises heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 28 (CDRH1 ), SEQ ID NO: 29 (CDRH2), and SEQ ID NO: 30 (CDRH3), respectively, and light chain CDR1, CDR2, and CDR3 sequences according to SEQ ID NO: 12 (CDRL1 ), SEQ ID NO: 31 or 32 (CDRL2), and SEQ ID NO: 33 (CDRL3), respectively.
  • the antibody or the antigen-binding fragment thereof comprises heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 36 (CDRH1 ), SEQ ID NO: 37 (CDRH2), and SEQ ID NO: 38 (CDRH3), respectively, and light chain CDR1, CDR2, and CDR3 sequences according to SEQ ID NO: 39 (CDRL1 ), SEQ ID NO: 40 or 41 (CDRL2), and SEQ ID NO: 42 (CDRL3), respectively.
  • the antibody or the antigen-binding fragment thereof comprises heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 45 (CDRH1 ), SEQ ID NO: 46 (CDRH2), and SEQ ID NO: 47 (CDRH3), respectively, and light chain CDR1, CDR2, and CDR3 sequences according to SEQ ID NO: 48 (CDRL1 ), SEQ ID NO: 40 or 49 (CDRL2), and SEQ ID NO: 42 (CDRL3), respectively.
  • the antibody or the antigen-binding fragment thereof comprises heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 52 (CDRH1 ), SEQ ID NO: 37 (CDRH2), and SEQ ID NO: 38 (CDRH3), respectively, and light chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 53 (CDRL1 ), SEQ ID NO: 40 or 41 (CDRL2), and SEQ ID NO: 42 (CDRL3), respectively.
  • the antibody or the antigen-binding fragment thereof comprises heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 65 (CDRH1 ), SEQ ID NO: 66 (CDRH2), and SEQ ID NO: 67 (CDRH3), respectively, and light chain CDR1, CDR2, and CDR3 sequences according to SEQ ID NO: 68 (CDRL1 ), SEQ ID NO: 40 or 69 (CDRL2), and SEQ ID NO: 70 (CDRL3), respectively.
  • the antibody or the antigen-binding fragment thereof comprises heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 207 (CDRH1 ), SEQ ID NO: 208 (CDRH2), and SEQ ID NO: 209 (CDRH3), respectively, and light chain CDR1, CDR2, and CDR3 sequences according to SEQ ID NO: 210 (CDRL1 ), SEQ ID NO: 211 or 212 (CDRL2), and SEQ ID NO: 213 (CDRL3), respectively.
  • the antibody or the antigen-binding fragment thereof comprises heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 216 (CDRH1 ), SEQ ID NO: 217 (CDRH2), and SEQ ID NO: 218 (CDRE13), respectively, and light chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 219 (CDRL1 ), SEQ ID NO: 220 or 221 (CDRL2), and SEQ ID NO: 222 (CDRL3), respectively.
  • the antibody or the antigen-binding fragment thereof comprises heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 225 (CDRH1 ), SEQ ID NO: 226 (CDRH2), and SEQ ID NO: 227 (CDRH3), respectively, and light chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 228 (CDRL1 ), SEQ ID NO: 229 or 230 (CDRL2), and SEQ ID NO: 231 (CDRL3), respectively.
  • the antibody or the antigen-binding fragment thereof comprises heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 234 (CDRH1 ), SEQ ID NO: 235 (CDRH2), and SEQ ID NO: 236 (CDRH3), respectively, and light chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 237 (CDRL1 ), SEQ ID NO: 211 or 238 (CDRL2), and SEQ ID NO: 239 (CDRL3), respectively.
  • the antibody or the antigen-binding fragment thereof comprises heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 242 (CDRH1 ), SEQ ID NO: 243 (CDRH2), and SEQ ID NO: 244 (CDRH3), respectively, and light chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 245 (CDRL1 ), SEQ ID NO: 31 or 32 (CDRL2), and SEQ ID NO: 246 (CDRL3), respectively.
  • the antibody or the antigen-binding fragment thereof comprises heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 249 (CDRH1 ), SEQ ID NO: 250 (CDRH2), and SEQ ID NO: 251 (CDRH3), respectively, and light chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 252 (CDRL1 ), SEQ ID NO: 253 or 254 (CDRL2), and SEQ ID NO: 255 (CDRL3), respectively.
  • the antibody or the antigen-binding fragment thereof comprises heavy chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 258 (CDRH1 ), SEQ ID NO: 259 (CDRH2) and SEQ ID NO: 260 (CDRH3), respectively, and light chain CDR1 , CDR2, and CDR3 sequences according to SEQ ID NO: 219 (CDRL1 ), SEQ ID NO: 220 or 221 (CDRL2), and SEQ ID NO: 261 (CDRL3), respectively.
  • the antibody or the antigen-binding fragment thereof may comprise (i) a heavy chain variable region comprising an amino acid sequence having at least 70% or 75% identity to SEQ ID NO: 16 and a light chain variable region comprising an amino acid sequence having at least 70% or 75% identity to SEQ ID NO: 17; or (ii) a heavy chain variable region comprising an amino acid sequence having at least 70% or 75% identity to SEQ ID NO: 18 and a light chain variable region comprising an amino acid sequence having at least 70% or 75% identity to SEQ ID NO: 19; or (iii) a heavy chain variable region comprising an amino acid sequence having at least 70% or 75% identity to SEQ ID NO: 26 and a light chain variable region comprising an amino acid sequence having at least 70% or 75% identity to SEQ ID NO: 27; or (iv) a heavy chain variable region comprising an amino acid sequence having at least 70% or 75% identity to SEQ ID NO: 34 and a light chain variable region comprising an amino acid sequence having at least 70% or 75% identity to SEQ ID NO:
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 70% or more (e.g., 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 16 and a light chain variable region (VL) comprising the amino acid sequence having 70% or more (e.g., 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%
  • the CDR sequences as defined above may be maintained.
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 70% or more (e.g., 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%,
  • VH heavy chain variable region
  • VL light chain variable region
  • the CDR sequences as defined above may be maintained.
  • CDR sequences as defined above may be maintained.
  • VL light chain variable region
  • CDR sequences as defined above may be maintained.
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 70% or more (e.g., 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%,
  • VH heavy chain variable region
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 70% or more (e.g., 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%,
  • VH heavy chain variable region
  • CDR sequences as defined above may be maintained.
  • CDR sequences as defined above may be maintained.
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 70% or more (e.g., 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%,
  • VH heavy chain variable region
  • VL light chain variable region
  • CDR sequences as defined above may be maintained.
  • dasheavy chain CDR1 , CDR2, and CDR3 sequences as set forth in SEQ ID NO: 65, SEQ ID NO: 66, and SEQ ID NO: 67, respectively; and light chain CDR1 , CDR2, and CDR3 sequences as set forth in SEQ ID NO: 68, SEQ ID NO: 40 (or 69), and SEQ ID NO: 70, respectively may be maintained.
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 70% or more (e.g., 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 214 and a light chain variable region (VL) comprising the amino acid sequence having 70% or more (e.g., 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 93%, 93%, 9H
  • the CDR sequences as defined above may be maintained.
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 70% or more (e.g., 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 223 and a light chain variable region (VL) comprising the amino acid sequence having 70% or more (e.g., 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 93%,
  • the CDR sequences as defined above may be maintained.
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 70% or more (e.g., 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 232 and a light chain variable region (VL) comprising the amino acid sequence having 70% or more (e.g., 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 93%, 93%,
  • CDR sequences as defined above may be maintained.
  • CDR sequences as defined above dasheavy chain CDR1 , CDR2, and CDR3 sequences as set forth in SEQ ID NO: 225, SEQ ID NO: 226, and SEQ ID NO: 227, respectively; and light chain CDR1 , CDR2, and CDR3 sequences as set forth in SEQ ID NO: 228, SEQ ID NO: 229 (or 230), and SEQ ID NO: 231 , respectively
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 70% or more (e.g., 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 240 and a light chain variable region (VL) comprising the amino acid sequence having 70% or more (e.g., 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 93%, 93%,
  • CDR sequences as defined above may be maintained.
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 70% or more (e.g., 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 247 and a light chain variable region (VL) comprising the amino acid sequence having 70% or more (e.g., 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 93%,
  • CDR sequences as defined above may be maintained.
  • CDR sequences as defined above dasheavy chain CDR1 , CDR2, and CDR3 sequences as set forth in SEQ ID NO: 242, SEQ ID NO: 243, and SEQ ID NO: 244, respectively; and light chain CDR1 , CDR2, and CDR3 sequences as set forth in SEQ ID NO: 245, SEQ ID NO: 31 (or 32), and SEQ ID NO: 246, respectively
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 70% or more (e.g., 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 256 and a light chain variable region (VL) comprising the amino acid sequence having 70% or more (e.g., 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 93%, 93%,
  • CDR sequences as defined above may be maintained.
  • CDR sequences as defined above may be maintained.
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 75% or more (e.g., 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 16 and a light chain variable region (VL) comprising the amino acid sequence having 75% or more (e.g., 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 17.
  • VH heavy chain variable region
  • VL light chain variable region
  • the CDR sequences as defined above may be maintained.
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 75% or more (e.g., 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 26 and a light chain variable region (VL) comprising the amino acid sequence having 75% or more (e.g., 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 27.
  • VH heavy chain variable region
  • CDR sequences as defined above may be maintained.
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 75% or more (e.g., 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 34 and a light chain variable region (VL) comprising the amino acid sequence having 75% or more (e.g., 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 35.
  • VH heavy chain variable region
  • VL light chain variable region
  • CDR sequences as defined above may be maintained.
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 75% or more (e.g., 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 50 and a light chain variable region (VL) comprising the amino acid sequence having 75% or more (e.g., 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 51 .
  • VH heavy chain variable region
  • the CDR sequences as defined above may be maintained.
  • dasheavy chain CDR1, CDR2, and CDR3 sequences as set forth in SEQ ID NO: 216, SEQ ID NO: 217, and SEQ ID NO: 218, respectively; and light chain CDR1 , CDR2, and CDR3 sequences as set forth in SEQ ID NO: 219, SEQ ID NO: 220 (or 221 ), and SEQ ID NO: 222, respectively may be maintained.
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 75% or more (e.g., 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 232 and a light chain variable region (VL) comprising the amino acid sequence having 75% or more (e.g., 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 233.
  • VH heavy chain variable region
  • CDR sequences as defined above may be maintained.
  • CDR sequences as defined above dasheavy chain CDR1 , CDR2, and CDR3 sequences as set forth in SEQ ID NO: 225, SEQ ID NO: 226, and SEQ ID NO: 227, respectively; and light chain CDR1 , CDR2, and CDR3 sequences as set forth in SEQ ID NO: 228, SEQ ID NO: 229 (or 230), and SEQ ID NO: 231 , respectively
  • CDR sequences as defined above may be maintained.
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 75% or more (e.g., 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 247 and a light chain variable region (VL) comprising the amino acid sequence having 75% or more (e.g., 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 248.
  • VH heavy chain variable region
  • CDR sequences as defined above may be maintained.
  • CDR sequences as defined above dasheavy chain CDR1 , CDR2, and CDR3 sequences as set forth in SEQ ID NO: 242, SEQ ID NO: 243, and SEQ ID NO: 244, respectively; and light chain CDR1 , CDR2, and CDR3 sequences as set forth in SEQ ID NO: 245, SEQ ID NO: 31 (or 32), and SEQ ID NO: 246, respectively
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 75% or more (e.g., 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 256 and a light chain variable region (VL) comprising the amino acid sequence having 75% or more (e.g., 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 257.
  • VH heavy chain variable region
  • CDR sequences as defined above may be maintained.
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 75% or more (e.g., 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 262 and a light chain variable region (VL) comprising the amino acid sequence having 75% or more (e.g., 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 263.
  • VH heavy chain variable region
  • VL light chain variable region
  • CDR sequences as defined above may be maintained.
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 80% or more (e.g., 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 16 and a light chain variable region (VL) comprising the amino acid sequence having 80% or more (e.g., 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 1 7.
  • VH heavy chain variable region
  • VL light chain variable region
  • the CDR sequences as defined above may be maintained.
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 80% or more (e.g., 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 18 and a light chain variable region (VL) comprising the amino acid sequence having 80% or more (e.g., 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 19.
  • VH heavy chain variable region
  • VL light chain variable region
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 80% or more (e.g., 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 26 and a light chain variable region (VL) comprising the amino acid sequence having 80% or more (e.g., 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 27.
  • VH heavy chain variable region
  • VL light chain variable region
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 80% or more (e.g., 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 34 and a light chain variable region (VL) comprising the amino acid sequence having 80% or more (e.g., 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 35.
  • VH heavy chain variable region
  • VL light chain variable region
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 80% or more (e.g., 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 54 and a light chain variable region (VL) comprising the amino acid sequence having 80% or more (e.g., 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 55.
  • VH heavy chain variable region
  • VL light chain variable region
  • CDR sequences as defined above may be maintained.
  • CDR sequences as defined above may be maintained.
  • CDR sequences as defined above may be maintained.
  • CDR sequences as defined above dasheavy chain CDR1 , CDR2, and CDR3 sequences as set forth in SEQ ID NO: 242, SEQ ID NO: 243, and SEQ ID NO: 244, respectively; and light chain CDR1 , CDR2, and CDR3 sequences as set forth in SEQ ID NO: 245, SEQ ID NO: 31 (or 32), and SEQ ID NO: 246, respectively
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 80% or more (e.g., 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 256 and a light chain variable region (VL) comprising the amino acid sequence having 80% or more (e.g., 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 257.
  • VH heavy chain variable region
  • VL light chain variable region
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 85% or more (e.g., 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 16 and a light chain variable region (VL) comprising the amino acid sequence having 85% or more (e.g., 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 17.
  • VH heavy chain variable region
  • VL light chain variable region
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 85% or more (e.g., 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 18 and a light chain variable region (VL) comprising the amino acid sequence having 85% or more (e.g., 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 19.
  • VH heavy chain variable region
  • VL light chain variable region
  • the CDR sequences as defined above may be maintained.
  • CDR sequences as defined above may be maintained.
  • CDR sequences as defined above may be maintained.
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 85% or more (e.g., 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 214 and a light chain variable region (VL) comprising the amino acid sequence having 85% or more (e.g., 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 215.
  • VH heavy chain variable region
  • VL light chain variable region
  • CDR sequences as defined above may be maintained.
  • CDR sequences as defined above dasheavy chain CDR1 , CDR2, and CDR3 sequences as set forth in SEQ ID NO: 225, SEQ ID NO: 226, and SEQ ID NO: 227, respectively; and light chain CDR1 , CDR2, and CDR3 sequences as set forth in SEQ ID NO: 228, SEQ ID NO: 229 (or 230), and SEQ ID NO: 231 , respectively
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 85% or more (e.g., 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 256 and a light chain variable region (VL) comprising the amino acid sequence having 85% or more (e.g., 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 257.
  • VH heavy chain variable region
  • VL light chain variable region
  • CDR sequences as defined above may be maintained.
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 90% or more (e.g., 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 16 and a light chain variable region (VL) comprising the amino acid sequence having 90% or more (e.g., 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 17.
  • VH heavy chain variable region
  • VL light chain variable region
  • the CDR sequences as defined above may be maintained.
  • CDR sequences as defined above may be maintained.
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 90% or more (e.g, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 34 and a light chain variable region (VL) comprising the amino acid sequence having 90% or more (e.g, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 35.
  • VH heavy chain variable region
  • VL light chain variable region
  • CDR sequences as defined above may be maintained.
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 90% or more (e.g., 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 43 and a light chain variable region (VL) comprising the amino acid sequence having 90% or more (e.g., 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 44.
  • VH heavy chain variable region
  • VL light chain variable region
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 90% or more (e.g., 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 50 and a light chain variable region (VL) comprising the amino acid sequence having 90% or more (e.g., 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 51 .
  • VH heavy chain variable region
  • VL light chain variable region
  • CDR sequences as defined above may be maintained.
  • CDR sequences as defined above may be maintained.
  • the CDR sequences as defined above may be maintained.
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 90% or more (e.g., 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 223 and a light chain variable region (VL) comprising the amino acid sequence having 90% or more (e.g., 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 224.
  • VH heavy chain variable region
  • VL light chain variable region
  • CDR sequences as defined above may be maintained.
  • CDR sequences as defined above dasheavy chain CDR1 , CDR2, and CDR3 sequences as set forth in SEQ ID NO: 225, SEQ ID NO: 226, and SEQ ID NO: 227, respectively; and light chain CDR1 , CDR2, and CDR3 sequences as set forth in SEQ ID NO: 228, SEQ ID NO: 229 (or 230), and SEQ ID NO: 231 , respectively
  • CDR sequences as defined above may be maintained.
  • CDR sequences as defined above may be maintained.
  • CDR sequences as defined above dasheavy chain CDR1 , CDR2, and CDR3 sequences as set forth in SEQ ID NO: 242, SEQ ID NO: 243, and SEQ ID NO: 244, respectively; and light chain CDR1 , CDR2, and CDR3 sequences as set forth in SEQ ID NO: 245, SEQ ID NO: 31 (or 32), and SEQ ID NO: 246, respectively
  • CDR sequences as defined above may be maintained.
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 95% or more (e.g., 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 50 and a light chain variable region (VL) comprising the amino acid sequence having 95% or more (e.g., 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 51 .
  • VH heavy chain variable region
  • VL light chain variable region
  • CDR sequences as defined above may be maintained.
  • CDR sequences as defined above dasheavy chain CDR1 , CDR2, and CDR3 sequences as set forth in SEQ ID NO: 225, SEQ ID NO: 226, and SEQ ID NO: 227, respectively; and light chain CDR1 , CDR2, and CDR3 sequences as set forth in SEQ ID NO: 228, SEQ ID NO: 229 (or 230), and SEQ ID NO: 231 , respectively
  • the antibody of the invention comprises (i) a heavy chain variable region (VH) comprising an amino acid sequence having 95% or more (e.g., 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 256 and a light chain variable region (VL) comprising the amino acid sequence having 95% or more (e.g., 96%, 97%, 98%, 99% or more) identity to SEQ ID NO: 257.
  • VH heavy chain variable region
  • VL light chain variable region
  • the antibody, or an antigen-binding fragment thereof, according to the present invention may comprise a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 26 and a light chain variable region comprising the amino acid sequence according to SEQ ID NO: 27.
  • the antibody is of the allotype d m3 with no G1 m1 (G1 m3,-1 ). In some embodiments, the antibody is of the G1 m17,1 allotype. In some embodiments, the antibody is of the G1 m3,1 allotype. In some embodiments, the antibody is of the allotype G1 m17 with no G1 m1 (G 1 ml 7,-1 ).
  • these allotypes may be combined (or not combined) with the G1 m2, G1 m27 or G1 m28 allotype. For example, the antibody may be of the G1 m! 7,1 ,2 allotype.
  • the Fc moiety may be modified such that it varies in amino acid sequence from the complete Fc moiety of a naturally occurring immunoglobulin molecule, while retaining at least one desirable function conferred by the naturally-occurring Fc moiety.
  • Such functions include Fc receptor (FcR) binding, antibody half-life modulation, ADCC function, protein A binding, protein C binding, and complement binding.
  • FcR Fc receptor
  • ADCC ADCC function
  • protein A binding protein C binding
  • complement binding complement binding.
  • two regions of native IgG Fc appear to be critical for interactions of FcyRDs and IgGs, namely (i) the lower hinge site of IgG Fc, in particular amino acid residues L, L, G, G (234 - 237, EU numbering), and (ii) the adjacent region of the CH2 domain of IgG Fc, in particular a loop and strands in the upper CH2 domain adjacent to the lower hinge region, e.g. in a region of P331 (Wines, B.D., et al., J. Immunol. 2000; 164: 5313 - 5318).
  • the invention also provides a nucleic acid molecule comprising a polynucleotide encoding the antibody according to the present invention, or an antigenbinding fragment thereof, as described above.
  • nucleic acid molecules and/or polynucleotides include, e.g., a recombinant polynucleotide, a vector, an oligonucleotide, an RNA molecule such as an rRNA, an mRNA, an miRNA, an siRNA, or a tRNA, or a DNA molecule such as a cDNA.
  • Nucleic acids may encode the light chain and/or the heavy chain of an antibody. In other words, the light chain and the heavy chain of the antibody may be encoded by the same nucleic acid molecule (e.g., in bicistronic manner). Alternatively, the light chain and the heavy chain of the antibody may be encoded by distinct nucleic acid molecules.
  • the nucleic acid molecule may be manipulated to insert, delete or alter certain nucleic acid sequences. Changes from such manipulation include, but are not limited to, changes to introduce restriction sites, to amend codon usage, to add or optimize transcription and/or translation regulatory sequences, etc. It is also possible to change the nucleic acid to alter the encoded amino acids. For example, it may be useful to introduce one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) amino acid substitutions, deletions and/or insertions into the antibody's amino acid sequence.
  • the second nucleic acid molecule comprises a polynucleotide encoding the light chain of an antibody, or an antigen-binding fragment thereof, the polynucleotide comprising: (A) nucleotide sequences according to SEQ ID NOs 79, 80 (or 81 ), and 82, or sequence variants thereof; or (B) nucleotide sequences according to SEQ ID NOs 79, 80 (or 86), and 82, or sequence variants thereof; or (C) nucleotide sequences according to SEQ ID NOs 92, 93 (or 94), and 95, or sequence variants thereof; or (D) nucleotide sequences according to SEQ ID NOs 79, 101 (or 102), and 103, or sequence variants thereof; or (E) nucleotide sequences according to SEQ ID NOs 109, 110 (or 1 1 1 ), and 1 12, or sequence variants thereof; or (F) nucleotide sequences according to SEQ ID NOs
  • Such a combination usually encodes the antibody, or an antigen-binding fragment thereof, of the present invention as described above.
  • the above description regarding the (general) features of the nucleic acid molecule of the invention applies accordingly to the first and second nucleic acid molecule of the combination.
  • preferred sequence combinations are those of the combined six CDR sequences (or the combined VH/VL sequences) of the exemplified antibodies shown in Table 2.
  • the cells of the present invention may be transfected stably or transiently with the vector according to the present invention, e.g. for expressing the antibody according to the present invention.
  • the cells are stably transfected with the vector according to the present invention encoding the antibody according to the present invention.
  • the cells are transiently transfected with the vector according to the present invention encoding the antibody according to the present invention.
  • WO 2010/046775 Another exemplified method is described in WO 2010/046775.
  • plasma cells are cultured in limited numbers, or as single plasma cells in microwell culture plates.
  • Antibodies can be isolated from the plasma cell cultures.
  • Any suitable host cell/vector system may be used for expression of the DNA sequences encoding the antibody molecules of the present invention.
  • Eukaryotic, e.g., mammalian, host cell expression systems may be used for production of antibody molecules, such as complete antibody molecules.
  • Suitable mammalian host cells include, but are not limited to, CHO, HEK293T, PER.C6, NSO, myeloma or hybridoma cells.
  • prokaryotic, e.g. bacterial host cell expression systems may be used for the production of antibody molecules, such as complete antibody molecules.
  • Suitable bacterial host cells include, but are not limited to, £ coli cells.
  • recombinant cells of the invention can then be used for expression and culture purposes. They are particularly useful for expression of antibodies for large-scale pharmaceutical production. They can also be used as the active ingredient of a pharmaceutical composition. Any suitable culture technique can be used, including but not limited to static culture, roller bottle culture, ascites fluid, hollow-fiber type bioreactor cartridge, modular minifermenter, stirred tank, microcarrier culture, ceramic core perfusion, etc.
  • the invention also comprises a method for preparing an antibody (e.g., for pharmaceutical use) according to the present invention, comprising the steps of: (i) obtaining and/or sequencing one or more nucleic acids (e.g., heavy and light chain genes from the selected B cell clone or the cultured plasma cells) encoding the antibody of interest; (ii) inserting the nucleic acid(s) into or using the nucleic acid(s) sequence(s) to prepare an expression vector; (iii) transfecting a host cell (for expression of the antibody of interest); (iv) culturing or subculturing the transfected host cells, in particular under conditions where the antibody of interest is expressed; and, optionally, (v) purifying the antibody of interest.
  • nucleic acids e.g., heavy and light chain genes from the selected B cell clone or the cultured plasma cells
  • the present invention also provides a pharmaceutical composition comprising one or more of:
  • a vehicle is typically understood to be a material that is suitable for storing, transporting, and/or administering a compound, such as a pharmaceutically active compound, in particular the antibodies according to the present invention.
  • the vehicle may be a physiologically acceptable liquid, which is suitable for storing, transporting, and/or administering a pharmaceutically active compound, in particular the antibodies according to the present invention.
  • compositions of this invention may be administered by any number of routes including, but not limited to, oral, intravenous, intramuscular, intra-arterial, intramedullary, intraperitoneal, intrathecal, intraventricular, transdermal, transcutaneous, topical, subcutaneous, intranasal, enteral, sublingual, intravaginal or rectal routes. Hyposprays may also be used to administer the pharmaceutical compositions of the invention.
  • the pharmaceutical composition may be prepared for oral administration, e.g. as tablets, capsules and the like, for topical administration, or as injectable, e.g. as liquid solutions or suspensions.
  • the pharmaceutical composition is an injectable. Solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection are also encompassed, for example the pharmaceutical composition may be in lyophilized form.
  • inventive pharmaceutical composition may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, e.g. including accessible epithelial tissue. Suitable topical formulations are readily prepared for each of these areas or organs.
  • inventive pharmaceutical composition may be formulated in a suitable ointment, containing the inventive pharmaceutical composition, particularly its components as defined above, suspended or dissolved in one or more carriers. Carriers for topical administration include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the inventive pharmaceutical composition can be formulated in a suitable lotion or cream.
  • the amount of the antibody in the pharmaceutical composition according to the present invention may not exceed 1 g or 500 mg. In some embodiments, for a single dose, the amount of the antibody in the pharmaceutical composition according to the present invention, may not exceed 200 mg, or 100 mg. For example, for a single dose, the amount of the antibody in the pharmaceutical composition according to the present invention, may not exceed 50 mg.
  • a method of preparing a pharmaceutical composition comprises the step of: admixing an antibody with one or more pharmaceutically-acceptable carriers, wherein the antibody is a monoclonal antibody that was obtained from a transformed B cell or a cultured plasma cell of the invention.
  • compositions may comprise a sugar alcohol (e.g., mannitol) or a disaccharide (e.g., sucrose or trehalose) e.g., at around 15-30 mg/ml (e.g., 25 mg/ml), particularly if they are to be lyophilized or if they include material which has been reconstituted from lyophilized material.
  • a sugar alcohol e.g., mannitol
  • a disaccharide e.g., sucrose or trehalose
  • the pH of a composition for lyophilization may be adjusted to between 5 and 8, or between 5.5 and 7, or around 6.1 prior to lyophilization.
  • compositions of the invention may also comprise one or more immunoregulatory agents.
  • one or more of the immunoregulatory agents include(s) an adjuvant.
  • the present invention also provides the use of the antibody according to the present invention, or an antigen-binding fragment thereof, the nucleic acid molecule (or the combination of nucleic acid molecules) according to the present invention, the vector (or the combination of vectors) according to the present invention, the cell according to the present invention, or the pharmaceutical composition according to the present invention in the manufacture of a medicament for prophylaxis, treatment or attenuation of coronavirus infection.
  • human coronavirus OC43 HoV-OC43
  • human coronavirus HKU1 HoV- HKU1
  • human coronavirus 229E HoV-229E
  • human coronavirus NL63 HoV-NL63
  • MERS- CoV Middle East respiratory syndrome-related coronavirus
  • SARS-CoV Severe acute respiratory syndrome coronavirus
  • SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2
  • the present invention also provides a combination (therapy), as well as a kit-of-parts, comprising (i) the antibody according to the present invention, or an antigen-binding fragment thereof, the nucleic acid molecule (or the combination of nucleic acid molecules) according to the present invention, the vector (or the combination of vectors) according to the present invention, the cell according to the present invention or the pharmaceutical composition according to the present invention; and (ii) a molecule that can mimic binding to a spike protein receptor, in particular binding to ACE2.
  • the antibody according to the present invention, or an antigen-binding fragment thereof, the nucleic acid molecule (or the combination of nucleic acid molecules) according to the present invention, the vector (or the combination of vectors) according to the present invention, the cell according to the present invention or the pharmaceutical composition according to the present invention may be combined with recombinant soluble human ACE2 protein, e.g.
  • Suitable antibodies mimicking ACE2, which may be useful for the combination with the antibody according to the present invention, or an antigen-binding fragment thereof, the nucleic acid molecule (or the combination of nucleic acid molecules) according to the present invention, the vector (or the combination of vectors) according to the present invention, the cell according to the present invention or the pharmaceutical composition according to the present invention are known in the art and described, for example, in Tortorici et al., 2020 (Tortorici MA, Beltramello M, Lempp FA, et al. Ultrapotent human antibodies protect against SARS-CoV-2 challenge via multiple mechanisms. Science. 2020;370(6519):950-957.
  • the recombinant peptide, polypeptide or protein comprises an amino acid sequence according to general formula I or II, wherein X, is A, L or F; X 2 is I or L; and X 3 is N, S, T or D, preferably wherein X 1 is A, L or F; X 2 is I or L; and X 3 is N, S or D.
  • amino acid sequence with at least 80% sequence identity to SEQ ID NO: 8 is preferably mutated at positions X 1 and X 3 of general formula I or at positions X 2 and X 3 of general formula I.
  • An amino acid sequence with at least 90% sequence identity to SEQ ID NO: 8 is preferably mutated at position X 1 , X 2 or X 3 of general formula I.
  • the recombinant peptide, polypeptide or protein comprises (or consists of) an amino acid sequence according to SEQ ID NO: 8.
  • the recombinant peptide, polypeptide or protein comprises (or consists of) an amino acid sequence according to SEQ ID NO: 265 or a sequence variant thereof having at least 70% sequence identity, preferably at least 80% sequence identity and more preferably at least 90% sequence identity.
  • SEQ ID NO: 265 may include one or more (e.g., 1 , 2, 3, 4 or 5) mutations, preferably at any one of positions F3, 14, L7, N10 and/or K1 1 of SEQ ID NO: 265.
  • SEQ ID NO: 265 may include up to three (1 , 2 or 3) mutations.
  • the recombinant peptide, polypeptide or protein comprises (or consists of) an amino acid sequence according to SEQ ID NO: 265 or a sequence variant thereof, wherein R 1 , E 5 and F 9 of SEQ ID NO: 265 are maintained. In some embodiments, the recombinant peptide, polypeptide or protein comprises (or consists of) an amino acid sequence according to SEQ ID NO: 265 or a sequence variant thereof, wherein R 1 , E 5 and F 9 of SEQ ID NO: 265 may be maintained and wherein
  • Ku is substituted with V, T, S, M, I, G, F, E or A, preferably with T, S, M, G, E or A.
  • the recombinant peptide, polypeptide or protein comprises (or consists of) an amino acid sequence according to SEQ ID NO: 267 or a sequence variant thereof having at least 70% sequence identity, preferably at least 80% sequence identity and more preferably at least 90% sequence identity.
  • SEQ ID NO: 267 may include one or more (e.g., 1 , 2, 3, 4 or 5) mutations, preferably at any one of positions F4, I5, L8, N1 1 and/or K12 of SEQ ID NO: 267.
  • SEQ ID NO: 267 may include up to three (1 , 2 or 3) mutations.
  • the recombinant peptide, polypeptide or protein does not contain non-conserved epitopes. In some embodiments, the recombinant peptide, polypeptide or protein does not contain an RBD sequence of a coronavirus spike protein. In some embodiments, the recombinant peptide, polypeptide or protein contains a fragment of the coronavirus spike S2 protein, which does not contain a transmembrane domain. In some embodiments, the recombinant peptide, polypeptide or protein contains a fragment of the coronavirus spike S2 protein, which does not contain a heptad repeat (of the coronavirus spike protein).
  • the recombinant peptide, polypeptide or protein contains a fragment of the coronavirus spike S2 protein, which does not contain a central helix (of the coronavirus spike protein). Fragments of the spike protein, in particular fragments restricted to the above-mentioned sequence motifs of the fusion peptide, may be advantageous to specifically elicit an immune response with broadly coronavirus targeting antibodies, while antibodies eliciting viral escape mutants, such as antibodies targeting the RBD, can be avoided.
  • the targeting peptide may have a length of no more than 1000 amino acids, preferably of no more than 500 amino acids, more preferably of no more than 200 amino acids, even more preferably of no more than 100 amino acids, still more preferably of no more than 80 amino acids, particularly preferably of no more than 70 amino acids and most preferably of no more than 50 amino acids.
  • the targeting peptide may have a length from 3 to 70 amino acids.
  • the recombinant peptide, polypeptide or protein according to the present invention may further comprise an immunogenic (poly)peptide.
  • an immunogenic (poly)peptide increases the immunogenicity of the peptide according to the present invention.
  • an immunogenic peptide is, by itself, immunogenic, i.e. able to elicit an immune response.
  • an immunogenic peptide may comprise an antigen/immunogen distinct from the peptide according to the present invention.
  • Many immunogenic peptides are known in the art. Moreover, it is well known to the skilled person how immunogenic peptides can be designed, for example as described in Flower D.R., 2013, Nature Chemical Biology 9(12): 749-753: Designing immunogenic peptides.
  • a "(protein) nanoparticle” refers in particular to a multi-subunit, protein-based polyhedron shaped structure.
  • the subunits are usually each composed of proteins or polypeptides (for example a glycosylated polypeptide), and, optionally of single or multiple features of the following: nucleic acids, prosthetic groups, organic and inorganic compounds.
  • Non-limiting examples of protein nanoparticles include ferritin nanoparticles (see, e.g., Zhang, Y. /nt. J. Mol.
  • ferritin, encapsulin, SOR, lumazine synthase, or pyruvate dehydrogenase monomers are linked to an immunogen according to the present invention as disclosed herein (for example, the recombinant peptide, polypeptide or protein as described herein) and selfassembled into a protein nanoparticle presenting the disclosed antigens on its surface, which can be administered to a subject to stimulate an immune response to the immunogen.
  • Non-limiting example of nanoparticles include ferritin nanoparticles, encapsulin nanoparticles and Sulfur Oxygenase Reductase (SOR) nanoparticles, which are comprised of an assembly of monomeric subunits including ferritin proteins, encapsulin proteins and SOR proteins, respectively.
  • SOR Sulfur Oxygenase Reductase
  • the fusion protein self-assembles into a nanoparticle under appropriate conditions.
  • the pharmaceutical composition in particular the vaccine, may optionally also contain a pharmaceutically acceptable carrier, diluent and/or excipient.
  • a pharmaceutically acceptable carrier may facilitate administration, it should not itself induce the production of antibodies harmful to the individual receiving the composition. Nor should it be toxic.
  • Suitable carriers may be large, slowly metabolized macromolecules such as proteins, polypeptides, liposomes, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers and inactive virus particles.
  • the pharmaceutically acceptable carrier, diluent and/or excipient in the pharmaceutical composition according to the present invention is not an active component in respect to coronavirus infection.
  • liposomes or e.g. biodegradable polymer microspheres, lactide and glycolide, polyphosphazenes, beta-glucan, or e.g. proteinoids.
  • a list of typically used vaccine adjuvants may also be found in "Vaccine Adjuvants", edited by D.T. O'Hogan, Humana Press 2000.
  • the adjuvant comprised in the inventive composition may also include e.g.
  • Figure 2 shows for Example 4 the results of the epitope mapping study, wherein the CLM20_B8 antibody of Example 3 was tested against 118 15-mer peptides (overlapping of 10 peptides) spanning the entire S2 protein, as illustrated in the schematic drawing of the spike protein.
  • Figure 5 shows for Example 5 the results of a substitution scan analysis where each amino acid in the fusion peptide sequence K 8 I I PSKRSFIEDLLFNKVTLAD 8 3O (SEQ ID NO: 266) was substituted stepwise with all 20 main amino acids for antibodies CLM20_C9 (A), ISR42_E7 (B), CLM20_B8 (C), CSC3_H1 (D), E371. F8 (E), E1373_G3 (F), E2121_B7 (G) and E2418_G12 (H). Results are shown as heatmaps with the fusion peptide epitope amino acids at the x-axes and substitution amino acids at the y-axes. The binding affinity (in %) relative to the native residue (KPSKRSFIEDLLFNKVTLAD; SEQ ID NO: 266) is shown.
  • Figure 6 shows for Example 6 the results for SARS-CoV, SARS-CoV-2, MERS and 229E pseudovirus neutralization for each of the antibodies as indicated in the figure.
  • Titrating doses of purified antibodies were assessed for their ability to neutralize: SARS-CoV-2 pseudotyped particles in 293T-ACE2-TMPRSS2 cell lines; SARS-CoV in 293T-ACE2-TMPRSS2 cel! line; MERS-CoV in Huh7- TMPRSS2 cell line; and 229E in Huh7-TMPRSS2 cell line.
  • EC50 neutralization values ( ⁇ g/ml) are shown.
  • Purified antibodies were tested against a panel of 1 18 15-mer peptides (overlapping of 10) spanning the entire SARS-CoV-2 S2 protein (Spike676-Spike1273). Briefly, each well of the plate was coated with 8ug/ml of each of the 1 18 15-mer peptides. ELISA was performed as described above using 0.6ug/ml of purified CLM20_B8 antibody as primary antibody in each individual well.
  • E2418_G12 Fab and scFv formats and CSC3_H1 scFv formats were more effective in inhibiting the fusion activity compared to their respective full length IgG. This indicates that smaller antibody footprints, such as Fab fragments, scFv or nanobodies have more potent neutralization capacity.
  • Results are shown in Figure 8. The bindings of all antibodies are enhanced in the presence of recombinant ACE2-mFc in a dose dependent manner, indicating that the spike protein undergoes a conformational change after ACE2 binding, and the FP epitope is exposed in the intermediate conformation.
  • Example 10 In vivo neutralization of live viruses

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Abstract

La présente invention concerne des anticorps et des fragments de liaison à l'antigène de ceux-ci, qui se lient à la protéine de spicule (S) des coronavirus. Les anticorps, et des fragments de liaison à l'antigène de ceux-ci, ciblent sur un large spectre des coronavirus, comprenant différents alpha-et bêta-coronavirus. L'invention concerne également des acides nucléiques qui codent pour de tels anticorps et fragments d'anticorps et des cellules qui expriment de tels anticorps et fragments d'anticorps. De plus, l'invention concerne l'utilisation des anticorps et des fragments d'anticorps dans le traitement et le diagnostic d'une infection à coronavirus. En outre, l'invention concerne un peptide, un polypeptide ou une protéine de recombinaison comprenant l'épitope, auquel les anticorps se lient, et pouvant être utile dans la vaccination.
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CN118440186A (zh) * 2023-01-05 2024-08-06 郴州市第一人民医院 一种广谱抗SARS-like冠状病毒和/或新冠突变株的抗体及其应用
CN118852420A (zh) * 2024-08-16 2024-10-29 东北农业大学 一种猪δ冠状病毒中和性单克隆抗体及其应用
CN119592517A (zh) * 2024-10-08 2025-03-11 河南农业大学 一种抗猪δ冠状病毒S2亚基的单克隆抗体及其杂交瘤细胞株和应用

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CN118440186A (zh) * 2023-01-05 2024-08-06 郴州市第一人民医院 一种广谱抗SARS-like冠状病毒和/或新冠突变株的抗体及其应用
CN118852420A (zh) * 2024-08-16 2024-10-29 东北农业大学 一种猪δ冠状病毒中和性单克隆抗体及其应用
CN119592517A (zh) * 2024-10-08 2025-03-11 河南农业大学 一种抗猪δ冠状病毒S2亚基的单克隆抗体及其杂交瘤细胞株和应用
CN119592517B (zh) * 2024-10-08 2025-09-19 河南农业大学 一种抗猪δ冠状病毒S2亚基的单克隆抗体及其杂交瘤细胞株和应用

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