WO2024026553A1 - Nouvel épitope antigénique anti-sars-cov-2 et ses utilisations - Google Patents
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Classifications
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- 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
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- 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
- A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
- A61K2039/575—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 humoral response
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- 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
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
- C07K16/1002—Coronaviridae
- C07K16/1003—Severe acute respiratory syndrome coronavirus 2 [SARS‐CoV‐2 or Covid-19]
-
- 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
- C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
-
- 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
- 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
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/16011—Human Immunodeficiency Virus, HIV
- C12N2740/16041—Use of virus, viral particle or viral elements as a vector
- C12N2740/16043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
-
- 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
- C12N2770/20022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
-
- 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 disclosure generally relates to viral infection, and more particularly to the prevention and/or treatment of coronavirus infection such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
- coronavirus infection such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
- SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
- Coronaviruses are large, roughly spherical, RNA viruses with bulbous surface projections that cause diseases in mammals and birds. In humans, these viruses cause respiratory tract infections that can range from mild to lethal. Mild illnesses include some cases of the common cold (which is also caused by other viruses, predominantly rhinoviruses), while more lethal varieties can cause severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and Coronavirus disease 2019 (COVID-19). Coronaviruses have four structural proteins, namely the Spike (S), Envelope (E), and Membrane (M) proteins, forming the viral envelope, as well as the Nucleocapsid (N) protein, holding the viral RNA genome.
- S Spike
- E Envelope
- M Membrane
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the strain of coronavirus that causes COVID-19, the respiratory illness responsible for the COVID-19 pandemic.
- the spike protein SARS-CoV-2 is the glycoprotein responsible for allowing the virus to attach to and fuse with the membrane of a host cell; specifically, its S1 subunit catalyzes attachment, the S2 subunit fusion.
- the main receptor involved in SARS-CoV-2 entry into human cells is the angiotensin converting enzyme 2 (ACE2).
- TMPRSS2 protease transmembrane protease, serine 2
- SARS-CoV-2 Multiple variants of SARS-CoV-2 are circulating globally and within the United States. Three new variants that have rapidly become dominant within their countries have aroused concerns: B.1.1.7 (also known as VCC-202012/01), 501Y.V2 (B.1.351), and P.1 (B.1.1.28.1).
- the B.1.1.7 variant (23 mutations with 17 amino acid changes) was first described in the United Kingdom in December 2020; the 501Y.V2 variant (23 mutations with 17 amino acid changes) was initially reported in South Africa in December 2020; and the P.1 variant (approximately 35 mutations with 17 amino acid changes) was reported in Brazil in January 2021 .
- the B.1.1.7 variant had been reported in 93 countries, the 501Y.V2 variant in 45, and the P.1 variant in 21. All three variants have the N501Y mutation, which changes the amino acid asparagine (N) to tyrosine (Y) at position 501 in the receptor-binding domain of the spike protein.
- the 501Y.V2 and P.1 variants both have two additional receptor-binding-domain mutations, K417N/T and E484K. These mutations increase the binding affinity of the receptorbinding domain to the angiotensin-converting enzyme 2 (ACE2) receptor.
- ACE2 angiotensin-converting enzyme 2
- SARS-CoV-2 variants B.1.427 and B.1.429, which were first detected in California, have been shown to be approximately 20% more transmissible than preexisting variants and have been classified by the CDC as variants of concern. Studies on these variants have provided compelling evidence that they have the potential to escape naturally-induced immunity as well as the immunity induced by currently approved vaccines.
- SARS-CoV-2 the etiologic agent of COVID-19
- the current pandemic is aggravated by the apparition of variants of concern that are feared to result in an antigenic drift that could evade vaccine-elicited immune responses.
- the present invention provides the following items 1 to 39:
- the antigenic peptide of item 1 which comprises at least 6 contiguous amino acids from the sequence DKYFKNHTSPD.
- the antigenic peptide of item 1 which comprises at least 7 contiguous amino acids from the sequence DKYFKNHTSPD.
- the antigenic peptide of item 1 which comprises at least 8 contiguous amino acids from the sequence DKYFKNHTSPD.
- the antigenic peptide of item 1 which comprises at least 9 contiguous amino acids from the sequence DKYFKNHTSPD.
- the antigenic peptide of item 1 which comprises the amino acid sequence DKYFKNHTSPD.
- a conjugate comprising the antigenic peptide of any one of items 1 to 10 conjugated to a vaccine carrier.
- a vesicle comprising the antigenic peptide of any one of items 1 to 10, the conjugate of item 11 , or the nucleic acid of item 12 or 13.
- a pharmaceutical composition comprising the antigenic peptide of any one of items 1 to 10 the conjugate of item 11 , the nucleic acid of item 12 or 13, or the vesicle of item 14, and a pharmaceutically acceptable excipient.
- a vaccine comprising the antigenic peptide of any one of items 1 to 10, the conjugate of item 11 , the nucleic acid of item 12 or 13, the vesicle of item 14, or the composition of item 15, and a vaccine adjuvant.
- a method for inducing an immune response against a beta-coronavirus in a subject in need thereof comprising administering to the subject an effective amount of the antigenic peptide of any one of items 1 to 10, the conjugate of item 11 , the nucleic acid of item 12 or 13, the vesicle of item 14, the composition of item 15, or the vaccine of item 16.
- a method for preventing or treating a beta-coronavirus infection or a related disease in a subject in need thereof comprising administering to the subject an effective amount of the antigenic peptide of any one of items 1 to 10, the conjugate of item 11 , the nucleic acid of item 12 or 13, the vesicle of item 14, the composition of item 15, or the vaccine of item 16.
- a method for reducing the risk of developing a beta-coronavirus-related disease or the severity thereof in a subject in need thereof comprising administering to the subject an effective amount of the antigenic peptide of any one of items 1 to 10, the conjugate of item 11 , the nucleic acid of item 12 or 13, the vesicle of item 14, the composition of item 15, or the vaccine of item 16.
- beta-coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the beta-coronavirus-related disease is Coronavirus disease 2019 (COVID-19).
- SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
- coronavirus-related disease is Coronavirus disease 2019 (COVID-19).
- beta-coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the beta-coronavirus-related disease is Coronavirus disease 2019 (COVID-19).
- SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
- coronavirus-related disease is Coronavirus disease 2019 (COVID-19).
- SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
- SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
- COVID-19 Coronavirus disease 2019
- a pharmaceutical composition comprising the isolated antibody or antigen-binding fragment thereof of item 32 or 33, and a pharmaceutically acceptable excipient.
- a method for identifying neutralizing antibodies against a beta-coronavirus comprising contacting the antigenic peptide defined in any one of items 1 to 10 with a composition comprising antibody candidates, wherein the antibodies that bind to the antigenic peptide are neutralizing antibodies against a beta-coronavirus
- FIGs. 1A-D show the cell-surface staining of 293T cells expressing full-length Spike harboring mutations from different SARS-CoV-2 variants, namely the B.1.1.7 variant (FIG. 1A), the B.1.351 variant (FIG. 1B), the B.1.525 variant (FIG. 1 C) and other variants of interest (FIG. 1D).
- the recognition of cell-surface Spike by CV3-25 mAb was determined by flow cytometry using fluorescent anti-human IgG secondary Abs.
- the graphs represent the median fluorescence intensities (MFI) obtained on the GFP+ transfected cell population. Error bars indicate means ⁇ SEM.
- FIG. 2 shows that CV3-25 neutralizes Spike variants efficiently.
- Pseudoviral particles coding for the luciferase reporter gene and bearing the SARS-CoV-2 Spike glycoproteins from the Wuhan original strain or the B.1.1.7 variant were used to infect 293T-ACE2 cells.
- Neutralizing activity was measured by incubating pseudoviruses with titrated concentrations of CV3-25 mAb at 37°C for 1 h prior to infection of 293T-ACE2 cells. Error bars indicate means ⁇ SEM.
- FIGs. 3A-C show that CV3-25 recognizes the Spike connector domain.
- FIG. 3A SARS- CoV-2 Spike sequence depicting the different subunits and domains composing the full length Spike protein. Pools of peptide covering the whole S2 subunit sequence were used to identify the region recognized by CV3-25 mAb.
- FIG. 3B SARS-CoV-2 Spike structure depiction from reference 10 with the connector domain (CD) region is highlighted.
- FIG. 3C Indirect ELISA was performed using SARS-CoV-2 S2 peptide pools and incubation with the CV3-25 mAb. CV3-25 binding was detected using HRP-conjugated anti-human IgG and was quantified by relative light units (RLU). Peptide pools with significant positive signal were highlighted by arrows (peptide pools #49 and #50).
- FIGs. 4A-C show that CV3-25 recognizes a linear peptide located in the Spike connector domain.
- FIG. 4A Depiction of the SARS-CoV-2 Spike individual peptides from the peptide pools #49 and #50, with a 4 amino acid residue overhang. Individual peptides covering the S2 connector domain region were used to identify the region recognized by CV3-25 mAb.
- FIG. 4B Indirect ELISA was performed using SARS-CoV-2 S2 individual peptides and incubation with the CV3-25 mAb. CV3-25 binding was detected using HRP-conjugated anti-human IgG and was quantified by relative light units (RLU).
- RLU relative light units
- FIG. 4C Amino acid sequence of peptides recognized by CV3-25 (peptides #288 (SEQ ID NO:3) and #289 (SEQ ID NO:4), indicated by arrows) and of neighboring peptides not recognized by CV3-25 (peptides #287 (SEQ ID NO:2) and #290 (SEQ ID NO:5)).
- FIG. 4D is a graph showing cell-surface staining of 293T cells expressing the wild-type SARS-CoV-2 Spike with CV3-25 mAb in presence of increasing concentrations of S2 peptides #288 (15-mer), #289 (15-mer), #289 (11-mer) or a scrambled peptide (15-mer) as a control.
- the graphs show the median fluorescence intensities (MFIs) normalized to the condition without any peptide (OpM). Error bars indicate means ⁇ SEM.
- MFIs median fluorescence intensities
- FIG. 4E Pseudoviruses encoding for the luciferase reporter gene and bearing SARS- CoV-2 Spike D614G were used to infect 293T-hACE2 target cells. Pseudovirions were incubated with CV3-2 5mAb (10pg/mL) in presence of increasing concentrations of S2 peptide #289, or peptide scramble as a control, for 1 h at 37°C prior infection of 293T-hACE2 cells for 48h at 37°C. Error bars indicate means ⁇ SEM. Statistical significance was tested using an unpaired T test. These results were obtained from at least 3 independent experiments.
- FIGs. 4F-G Binding of CV3-25 (FIG. 4F) and CV3-1 (FIG. 4G) to 293T cells expressing selected full-length Spike harboring S2 mutations.
- the graphs shown the median fluorescence intensities (MFIs). Dashed lines indicate the reference value obtained with Spike D614G(WT). These results were obtained in 3 independent experiments. Statistical significance was tested using a paired T test (**p ⁇ 0.01 ; ***p ⁇ 0.001 ; ****p ⁇ 0.0001 ; ns, non-significant).
- FIG. 4H shows a sequence alignment of the S glycoprotein stem-peptide regions from representative beta-coronaviruses and two human alpha-coronaviruses. The identical residues relative SARS-CoV-2 S protein are in bold and the conservative changes are underlined.
- FIG. 4I shows a sequence alignment of the 1149-1167 domains from various SARS- CoV-2 variants of interest.
- FIGs. 5A and 5B depict the amino acid sequences of the variable regions of the heavy chain (FIG. 5A, SEQ ID NO:6) and light chain (FIG. 5B, SEQ ID NO:7) of the CV3-25 mAb.
- the term “about” has its ordinary meaning.
- the term “about” is used to indicate that a value includes an inherent variation of error for the device or the method being employed to determine the value, or encompass values close to the recited values, for example within 10% or 5% of the recited values (or range of values).
- the present inventors have identified the epitope recognized by antibody CV3-25 on the SARS-CoV-2 Spike S2 subunit, defined as a linear peptide located on the connector domain region.
- This linear peptide was shown to be fully conserved in various SARS-CoV-2 variants, and highly conserved among various betacoronaviruses, which is consistent with the demonstration that antibody CV3-25 has the ability to potently neutralize SARS-CoV-2 and its different variants, including the B.1.351 variant (South Africa) and the B.1.1.7 variant (UK) variants of concern (VOC), as well as the closely related SARS-CoV-1 (2,3).
- VOC closely related SARS-CoV-1
- the present disclosure provides a peptide, e.g., an antigenic peptide, of 20 amino acid or less comprising or consisting of at least 5 contiguous amino acids from the sequence DKYFKNHTSPD (SEQ ID NO:1).
- the 5 contiguous amino acids may be DKYFK (SEQ ID NO:8), KYFKN (SEQ ID NO:9), YFKNH (SEQ ID NQ:10), FKNHT (SEQ ID NO:11), KNHTS (SEQ ID NO:12), NHTSP (SEQ ID NO:13) or HTSPD (SEQ ID NO:14).
- the antigenic peptide comprises or consists of at least 6 contiguous amino acids from the sequence DKYFKNHTSPD (SEQ ID NO:1).
- the 6 contiguous amino acids may be DKYFKN (SEQ ID NO: 15), KYFKNH (SEQ ID NO: 16), YFKNHT (SEQ ID NO: 17), FKNHTS (SEQ ID NO:18), KNHTSP (SEQ ID NO:19), or NHTSPD (SEQ ID NO:20).
- the antigenic peptide comprises or consists of at least 7 contiguous amino acids from the sequence DKYFKNHTSPD (SEQ ID NO:1).
- the 7 contiguous amino acids may be DKYFKNH (SEQ ID NO:21), KYFKNHT (SEQ ID NO:22), YFKNHTS (SEQ ID NO:23), FKNHTSP (SEQ ID NO:24) or KNHTSPD (SEQ ID NO:25).
- the antigenic peptide comprises or consists of at least 8 contiguous amino acids from the sequence DKYFKNHTSPD (SEQ ID NO:1).
- the 8 contiguous amino acids may be DKYFKNHT (SEQ ID NO:26), KYFKNHTS (SEQ ID NO:27), YFKNHTSP (SEQ ID NO:28) or FKNHTSPD (SEQ ID NO:29).
- the antigenic peptide comprises or consists of at least 9 contiguous amino acids from the sequence DKYFKNHTSPD (SEQ ID NO:1).
- the 9 contiguous amino acids may be DKYFKNHTS (SEQ ID NQ:30), KYFKNHTSP (SEQ ID NO:31) or YFKNHTSPD (SEQ ID NO:32).
- the antigenic peptide has a length of 19, 18, 17, 16 or 15 amino acids or less. In further embodiments, the antigenic peptide has a length of 14, 13, 12 or 11 amino acids or less.
- the antigenic peptide has a length of 5, 6 or 7 amino acids or more. In further embodiments, the antigenic peptide has a length of 8, 9 or 10 amino acids or more.
- the antigenic peptide comprises 5, 6, 7 residues to 18, 19 or 20 residues. In embodiments, the antigenic peptide comprises 5, 6, 7 residues to 13, 14 or 15 residues. In further embodiments, the antigenic peptide comprises 7 or 8 residues to 12 or 13 residues, or from 8 or 9 residues to 11 or 12 residues. In further embodiments, the antigenic peptide comprises 8, 9, 10, 11 or 12 amino acids. In another embodiment, the antigenic peptide comprises at least 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14 or amino acids from the sequence KEELDKYFKNHTSPDVDLG (SEQ ID NO:33).
- the antigenic peptide may comprise or consists of sequences such as LDKYFK (SEQ ID NO:34), LDKYFKN (SEQ ID NO:35), LDKYFKNH (SEQ ID NO:36), LDKYFKNHT (SEQ ID NO:37), LDKYFKNHTS (SEQ ID NO:38), LDKYFKNHTSP (SEQ ID NO:39), LDKYFKNHTSPD (SEQ ID NQ:40), ELDKYFK (SEQ ID NO:41), ELDKYFKN (SEQ ID NO:42), ELDKYFKNH (SEQ ID NO:43), ELDKYFKNHT (SEQ ID NO:44), ELDKYFKNHTS (SEQ ID NO:45), ELDKYFKNHTSP (SEQ ID NO:46), ELDKYFKNHTSPD (SEQ ID NO:47), EELDKYFKNH (SEQ ID NO:48),
- the antigenic peptide comprises or consists of the amino acid sequence KEELDKYFKNHTSPD (SEQ ID NO:59). In an embodiment, the antigenic peptide comprises or consists of the amino acid sequence DKYFKNHTSPDVDLG (SEQ ID NO:87). In an embodiment, the antigenic peptide comprises or consists of the amino acid sequence DKYFKNHTSPDVD (SEQ ID NO:73) In an embodiment, the antigenic peptide comprises or consists of the amino acid sequence DKYFKNHTSPD (SEQ ID NO:1).
- antigenic peptide refers to a peptide that comprises an epitope bound by antibodies that specifically recognize the Spike (S) protein of a coronavirus, more specifically a beta-coronavirus, such as SARS-CoV-2.
- S Spike
- coronavirus more specifically a beta-coronavirus, such as SARS-CoV-2.
- the above-mentioned antigenic peptide may comprise, further to the sequence defined above, one more amino acids (naturally occurring or synthetic) covalently linked to the amino- and/or carboxy-termini of said sequence.
- the above- mentioned antigenic peptide comprises up to 5 additional amino acids at the N- and/or C-termini to the sequence defined above.
- the above-mentioned antigenic peptide comprises up to 5, 4, 3, 2, or 1 additional amino acids at the N- and/or C-termini of the sequence defined above.
- the additional amino acids at the N- and/or C-termini of the sequence are not the amino acid(s) flanking the sequence defined in the Spike protein.
- the antigenic peptide does not comprise more than 19, 18, 17, 16, 15, 14, 13, 12, 11 or 10 consecutive amino acids from the Spike protein of a coronavirus, preferably SARS- CoV-2.
- the native amino-terminal and/or carboxy-terminal end of the peptide may be modified using amino-terminal and/or carboxy-terminal modifying groups.
- amino-terminal modifying group refers to a moiety commonly used in the art of peptide chemistry to replace or modify the native NH 2 terminal group of the antigenic peptide, for example to increase its stability and/or susceptibility to protease digestion.
- the amino-terminal modifying group may be a straight chained or branched alkyl group of one to eight carbons, or an acyl group (R A -CO-), wherein R A is a hydrophobic moiety (e.g., alkyl, such as methyl, ethyl, propyl, butanyl, iso-propyl, or iso-butanyl), or an aroyl group (Ar-CO-), wherein Ar is an aryl group.
- R A is a hydrophobic moiety
- Ar is an aryl group.
- the acyl group may be a C1-C16 or C3-C16 acyl group (linear or branched, saturated or unsaturated), such as a saturated Ci-C 6 acyl group (linear or branched) or an unsaturated C 3 -C 6 acyl group (linear or branched), for example an acetyl group (CH3-CO-, Ac).
- the antigenic peptide has a native NH 2 terminal group.
- carboxy-terminal modifying group refers to a moiety commonly used in the art of peptide chemistry to replace or modify the native CO 2 H terminal group of the peptide, for example to increase its stability and/or susceptibility to protease digestion.
- the carboxy-terminal modifying group may be:
- an amine attached to the carboxyl group (-C( O)-NR B R c ), the amine being a primary, secondary or tertiary amine, and preferably the amine is an aliphatic amine preferably of one to ten carbons, such as methyl amine, iso-butylamine, iso-valerylamine or cyclohexylamine, an aromatic amine or an arylalkyl amine, such as aniline, napthylamine, benzylamine, cinnamylamine, or phenylethylamine, a preferred amine being -NH 2 ,
- a hydroxyalkyl i.e. an alcohol
- a hydroxyalkyl i.e. an alcohol
- the antigenic peptide has a native CO 2 H terminal group.
- the antigenic peptide may also be a peptidomimetic.
- a peptidomimetic is typically characterised by retaining the polarity, three-dimensional size and functionality (bioactivity) of its peptide equivalent, but wherein one or more of the peptide bonds/linkages have been replaced, often by more stable linkages.
- the bond which replaces the amide bond conserves many or all of the properties of the amide bond, e.g. conformation, steric bulk, electrostatic character, potential for hydrogen bonding, etc.
- Typical peptide bond replacements include esters, polyamines and derivatives thereof as well as substituted alkanes and alkenes, such as aminomethyl and ketomethylene.
- Such peptidomimetics may have greater chemical stability, enhanced biological/pharmacological properties (e.g., half-life, absorption, potency, efficiency, etc.) and/or reduced antigenicity relative its peptide equivalent.
- the antigenic peptide only comprises native peptide bonds.
- Antigenic peptides may be synthesized using methods well known in the art, for example by solid-phase synthesis as well as by conventional organic synthesis.
- the antigenic peptide described herein may further comprise one or more modifications that confer additional biological properties to the antigenic peptide such as protease resistance, plasma protein binding, increased plasma half-life, intracellular penetration, etc.
- modifications include, for example, covalent attachment of molecules/moiety to the antigenic peptide (e.g., the molecule in formula II above) such as fatty acids (e.g., C 6 -Ci 8 ), attachment of proteins such as albumin (see, e.g., U.S. Patent No. 7,268,113); sugars/polysaccharides (glycosylation), biotinylation or PEGylation (see, e.g., U.S. Patent Nos. 7,256,258 and 6,528,485).
- the antigenic peptide may also be conjugated to a molecule that increases its immunogenicity, including carrier proteins such as keyhole limpet hemocyanin (KLH), bovine serum albumin (BSA), human serum albumin (HSA) and ovalbumin (OVA), and/or polysaccharides.
- KLH keyhole limpet hemocyanin
- BSA bovine serum albumin
- HSA human serum albumin
- OVA ovalbumin
- the present disclosure provides a conjugate comprising the antigenic peptide described herein and one or more additional molecules or agents (hereinafter secondary molecules or agents).
- the antigenic peptide may be conjugated to any type of synthetic or natural secondary molecules or agents, such as peptides, proteins, saccharides/polysaccharides, lipids, naturally-occurring or synthetic polymers/co-polymers, etc. to modify one or more properties of the antigenic peptide.
- the antigenic peptide is conjugated to a vaccine carrier, i.e. a molecule or agent that increases the immunogenicity of the antigenic peptide, such as polysaccharides derived from microorganisms (e.g., bacteria).
- vaccine carriers examples include tetanus toxoid (TT), diphtheria toxoid (D) and mutant diphtheria toxin (CRM 197).
- TT tetanus toxoid
- D diphtheria toxoid
- CCM 197 mutant diphtheria toxin
- the antigenic peptide may be conjugated to more than one secondary molecules or agents (which may be the same or different), or several antigenic peptide molecules may be conjugated to a single secondary molecule or agent, such as a vaccine carrier.
- the antigenic peptide described herein is conjugated to a selfassembling peptide or protein, i.e. a peptide or protein having the ability to form aggregates or supramolecular structures (e.g., nanoparticles).
- Such peptides or proteins may comprise selfassembling motifs such as coiled-coil motifs and/or p-sheet-rich quaternary motifs (e.g., cross-p- sheet), and have the ability to form assemblies mimicking viral capsid structures including nanorings, polyhedral cages and nanoparticles, or pathogen-associated suprastructures (bacterial flagella and pili) including nanofilaments (or fibrils) and nanotubes.
- selfassembling motifs such as coiled-coil motifs and/or p-sheet-rich quaternary motifs (e.g., cross-p- sheet)
- p-sheet-rich quaternary motifs e.g., cross-p- sheet
- selfassembling peptides or proteins examples include the Q11 synthetic peptide (Ac-QQKFQFQFEQQ-Am), peptide (SNNFGAILSS-Am) derived from the amyloidogenic peptide islet amyloid polypeptide (IAPP), p-annulus peptide (INHVGGTGGAIMAPVAVTRQLVGS) from tomato bushy stunt virus capsid, the D123-Ferritin peptide, engineered outer domain germline targeting (eOD-GT6, eOD- GT8), IMX313 (coiled-coil heptamerizing domain of the complement C4 binding protein (C4bp)), Lumazine synthase, E2, 110 peptide, Coil29, FliC, LS, SAP and nucleoprotein (see, e.g., Zottig et al., Nanomaterials 2020, 10, 1008).
- Q11 synthetic peptide Ac-QQKFQFQFEQQ-Am
- the conjugate comprises a covalent link or bond between the antigenic peptide and the molecule conjugated thereto.
- the molecule may be conjugated directly to the antigenic peptide, or indirectly via a linker.
- the linker may be a polypeptide linker comprising one or more amino acids or another type of chemical linker (e.g., a carbohydrate linker, a lipid linker, a fatty acid linker, a polyether linker, PEG, etc.
- the molecule may be conjugated/attached to the side chain of one the amino acids of the antigenic peptide.
- Methods for conjugating moieties to side-chains of amino acids are well known in the art.
- chemical groups that react with primary amines (-NH2) present in the side-chain of lysine residues such as isothiocyanates, isocyanates, acyl azides, NHS esters, sulfonyl chlorides, aldehydes, glyoxals, epoxides, oxiranes, carbonates, aryl halides, imidoesters, carbodiimides, anhydrides, and fluorophenyl esters may be used to conjugate the molecule to the antigenic peptide.
- the present disclosure provides a nucleic acid (isolated) encoding the herein-mentioned antigenic peptide.
- the nucleic acid comprises from about 15 nucleotides to about 60 nucleotides, from about 18 to about 45 nucleotides, for example 24, 27, 30, 33, 36, 39, 42 or 45 nucleotides.
- isolated refers to a peptide or nucleic molecule separated from other components that are present in the natural environment of the molecule or a naturally occurring source macromolecule (e.g., including other nucleic acids, proteins, lipids, sugars, etc.).
- “Synthetic”, as used herein, refers to a peptide or nucleic molecule that is not isolated from its natural sources, e.g., which is produced through recombinant technology or using chemical synthesis.
- the nucleic acid (DNA, RNA) encoding the antigenic peptide of the disclosure comprises any one of the sequences defined above.
- the nucleic acid encoding the antigenic peptide is an mRNA molecule.
- a nucleic acid of the disclosure may be used for recombinant expression of the antigenic peptide of the disclosure, and may be included in a vector or plasmid, such as a cloning vector or an expression vector, which may be transfected into a host cell.
- the disclosure provides a cloning, expression or viral vector or plasmid comprising a nucleic acid sequence encoding the antigenic peptide of the disclosure.
- a nucleic acid encoding an antigenic peptide of the disclosure may be incorporated into the genome of the host cell. In either case, the host cell expresses the antigenic peptide or protein encoded by the nucleic acid.
- host cell refers not only to the particular subject cell, but to the progeny or potential progeny of such a cell.
- a host cell can be any prokaryotic (e.g., E. coll) or eukaryotic cell (e.g., insect cells, yeast or mammalian cells) capable of expressing the antigenic peptide described herein.
- the vector or plasmid contains the necessary elements for the transcription and translation of the inserted coding sequence, and may contain other components such as resistance genes, cloning sites, etc. Methods that are well known to those skilled in the art may be used to construct expression vectors containing sequences encoding peptides or polypeptides and appropriate transcriptional and translational control/regulatory elements operably linked thereto.
- a coding sequence that is operably linked to regulatory sequences refers to a configuration of nucleotide sequences wherein the coding sequences can be expressed under the regulatory control, that is, transcriptional and/or translational control, of the regulatory sequences.
- regulatory/control region or “regulatory/control sequence”, as used herein, refers to the non-coding nucleotide sequences that are involved in the regulation of the expression of a coding nucleic acid.
- regulatory region includes promoter sequences, regulatory protein binding sites, upstream activator sequences, and the like.
- the vector may have the necessary 5' upstream and 3' downstream regulatory elements such as promoter sequences such as CMV, PGK and EFla promoters, ribosome recognition and binding TATA box, and 3' UTR AAUAAA transcription termination sequence for the efficient gene transcription and translation in its respective host cell.
- promoter sequences such as CMV, PGK and EFla promoters
- ribosome recognition and binding TATA box such as ribosome recognition and binding TATA box
- 3' UTR AAUAAA transcription termination sequence for the efficient gene transcription and translation in its respective host cell.
- suitable promoters include the constitutive promoter of simian vims 40 (SV40) early promoter, mouse mammary tumor virus (MMTV), HIV LTR promoter, MoMuLV promoter, avian leukemia virus promoter, EBV immediate early promoter, and Rous sarcoma vims promoter.
- Human gene promoters may also be used, including, but not limited to the actin promoter, the myosin promoter, the hemoglobin promoter, and the creatine kinase promoter.
- inducible promoters are also contemplated as part of the vectors expressing the antigenic peptide. This provides a molecular switch capable of turning on expression of the polynucleotide sequence of interest or turning off expression.
- inducible promoters include, but are not limited to a metallothionine promoter, a glucocorticoid promoter, a progesterone promoter, or a tetracycline promoter.
- vectors are plasmid, autonomously replicating sequences, and transposable elements.
- Additional exemplary vectors include, without limitation, plasmids, phagemids, cosmids, artificial chromosomes such as yeast artificial chromosome (YAC), bacterial artificial chromosome (BAC), or Pl-derived artificial chromosome (PAC), bacteriophages such as lambda phage or M13 phage, and animal viruses.
- artificial chromosomes such as yeast artificial chromosome (YAC), bacterial artificial chromosome (BAC), or Pl-derived artificial chromosome (PAC), bacteriophages such as lambda phage or M13 phage
- animal viruses include, without limitation, retrovirus (including lentivirus), adenovirus, adeno-associated virus, herpesvirus (e.g., herpes simplex virus), poxvirus, baculovirus, papillomavirus, and papovavirus (e.g., SV40).
- expression vectors are Lenti-XTM Bicistronic Expression System (Neo) vectors (Clontrch), pCIneo vectors (Promega) for expression in mammalian cells; pLenti4A/5-DESTTM, pLenti6A/5-DESTTM, and pLenti6.2N5-GW/lacZ (Invitrogen) for lentivirus-mediated gene transfer and expression in mammalian cells.
- the coding sequences of the antigenic peptide disclosed herein can be ligated into such expression vectors for the expression of the TAP in mammalian cells.
- the nucleic acids encoding the antigenic peptide of the present disclosure are provided in a viral vector.
- a viral vector can be those derived from retrovirus, lentivirus, or foamy virus.
- the term, "viral vector,” refers to a nucleic acid vector construct that includes at least one element of viral origin and has the capacity to be packaged into a viral vector particle.
- the viral vector can contain the coding sequence for the various proteins described herein in place of nonessential viral genes.
- the vector and/or particle can be utilized for the purpose of transferring DNA, RNA or other nucleic acids into cells either in vitro or in vivo. Numerous forms of viral vectors are known in the art.
- the nucleic acid (DNA, RNA) encoding the antigenic peptide of the disclosure is comprised within a vesicle or any other suitable vehicle.
- the antigenic peptide, nucleic acid or conjugate is encapsulated in a vesicle or vesicle-like particle, such as a lipid vesicle (e.g., liposome, lipid nanoparticle).
- a lipid vesicle e.g., liposome, lipid nanoparticle.
- liposome is used herein in accordance with its usual meaning, referring to microscopic lipid vesicles composed of a bilayer of phospholipids or any similar amphipathic lipids encapsulating an internal aqueous medium.
- the liposomes may be unilamellar vesicles such as small unilamellar vesicles (SUVs), which typically have a diameter of less than 0.2 pm (e.g., between 0.02 and 0.2 pm), and large unilamellar vesicles (LUVs), and multilamellar vesicles (MLV), which typically have a diameter greater than 0.45 pm (in some cases greater than 1 pm).
- SUVs small unilamellar vesicles
- LUVs large unilamellar vesicles
- MLV multilamellar vesicles
- Exemplary liposomal membranes may be formed from a variety of vesicle-forming lipids, typically including dialiphatic chain lipids, typically phospholipids, but may include other components such as diglycerides, dialiphatic glycolipids, single lipids such as sphingomyelin and glycosphingolipid, cholesterol and derivatives thereof, and combinations thereof.
- the properties of the liposomes depend, among other factors, on the nature of the constituents. Consequently, if liposomes with certain characteristics are to be obtained, the charge of its polar group and/or the length and the degree of saturation of its fatty acid chains must be taken into account.
- liposomes may be modified, e.g., to incorporate cholesterol and other lipids into the membrane, change the number of lipidic bilayers, or covalently join natural molecules (e.g., proteins, polysaccharides, glycolipids, antibodies, enzymes) or synthetic molecules (e.g., polyethyl glycol) to the surface.
- natural molecules e.g., proteins, polysaccharides, glycolipids, antibodies, enzymes
- synthetic molecules e.g., polyethyl glycol
- compositions comprisinq the antiqenic peptide or conjugate
- the present disclosure provides a composition comprising the antigenic peptide, nucleic acid or conjugate defined herein.
- the composition further comprises the above-mentioned antigenic peptide, nucleic acid or conjugate and a carrier or excipient, in a further embodiment a pharmaceutically acceptable carrier or excipient.
- compositions may be prepared in a manner well known in the pharmaceutical art by mixing the antigenic peptide, nucleic acid or conjugate having a suitable degree of purity with one or more optional pharmaceutically acceptable carriers or excipients (see Remington: The Science and Practice of Pharmacy, by Loyd Allen, Jr, 2012, 22 nd edition, Pharmaceutical Press; Handbook of Pharmaceutical Excipients, by Rowe et al., 2012, 7 th edition, Pharmaceutical Press).
- the carrier/excipient can be suitable for administration of the antigenic peptide, nucleic acid or conjugate by any conventional administration route, for example, for oral, intravenous, parenteral, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intrathecal, epidural, intracisternal, intraperitoneal, intranasal or pulmonary (e.g., aerosol, nebulizer) administration.
- the carrier/excipient is adapted for administration of the antigenic peptide or conjugate by the intravenous or subcutaneous route.
- the carriers/excipients are adapted for administration of the antigenic peptide, nucleic acid or conjugate by the intravenous route. In another embodiment, the carriers/excipients are adapted for administration of the antigenic peptide, nucleic acid or conjugate by the subcutaneous route.
- An "excipient” as used herein has its normal meaning in the art and is any ingredient that is not an active ingredient (drug) itself. Excipients include for example binders, lubricants, diluents, fillers, thickening agents, disintegrants, plasticizers, coatings, barrier layer formulations, lubricants, stabilizing agent, release-delaying agents and other components.
- “Pharmaceutically acceptable excipient” as used herein refers to any excipient that does not interfere with effectiveness of the biological activity of the active ingredients and that is not toxic to the subject, i.e., is a type of excipient and/or is for use in an amount which is not toxic to the subject. Excipients are well known in the art, and the present system is not limited in these respects.
- one or more formulations of the dosage form include excipients, including for example and without limitation, one or more binders (binding agents), thickening agents, surfactants, diluents, release-delaying agents, colorants, flavoring agents, fillers, disintegrants/dissolution promoting agents, lubricants, plasticizers, silica flow conditioners, glidants, anti-caking agents, anti-tacking agents, stabilizing agents, anti-static agents, swelling agents and any combinations thereof.
- binders binding agents
- thickening agents surfactants, diluents, release-delaying agents, colorants, flavoring agents, fillers, disintegrants/dissolution promoting agents, lubricants, plasticizers, silica flow conditioners, glidants, anti-caking agents, anti-tacking agents, stabilizing agents, anti-static agents, swelling agents and any combinations thereof.
- excipient examples include water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, as well as combinations thereof.
- isotonic agents for example, sugars, polyalcohols, such as mannitol, sorbitol, or sodium chloride in the composition.
- additional examples of pharmaceutically acceptable substances are wetting agents or auxiliary substances, such as emulsifying agents, preservatives, or buffers, which increase the shelf life or effectiveness.
- composition may also comprise one or more additional active agents for the treatment the targeted disease/condition or for the management of symptom(s) of the targeted disease/condition (e.g., pain killers, anti-nausea agents, anti-inflammatory agents, immunotherapeutic agents, etc.).
- additional active agents for the treatment the targeted disease/condition or for the management of symptom(s) of the targeted disease/condition (e.g., pain killers, anti-nausea agents, anti-inflammatory agents, immunotherapeutic agents, etc.).
- the composition is an immunogenic composition or vaccine composition.
- the composition comprising the antigenic peptide, nucleic acid or conjugate defined herein further comprises a vaccine adjuvant.
- a vaccine adjuvant refers to a substance which, when added to an immunogenic agent such as an antigen (e.g., the antigenic peptide, nucleic acid or conjugate defined herein), non-specifically enhances or potentiates an immune response to the agent in the host upon exposure to the mixture.
- Suitable vaccine adjuvants include, for example: (1) mineral salts (aluminum salts such as aluminum phosphate and aluminum hydroxide, calcium phosphate gels), squalene, (2) oil-based adjuvants such as oil emulsions and surfactant based formulations, e.g., incomplete or complete Freud’s adjuvant, MF59 (microfluidised detergent stabilised oil-in-water emulsion), QS21 (purified saponin), AS02 [SBAS2] (oil-in-water emulsion + MPL + QS-21), (3) particulate adjuvants, e.g., virosomes (unilamellar liposomal vehicles incorporating influenza haemagglutinin), AS04 ([SBAS4] aluminum salt with MPL), ISCOMS (structured complex of saponins and lipids), polylactide co-glycolide (PLG), (4) microbial derivatives (natural and
- Phlei cell wall skeleton Phlei cell wall skeleton
- AGP [RC-529] (synthetic acylated monosaccharide), DC_Chol (lipoidal immunostimulators able to selforganize into liposomes), OM-174 (lipid A derivative), CpG motifs (synthetic oligonucleotides containing immunostimulatory CpG motifs), modified LT and CT (genetically modified bacterial toxins to provide non-toxic adjuvant effects), complete Freud’s adjuvant (comprising inactivated and dried mycobacteria) (5) endogenous human immunomodulators, e.g., hGM-CSF or hlL-12 (cytokines that can be administered either as protein or plasmid encoded), Immudaptin (C3d tandem array) and/or (6) inert vehicles, such as gold particles.
- endogenous human immunomodulators e.g., hGM-CSF or hlL-12 (cytokines that
- the present disclosure provides an isolated antibody or an antigenbinding fragment thereof that specifically binds to the antigenic peptide defined herein, with the proviso that the antibody is not an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:6 and a light chain comprising the amino acid sequence of SEQ ID NO:7 (e.g., CV3-25).
- antibody or antigen-binding fragment thereof refers to any type of antibody/antibody fragment including monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies, humanized antibodies, CDR-grafted antibodies, chimeric antibodies and antibody fragments so long as they exhibit the desired antigenic specificity/binding activity.
- Antibody fragments comprise a portion of a full-length antibody, generally an antigen binding or variable region thereof.
- antibody fragments include Fab, Fab', F(ab') 2 , and Fv fragments, diabodies, linear antibodies, single-chain antibody molecules (e.g., single-chain FV, scFV), single domain antibodies (e.g., from camelids), shark NAR single domain antibodies, and multispecific antibodies formed from antibody fragments.
- Antibody fragments can also refer to binding moieties comprising CDRs or antigen binding domains including, but not limited to, V H regions ( H, VH-VH), anticalins, PepBodies, antibody-T- cell epitope fusions (Troybodies) or Peptibodies.
- monoclonal antibody refers to an antibody from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are substantially similar and bind the same epitope(s), except for possible variants that may arise during production of the monoclonal antibody, such variants generally being present in minor amounts.
- Such monoclonal antibody typically includes an antibody comprising a variable region that binds a target (the antigenic peptide defined herein), wherein the antibody was obtained by a process that includes the selection of the antibody from a plurality of antibodies.
- the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones or recombinant DNA clones.
- the selected antibody can be further altered, for example, to improve affinity for the target, to humanize the antibody, to improve its production in cell culture, to reduce its immunogenicity in vivo, to create a multispecific antibody, etc., and that an antibody comprising the altered variable region sequence is also a monoclonal antibody of the present disclosure.
- the monoclonal antibody preparations are advantageous in that they are typically uncontaminated by other immunoglobulins.
- the modifier "monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
- the monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including the hybridoma method (e.g., Kohler et al., Nature, 256:495 (1975); Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563- 681 , (Elsevier, N.
- Methods 284(1-2):119-132 (2004) and technologies for producing human or human-like antibodies from animals that have parts or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences see, e.g., WO98/24893, WO96/34096, WO96/33735, and WO91/10741 , Jakobovits et al., Proc. Natl. Acad. Sci. USA, 90:2551 (1993); Jakobovits et al., Nature, 362:255-258 (1993); Bruggemann et al., Year in Immune, 7:33 (1993); U.S. Patent Nos.
- Antibodies capable of specifically binding to the antigenic peptide defined herein can also be produced using phage display technology. Antibody fragments that selectively bind to the antigenic peptide defined herein can then be isolated. Exemplary methods for producing such antibodies via phage display are disclosed, for example, in U.S. Patent No. 6,225,447.
- the monoclonal antibodies herein specifically include "chimeric” or “recombinant” antibodies in which a portion of the light and/or heavy chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81 :6851-6855 (1984)).
- Chimeric antibodies of interest herein include "humanized” antibodies.
- the antibody is a humanized antibody or an antigenbinding fragment thereof.
- Variations in the antibodies or antigen-binding fragments thereof described herein can be made, for example, using any of the techniques and guidelines for conservative and nonconservative mutations set forth, for instance, in U.S. Patent No. 5,364,934. Variations may be a substitution, deletion or insertion of one or more codons encoding the antibody that results in a change in the amino acid sequence as compared with the native sequence antibody. Optionally the variation is by substitution of at least one amino acid with any other amino acid in one or more of the domains of the antibody or antigen-binding fragment thereof.
- Guidance in determining which amino acid residue may be inserted, substituted or deleted without adversely affecting the desired activity may be found by comparing the sequence of the antibody or antigen-binding fragment thereof with that of homologous known protein molecules and minimizing the number of amino acid sequence changes made in regions of high homology.
- Amino acid substitutions can be the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, such as the replacement of a leucine with a serine, i.e., conservative amino acid replacements. Insertions or deletions may optionally be in the range of about 1 to 5 amino acids.
- the variation allowed may be determined by systematically making insertions, deletions or substitutions of amino acids in the sequence and testing the resulting variants for activity exhibited by the full-length or mature native sequence.
- the variant exhibit at least 50%, 55% or 60%, preferably at least 65, 70, 75, 80, 90, 95, 96, 97, 98 or 99% sequence identity with the sequence of the antibody or antigen-binding fragment thereof described herein, and maintain the ability to specifically bind to the antigenic peptide described herein.
- Identity refers to sequence identity between two polypeptides. Identity can be determined by comparing each position in the aligned sequences. Methods of determining percent identity are known in the art, and several tools and programs are available to align amino acid sequences and determine a percentage of identity including EMBOSS Needle, ClustalW, SIM, DIALIGN, etc. As used herein, a given percentage of identity with respect to a specified subject sequence, or a specified portion thereof, may be defined as the percentage of amino acids in the candidate derivative sequence identical with the amino acids in the subject sequence (or specified portion thereof), after aligning the sequences and introducing gaps, if necessary to achieve the maximum percent sequence identity, as generated by the Smith Waterman algorithm (Smith & Waterman, J. Mol. Biol.
- A"% identity value is determined by the number of matching identical amino acids divided by the sequence length for which the percent identity is being reported.
- Covalent modifications of antibodies or antigen-binding fragments thereof are included within the scope of this disclosure.
- Covalent modifications include reacting targeted amino acid residues of the antibody or antigen-binding fragment thereof with an organic derivatizing agent that is capable of reacting with selected side chains or the N- or C- terminal residues of the antibody or antigen-binding fragment thereof.
- Other modifications include deamidation of glutaminyl and asparaginyl residues to the corresponding glutamyl and aspartyl residues, respectively, hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or threonyl residues, methylation of the a-amino groups of lysine, arginine, and histidine side chains (T.E.
- Glycosylation may also be intentionally altered, for example by inhibiting fucosylation, in order to increase ADCC activity of the resulting antibody or antigen-binding fragment thereof, e.g., scFv-Fc.
- the antibody or antigen-binding fragment thereof is labelled or conjugated with one or more moieties.
- the antibody or antigen-binding fragment thereof may be labeled with one or more labels such as a biotin label, a fluorescent label, an enzyme label, a coenzyme label, a chemiluminescent label, or a radioactive isotope label.
- the antibody or antigen-binding fragment thereof is labelled with a detectable label, for example a fluorescent moiety (fluorophore).
- Useful detectable labels include fluorescent compounds (e.g., fluorescein isothiocyanate, Texas red, rhodamine, fluorescein, Alexa Fluor® dyes, and the like), radiolabels, enzymes (e.g., horseradish peroxidase, alkaline phosphatase and others commonly used in a protein detection assays), streptavidin/biotin, and colorimetric labels such as colloidal gold, colored glass or plastic beads (e.g., polystyrene, polypropylene, latex, etc.). Chemiluminescent compounds may also be used.
- Such labelled antibodies or antigen-binding fragments thereof may be useful, for example, for the detection of the antigenic peptide or of the Spike protein.
- the antibody or antigen-binding fragment thereof can also be conjugated to detectable or affinity tags that facilitate detection and/or purification of the antibody or antigenbinding fragment thereof. Such tags are well known in the art.
- detectable or affinity tags examples include polyhistidine tags (His-tags), polyarginine tags, polyaspartate tags, polycysteine tags, polyphenylalanine tags, glutathione S-transferase (GST) tags, Maltose binding protein (MBP) tags, calmodulin binding peptide (CBP) tags, Streptavidin/Biotin-based tags, HaloTag®, Profinity eXact® tags, epitope tags (such as FLAG, hemagglutinin (HA), HSV, S/S1 , c-myc, KT3, T7, V5, E2, and Glu-Glu epitope tags), reporter tags such as p-galactosidase (P-gal), alkaline phosphatase (AP), chloramphenicol acetyl transferase (CAT), and horseradish peroxidase (HRP) tags (see, e.g., Kimple et al., Curr Protoc Protein
- the antibody or antigen-binding fragment thereof can also be conjugated to one or more therapeutic or active agents (e.g., a drug), and thus may also be used therapeutically to deliver the therapeutic agent(s) (e.g., anti-viral agent or any other agent useful for the treatment of the disease or condition or for relieving one or more symptoms) into a cell or tissue, such as an infected cell.
- therapeutic agent(s) e.g., anti-viral agent or any other agent useful for the treatment of the disease or condition or for relieving one or more symptoms
- Any method known in the art for conjugating the antibody or antigen-binding fragment thereof to another moiety e.g., detectable moiety, active agent
- the present disclosure also provides a pharmaceutical composition
- a pharmaceutical composition comprising the antibody or antigen-binding fragment thereof described herein and a pharmaceutically acceptable excipient, such as one or more of the excipients described above.
- the antibody or antigen-binding fragment thereof described herein may be administered by any administration, such as the administration routes described above.
- the present disclosure also provides methods and uses of the antigenic peptide, nucleic acid, conjugate, antibody or antigen-binding fragment thereof, liposomes, pharmaceutical composition or vaccine described herein for the prevention and/or treatment of coronavirus infection and/or associated diseases and symptoms.
- the present disclosure provides a method for inducing an immune response against a coronavirus (e.g., a beta-coronavirus), such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in a subject in need thereof, the method comprising administering to the subject an effective amount of the antigenic peptide, conjugate, antibody or antigen-binding fragment thereof, (e.g., liposomes, lipid nanoparticles), pharmaceutical composition or vaccine described herein.
- a coronavirus e.g., a beta-coronavirus
- SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
- the present disclosure also provides the use of the antigenic peptide, conjugate, antibody or antigen-binding fragment thereof, (e.g., liposomes, lipid nanoparticles), pharmaceutical composition or vaccine described herein for inducing an immune response against a coronavirus, such as SARS-CoV-2 in a subject.
- the present disclosure also provides the use of the antigenic peptide, conjugate, antibody or antigen-binding fragment thereof, vesicles (e.g., liposomes, lipid nanoparticles), pharmaceutical composition or vaccine described herein for the manufacture of a medicament for inducing an immune response against a coronavirus, such as SARS-CoV-2 in a subject.
- the present disclosure provides a method for preventing a coronavirus infection or a related disease, such as SARS-CoV-2 infection or Coronavirus disease 2019 (COVID-19), in a subject in need thereof, the method comprising administering to the subject an effective amount of the antigenic peptide, nucleic acid, conjugate, antibody or antigen-binding fragment thereof, vesicles (e.g., liposomes, lipid nanoparticles), pharmaceutical composition or vaccine described herein.
- vesicles e.g., liposomes, lipid nanoparticles
- the present disclosure also provides the use of the antigenic peptide, conjugate, antibody or antigen-binding fragment thereof, vesicles (e.g., liposomes, lipid nanoparticles), pharmaceutical composition or vaccine described herein for preventing a coronavirus (e.g., SARS-CoV-2) infection or a coronavirus-related disease (e.g., COVID-19) in a subject.
- a coronavirus e.g., SARS-CoV-2
- coronavirus-related disease e.g., COVID-19
- the present disclosure also provides the use of the antigenic peptide, nucleic acid, conjugate, antibody or antigen-binding fragment thereof, vesicles (e.g., liposomes, lipid nanoparticles), pharmaceutical composition or vaccine described herein for the manufacture of a medicament for preventing a coronavirus (e.g., SARS-CoV-2) infection or a coronavirus-related disease (e.g., COVID-19) in a subject.
- a coronavirus e.g., SARS-CoV-2
- coronavirus-related disease e.g., COVID-19
- the present disclosure provides a method for reducing the risk of developing a coronavirus-related disease such as COVID-19, or the severity of a coronavirus- related disease (e.g., COVID-19) in a subject in need thereof, the method comprising administering to the subject an effective amount of the antigenic peptide, nucleic acid, conjugate, antibody or antigen-binding fragment thereof, vesicles (e.g., liposomes, lipid nanoparticles), pharmaceutical composition or vaccine described herein.
- vesicles e.g., liposomes, lipid nanoparticles
- the present disclosure also provides the use of the antigenic peptide, nucleic acid, conjugate, antibody or antigen-binding fragment thereof, vesicles (e.g., liposomes, lipid nanoparticles), pharmaceutical composition or vaccine described herein for the manufacture of a medicament for reducing the risk of developing a coronavirus-related disease such as COVID-19, or the severity of a coronavirus-related disease (e.g., COVID-19) in a subject, a coronavirus-related disease such as COVID-19, or the severity of a coronavirus-related disease (e.g., COVID-19).
- vesicles e.g., liposomes, lipid nanoparticles
- pharmaceutical composition or vaccine described herein for the manufacture of a medicament for reducing the risk of developing a coronavirus-related disease such as COVID-19, or the severity of a coronavirus-related disease (e.g., COVID-19) in a subject,
- the present disclosure provides a method for blocking the entry of a coronavirus (e.g., beta- coronavirus) such as SARS-CoV-2 in a cell, such as an ACE2-expressing cell, comprising the cell and/or virus with an effective amount of the antibody or antigen-binding fragment thereof described herein.
- a coronavirus e.g., beta- coronavirus
- SARS-CoV-2 a coronavirus
- a cell such as an ACE2-expressing cell
- Coronaviruses are large, roughly spherical, RNA viruses with bulbous surface projections that cause diseases in mammals and birds. In humans, these viruses cause respiratory tract infections that can range from mild to lethal. Mild illnesses include some cases of the common cold (which is also caused by other viruses, predominantly rhinoviruses), while more lethal varieties can cause severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19.
- the methods and uses defined herein are for the prevention, treatment and/or management of infections by human BetaCoronaviruses and/or associated diseases.
- Human Beta-Coronaviruses include OC43, HKU1 , MERS-CoV, SARS-CoV and SARS-CoV-2.
- the methods and uses defined herein are for the prevention, treatment and/or management of infections by SARS-CoV- 2 and associated disease (COVID-19).
- the methods and uses defined herein are for the prevention, treatment and/or management of infections by variants of the Wuhan original SARS-CoV-2 strain, such as the B.1.1.7 (also known as VOC-202012/01), 501Y.V2 (B.1.351), and/or P.1 (B.1.1.28.1) variants, as well as other variants such as the Omicron variants including the BA.1 , BA.2, BA.4 and BA.5 variants.
- the appropriate dosage of the antigenic peptide, conjugate, antibody or antigen-binding fragment thereof, liposomes, pharmaceutical composition or vaccine will depend on the type of disease or condition to be treated, the severity and course of the disease or condition, whether the antigenic peptide, conjugate, antibody or antigen-binding fragment thereof, vesicles, pharmaceutical composition or vaccine is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to antigenic peptide, conjugate, antibody or antigen-binding fragment thereof, vesicles, pharmaceutical composition or vaccine, and the discretion of the attending physician.
- the antigenic peptide, conjugate, antibody or antigen-binding fragment thereof, vesicles, pharmaceutical composition or vaccine may be suitably administered to the patient at one time or over a series of treatments. Preferably, it is desirable to determine the dose-response curve in vitro, and then in useful animal models prior to testing in humans.
- the present disclosure provides dosages for the antigenic peptide, conjugate, antibody or antigen-binding fragment thereof, vesicles, pharmaceutical composition or vaccine. For example, depending on the type and severity of the disease, about 1 pg/kg to to 1000 mg per kg (mg/kg) of body weight per day.
- the effective dose may be 0.5 mg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg/ 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg, 60 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, 200 mg/kg, and may increase by 25 mg/kg increments up to 1000 mg/kg, or may range between any two of the foregoing values.
- a typical daily dosage might range from about 1 pg/kg to 100 mg/kg or more, depending on the factors mentioned above.
- the term “treating” or “treatment” in reference to viral infection or disease is meant to refer to administration of the agent after infection that leads to a reduction/improvement in one or more symptoms or pathological features associated with said viral disease.
- Non-limiting examples include a decrease in viral load, reduction of cough, fever, fatigue, shortness of breath, reduction/prevention of acute respiratory distress syndrome (ARDS), reduction/prevention of multi-organ failure, septic shock, and blood clots, hospitalization, etc.
- ARDS acute respiratory distress syndrome
- preventing or prevention in reference to viral infection or disease is meant to refer to administration of the agent prior to infection that leads to protection from being infected or from developing the viral disease, to a delay in the development of the disease, or to a reduction of one or more symptoms or pathological features associated with the viral disease.
- the antigenic peptide, conjugate, antibody or antigen-binding fragment thereof, vesicles, pharmaceutical composition or vaccine described herein may be used alone or in combination with other prophylactic agents such as antivirals, anti-inflammatory agents, vaccines, immunotherapies, etc.
- the combination of active agents and/or compositions comprising same may be administered or co-administered (e.g., consecutively, simultaneously, at different times) in any conventional dosage form.
- Co-administration in the context of the present disclosure refers to the administration of more than one therapeutic in the course of a coordinated treatment to achieve an improved clinical outcome. Such co-administration may also be coextensive, that is, occurring during overlapping periods of time.
- a first agent e.g., the peptide, conjugate, antibody or antigen-binding fragment thereof, liposomes, pharmaceutical composition or vaccine described herein
- a second active agent e.g., an antiviral or anti-inflammatory agent
- the agents may in an embodiment be combined/formulated in a single composition and thus administered at the same time.
- the term "subject” is taken to mean warm blooded animals such as mammals, for example, cats, dogs, mice, guinea pigs, horses, bovine cows, sheep and humans.
- the subject is a mammal, and more particularly a human.
- the antigenic peptide described herein may also be used to identify neutralizing antibodies against a Coronavirus such as SARS-CoV-2. As shown in the examples below, antibodies that binds to the antigenic peptide are able to recognize the full-length Spike protein from the Wuhan original strain as well as full-length Spike harboring mutations from different SARS-CoV-2 variants such as the B.1.1.7 variant, the B.1.351 variant, the B.1.525 variant and others. Thus, the antigenic peptide described herein may be useful to screen and identify broadly neutralizing antibodies against SARS-CoV-2 based on their ability to bond to the antigenic peptide.
- Such assay may be performed, for example, by immobilizing the antigenic peptide on a solid support (e.g., resin, plate, column, etc.) and contacting the solid support with the antigenic peptide bound thereto with a composition (e.g., biological sample, culture medium, supernatant, etc.) comprising antibody candidates, and collecting/eluting the antibody candidates that bind to the solid support.
- a composition e.g., biological sample, culture medium, supernatant, etc.
- One or more washing steps and/or enrichment steps may be performed.
- the plasmid encoding the Spike of the B.1.1.7 variant was codon- optimized and synthesized by Genscript.
- 10 pg of Spike expressor and 2 pg of a green fluorescent protein (GFP) expressor (plRES2-eGFP) was transfected into 2 x 10 6 293T cells.
- 293T cells were stained with the CV3-25 monoclonal antibody (mAb) at a final concentration of 5pg/mL.
- mAb monoclonal antibody
- Alexa Fluor-647- conjugated goat anti-human IgG (H+L) Abs were used as secondary antibodies.
- the percentage of transfected cells was determined by gating the living cell population based on the basis of viability dye staining (Aqua Vivid, Invitrogen). Samples were acquired on a LSRII cytometer (BD Biosciences) and data analysis was performed using Flow Jo v10.7.1 (Tree Star).
- Target cells were infected with single-round luciferase-expressing lentiviral particles. Briefly, 293T cells were transfected by the calcium phosphate method with the pNL4.3 R-E- Luc plasmid (NIH AIDS Reagent Program) and a plasmid encoding for SARS-CoV- 2 Spike at a ratio of 5:4. Two days post-transfection, cell supernatants were harvested and stored at -80°C until use. 293T-ACE2 target cells (9) were seeded at a density of 1 x 10 4 cells/well in 96-well luminometer-compatible tissue culture plates (Perkin Elmer) 24 h before infection.
- Recombinant viruses in a final volume of 10OpL were incubated with the indicated semi-log diluted antibody concentrations for 1 h at 37°C and were then added to the target cells followed by incubation for 48 h at 37°C; cells were lysed by the addition of 30 pL of passive lysis buffer (Promega) followed by one freeze-thaw cycle.
- LB941 TriStar luminometer (Berthold Technologies) was used to measure the luciferase activity of each well after the addition of 10OpL of luciferin buffer (15 mM MgSO 4 , 15 mM KPO 4 [pH 7.8], 1 mM ATP, and 1 mM dithiothreitol) and 50pL of 1 mM d-luciferin potassium salt.
- Peptide ELISA enzyme-linked immunosorbent assay. This SARS-CoV-2 Spike peptide ELISA assay was adapted from a previously published method (9).
- Spike peptide pools or individual peptides purchased from JPT (1 g/ml), or bovine serum albumin (BSA) (1 g/ml) as a negative control, were prepared in PBS and were adsorbed to plates (MaxiSorp; Nunc) overnight at 4 °C. Coated wells were subsequently blocked with blocking buffer (Tris-buffered saline [TBS] containing 0.1% TweenTM20 and 2% BSA) for 1 hour at room temperature. Wells were then washed four times with washing buffer (Tris-buffered saline [TBS] containing 0.1% Tween20).
- TBS bovine serum albumin
- CV3-25 mAb (50 ng/ml), or CV3-1 (50 ng/ml) as a negative control were prepared in a diluted solution of blocking buffer (0.1 % BSA) and incubated with the peptide-coated wells for 90 minutes at room temperature. Plates were washed four times with washing buffer followed by incubation with anti- 1 gG secondary Abs (diluted in a diluted solution of blocking buffer [0.4% BSA]) for 1 hour at room temperature, followed by four washes.
- HRP enzyme activity was determined after the addition of a 1 :1 mix of Western Lightning oxidizing and luminol reagents (Perkin Elmer Life Sciences). Light emission was measured with a LB941 TriStar luminometer (Berthold Technologies).
- 293T-ACE2 target cells were infected with single-round luciferase-expressing lentiviral particles (Pre ' vost et al., 2020). Briefly, 293T cells were transfected by the calcium phosphate method with the lentiviral vector pNL4.3 R-E Luc (NIH AIDS Reagent Program) and a plasmid encoding for SARS-CoV-2 Spike at a ratio of 5:4. Two days post-transfection, cell supernatants were harvested and stored at 80 °C until further use.
- 293T- ACE2 target cells were seeded at a density of 1x10 4 cells/well in 96-well luminometer-compatible tissue culture plates (PerkinElmer) 24h before infection.
- recombinant viruses in a final volume of 100 mL were incubated with increasing concentrations of CV3-1 or CV3-25 (0.01-10 mg/mL) for 1 h at 37 C and were then added to the target cells followed by incubation for 48h at 37 C; cells were lysed by the addition of 30 mL of passive lysis buffer (Promega) followed by one freeze-thaw cycle.
- LB942 TriStar luminometer (Berthold Technologies) was used to measure the luciferase activity of each well after the addition of 100 mL of luciferin buffer (15 mM MgSO 4 ,15mM KH2PO 4 [pH 7.8], 1 mM ATP, and 1 mM dithiothreitol) and 50 mLof 1 mM D-luciferin potassium salt (Prolume).
- the neutralization half-maximal inhibitory dilution represents the antibody concentration inhibiting 50% of the infection of 293T-ACE2 cells by recombinant viruses bearing the indicated surface glycoproteins.
- CV3-25 (10 mg/mL) was pre-incubated in presence of increasing concentrations of peptide #289 (1153-DKYFKNHTSPDVDLG-1167) or a scramble version of the same peptide (DHDTKFLNYDPVGKS, SEQ ID NO: 103)
- Example 2 Results The results depicted in FIGs. 1A-D show that the CV3-25 mAb is able to recognize full- length Spike harboring mutations from different SARS-CoV-2 variants expressed at the cell surface of 293T cells expressing, namely the B.1.1.7 variant (FIG. 1 A), the B.1.351 variant (FIG. 1B), the B.1.525 variant (FIG. 1C) and other variants of interest (FIG. 1D). This provides evidence that the epitope recognized by the CV3-25 mAb is conserved among the various SARS-CoV-2 variants.
- the results depicted in FIG. 2 show that the CV3-25 mAb is able to block the infection of 293T-ACE2 cells by pseudoviral particles bearing the SARS-CoV-2 Spike glycoproteins from the Wuhan original strain or the B.1.1.7 variant.
- the CV3-25 mAb has also been shown to exhibit neutralization capacity against the B.1.351 variant (see reference 5, Figure 7D).
- FIG. 3A To determine the region of the Spike protein recognized by the CV3-25 mAb, pools of peptides covering the whole S2 subunit sequence were incubated with the CV3-25 mAb, and the binding was detected using HRP-conjugated anti-human IgG (FIG. 3A). As shown in FIG. 3C, two peptide pools from the Spike connector domain (CD, FIG. 3B) were able to bind the CV3-25 mAb (pools #49 and #50). Individual overlapping peptides of 15 amino acids (with 4 amino acid residue overhang) from pools #49 and #50 covering the S2 CD region (FIG. 4A) were used to identify the region recognized by CV3-25 mAb by indirect ELISA. As shown in FIG.
- Peptides #288 and #289 share the following sequence of 11 amino acids: DKYFKNHTSPD (FIG. 4C). The identified peptides (#288 and #289) were also tested in competition assays (FIG. 4D). Peptide #289 was the most potent at blocking the binding of CV3- 25 to SARS-CoV-2 S protein.
- the domain recognized by the CV3-25 mAb on SARS-CoV-2 S protein is fully conserved in various SARS-CoV-2 variants (FIG. 4H), and highly conserved among various beta-coronaviruses, notably lineage B beta-coronaviruses.
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Abstract
La présente demande concerne des peptides antigéniques qui sont reconnus par la neutralisation d'anticorps anti-SARS-CoV-2. Des anticorps neutralisants ciblant ces peptides antigéniques sont efficaces contre plusieurs variants du SARS-CoV-2. L'invention concerne également des conjugués, des vésicules, des compositions pharmaceutiques et des vaccins comprenant les peptides antigéniques, ainsi que des anticorps reconnaissant ces peptides antigéniques. Les peptides antigéniques et les acides nucléiques codant, les conjugués, les anticorps ou les fragments de liaison à l'antigène de ceux-ci, les vésicules, les compositions pharmaceutiques ou les vaccins décrits dans la description peuvent être utilisés pour la prévention et/ou le traitement d'une infection à coronavirus et/ou de maladies et de symptômes associés, tels que l'infection par le SARS-CoV-2 et/ou la COVID-19.
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