WO2021220246A1 - Polypeptides sras-cov-2 recombinants et leurs utilisations - Google Patents

Polypeptides sras-cov-2 recombinants et leurs utilisations Download PDF

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Publication number
WO2021220246A1
WO2021220246A1 PCT/IB2021/053641 IB2021053641W WO2021220246A1 WO 2021220246 A1 WO2021220246 A1 WO 2021220246A1 IB 2021053641 W IB2021053641 W IB 2021053641W WO 2021220246 A1 WO2021220246 A1 WO 2021220246A1
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WIPO (PCT)
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cov
subject
sars
recombinant polypeptide
recombinant
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PCT/IB2021/053641
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English (en)
Inventor
Ann Elizabeth Meyers
Anna-Lise Williamson
Edward Peter Rybicki
Emmanuel Aubrey MARGOLIN
Nicola Douglass
Rosamund CHAPMAN
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University Of Cape Town
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Publication of WO2021220246A1 publication Critical patent/WO2021220246A1/fr

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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
    • 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
    • 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

  • a recombinant polypeptide comprising the following formula:
  • the furin cleavage site of the first aspect of the invention facilitates the cleavage of the SARS-CoV-2 spike protein subunit 1 and SARS-CoV-2 spike protein subunit 2 of the SARS-CoV-2 spike protein from each other in the presence of a protease to facilitate formation of the mature prefusion glycoprotein complex.
  • the polypeptide comprises a sequence of SEQ ID NO:2 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO:2.
  • SEQ ID NO:2 amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO:2.
  • specific amino acid residues in the sequence could be altered in order to include the sequences of variants which have and will continue to emerge.
  • stabilizing mutations may be introduced into the sequence of SEQ ID NO:2 in order to minimize structural plasticity of the glycoprotein trimer and fix the antigen in a specific conformation.
  • the vaccine compositions, recombinant polypeptides and/or nucleic acids encoding the recombinant polypeptides described herein may be for use in methods of inducing an immune response against SARS-CoV-2 in a subject, methods of preventing or treating SARS-CoV-2 virus infection in a subject.
  • the methods described herein comprise administering either a prophylactically or a therapeutically effective amount of the vaccine composition, recombinant polypeptide and/or nucleic acids encoding the recombinant polypeptide to the subject.
  • the present invention also relates to use of the recombinant polypeptides and/or nucleic acids encoding the recombinant polypeptides in the manufacture of one or more medicaments for use in methods of preventing or treating SARS-CoV-2 virus infection in a subject, wherein the methods comprise administering a prophylactically or therapeutically effective amount of the one or more medicament to the subject.
  • the present invention also relates to methods of producing the recombinant polypeptides described herein in a cell.
  • the methods comprising the steps of: (i) transforming, transfecting or infiltrating a cell with the expression vectors described herein, (ii) expressing the recombinant polypeptides in the cell, and (iii) recovering the recombinant polypeptides from the cell.
  • transformation includes the process whereby a nucleic acid is transferred to a target cell.
  • the term includes infecting a cell with a vector-based viral vaccine such as LSDV or MVA, such that the DNA or RNA is transferred to the target cell.
  • a SARS-CoV-2 virus infection in a subject comprising administering a therapeutically effective amount of either the recombinant polypeptide, viral vector or nucleic acid encoding the recombinant polypeptide to the subject.
  • the subject is any organism which is capable of being infected with SARS-CoV-2, however preferably the subject is a feline, a mustelid, a canine or a human.
  • FIG. 1 Schematic of A) the native SARS-CoV-2 spike (S) coding sequence and B) the modified spike (SATM) antigen sequence for heterologous expression in vivo by vector-based vaccine candidates and as recombinant subunit vaccines.
  • the leader sequence is indicated by a dotted arrow.
  • the locations of the S1 and S2 subunits are indicated.
  • SP native signal peptide
  • TPA signal peptide from tissue plasminogen activator
  • RRAR native furin cleavage site
  • RRRRRR modified furin cleavage site
  • FD foldon trimerization domain
  • GSGSGS and GSGGSGGSG flexible linker peptides
  • HHHHHH polyhistidine affinity tag).
  • Figure 2 Modified nucleic acid sequence of the SARS-CoV-2 spike glycoprotein (SEQ ID NO:1 ).
  • SEQ ID NO: 2 expressed from the modified nucleic acid sequence of SEQ ID NO:1.
  • Figure 4 Restriction analysis to confirm the genetic integrity of recombinant plasmids encoding the SARS-CoV-2 SATM antigen. Restriction digests were performed as set out in Table 1 . Fragments following digestion were resolved on a 0.8% agarose gel.
  • Figure 6 Western blotting of fractions recovered during the purification of the recombinant SATM expressed in HEK293 cells.
  • Media clarified cell culture media before purification
  • F1 column flow-through
  • W1 wash buffer flow-through
  • Eluate concentrated protein after elution from the affinity resin).
  • Figure 7 Superdex Hiload 200 16/600 elution profile of recombinant spike glycoprotein expressed in HEK293 cells after affinity capture.
  • FIG 12 Immunofluorescence of expanded and purified modified vaccinia Ankara (MVA) encoding the SARS-CoV-2 SATM antigen in RK13 cells.
  • the recombinant virus encodes eGFP conferring the green colour.
  • the presence of the K1 L selection gene in the integrated coding region enables the recombinant virus, but not the parental virus to grow in RK13 cells.
  • nucleic acid and amino acid sequences listed in the accompanying sequence listing are shown using standard letter abbreviations for nucleotide bases, and the standard three letter abbreviations for amino acids. It will be understood by those of skill in the art that only one strand of each nucleic acid sequence is shown, but that the complementary strand is included by any reference to the displayed strand.
  • SEQ ID NO:1 Modified nucleic acid sequence of the SARS-CoV-2 spike glycoprotein.
  • SEQ ID NO:2 Amino acid sequence of the modified SARS-CoV-2 spike glycoprotein.
  • the present invention relates to a modified SARS-CoV-2 spike protein which can be used as a vaccine antigen or diagnostic antigen.
  • the modified SARS-CoV-2 vaccine antigen of the present invention may be prepared as a subunit vaccine or as a vector-based vaccine.
  • the vaccine antigen is modified for optimal expression and stability, and to promote the desired immune response.
  • the subunit vaccines were produced in both mammalian cell culture and in Nicotiana benthamiana plants. Mammalian cell-based protein production is the accepted industry paradigm for viral glycoprotein production. Plant-based protein production constitutes a potentially cheaper and rapidly scalable alternative that is suited for developing countries due to the lower infrastructure requirements for production.
  • the SARS-CoV-2 virion is approximately 50-200 nanometres in diameter.
  • SARS-CoV-2 has four structural proteins, known as the S (spike), E (envelope), M (membrane), and N (nucleocapsid) proteins.
  • the N protein holds the RNA genome, and the S, E, and M proteins together create the viral envelope.
  • the spike protein is the protein responsible for allowing the virus to attach to and fuse with the membrane of a host cell.
  • the modified proteins and compositions according to the invention may be used to prevent COVID-19 infection or conditions associated with COVID-19 infection.
  • SARS-CoV-2 has been shown to infect humans, felines, mustelids and canines. The time from exposure to onset of symptoms is typically around five days but may range from two to fourteen days. While the majority of cases result in mild symptoms, some progress to viral pneumonia, multiple organ failure and death.
  • a compound according to the invention includes, without limitation, a modified protein including the amino acid sequence of a Sars-Cov-2 S protein, or a derivative thereof.
  • the modified SARS-Cov-2 protein or derivative thereof may be selected from a polypeptide selected from the group consisting of SEQ ID NO:2 and having at least 80%, 85%, 90%, 95%, 97%, 98% or 99% sequence identity thereto.
  • a “protein,” “peptide” or “polypeptide” is any chain of two or more amino acids, including naturally occurring or non-naturally occurring amino acids or amino acid analogues, irrespective of post-translational modification (e.g., glycosylation or phosphorylation).
  • nucleic acid molecule is thus “complementary” to a second nucleic acid molecule if it hybridizes, under conditions of high stringency, with the second nucleic acid molecule.
  • a nucleic acid molecule according to the invention includes both complementary molecules.
  • the nucleic acid molecules of the invention may be operably linked to other sequences.
  • operably linked is meant that the nucleic acid molecules encoding the modified proteins of the invention and regulatory sequences are connected in such a way as to permit expression of the modified proteins when the appropriate molecules are bound to the regulatory sequences.
  • operably linked sequences may be contained in vectors or expression constructs which can be transformed or transfected into host cells for expression. It will be appreciated that any vector can be used for the purposes of expressing the modified proteins of the invention.
  • the vector provides the regulatory sequences for the expression of the modified protein. In further embodiments, the vector provides some regulatory sequences and the nucleotide or gene sequence provides other regulatory sequences. “Regulatory sequences” include but are not limited to promoters, transcription termination sequences, enhancers, splice acceptors, donor sequences, introns, ribosome binding sequences, poly(A) addition sequences, and/or origins of replication.
  • a therapeutically effective amount of a compound may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects.
  • any of the modified proteins or compositions of the present invention will vary depending on the symptoms, age and body weight of the subject, the nature and severity of the infection to be treated or prevented, the route of administration, and the form of the composition. Any of the compositions of the invention may be administered in a single dose or in multiple doses. The dosages of the compositions of the invention may be readily determined by techniques known to those of skill in the art or as taught herein.
  • a “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired prophylactic result, such as prevention of onset of a condition associated with Covid-19 infection.
  • a prophylactic dose is used in subjects prior to or at an earlier stage of disease, so that a prophylactically effective amount may be less than a therapeutically effective amount.
  • Dosage values may vary with the severity of the condition to be alleviated. For any particular subject, specific dosage regimens may be adjusted over time according to the individual need and the judgment of the person administering or supervising the administration of the modified proteins or compositions of the invention. Dosage ranges set forth herein are exemplary only and do not limit the dosage ranges that may be selected. The amount of active compound(s) in the composition may vary according to factors such as the disease state, age, sex, and weight of the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single dose may be administered, or multiple doses may be administered over time. It may be advantageous to formulate the compositions in dosage unit forms for ease of administration and uniformity of dosage.
  • preventing when used in relation to an infectious disease, or other medical disease or condition, is well understood in the art, and includes administration of a composition which reduces the frequency of or delays the onset of symptoms of a condition in a subject relative to a subject which does not receive the composition.
  • Prevention of a disease includes, for example, reducing the number of diagnoses of the infection in a treated population versus an untreated control population, and/or delaying the onset of symptoms of the infection in a treated population versus an untreated control population.
  • the invention also relates in part to a method of treating or preventing infection in a subject comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of the modified proteins or compositions of the present invention.
  • the invention may further relate to a vector-based vaccine, wherein the nucleic acid of SEQ ID NO:1 is inserted into a modified strain of the lumpy skin disease virus (LSDV).
  • LSDV lumpy skin disease virus
  • a C-terminal trimerization foldon (FD) domain derived from T4 phage fibritin and a polyhistidine tag were both incorporated at the C-terminal end of the coding sequence, following flexible linker sequences. Synthetic restriction sites were incorporated into the sequence flanking the gene to facilitate cloning: BshJ ⁇ and Hind ⁇ were added at the 5’ end whereas Xho ⁇ and EcoRI were included at the 3’ end.
  • the modified nucleic acid sequence is shown in Figure 2 (SEQ ID NO:1 ) and its corresponding amino acid sequence is shown in Figure 3 (SEQ ID N02).
  • Table 1 Restriction analysis to confirm the genetic integrity of recombinant plasmids encoding the SARS-CoV-2 SATM antigen. The enzymes used for analysis and the expected DNA fragment sizes are indicated.
  • Protein production was scaled up in T175 flasks using a 3:1 ratio of plasmid encoding the spike:plasmid encoding furin.
  • the cell culture media was harvested after 72 hours, filtered through a 0.22 mM Stericup® filter unit and purified with HisPurTM Cobalt resin as instructed by the manufacturer.
  • the flow through fractions during the purification were subjected to western blotting to verify that the protein had been efficiently captured (Figure 6).
  • Western blotting confirmed the successful purification of the spike antigen and that none of the protein was lost during purification.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
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  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
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Abstract

La présente invention concerne un polypeptide recombinant codant pour le vaccin candidat de protéine de spicule du SARS-CoV-2. L'invention concerne également des vecteurs comprenant des acides nucléiques codant pour le polypeptide recombinant. L'invention concerne spécifiquement les protéines recombinantes décrites dans la description, des procédés de production des protéines recombinantes et des compositions pharmaceutiques comprenant les protéines recombinantes et/ou les vecteurs comprenant un acide nucléique codant pour la protéine recombinante. Plus spécifiquement, l'invention concerne un vaccin à ADN, un vaccin contre le virus de la vaccine Ankara modifié et/ou un vaccin contre le virus de la dermatose nodulaire contagieuse codant pour la protéine recombinante de l'invention.
PCT/IB2021/053641 2020-04-30 2021-04-30 Polypeptides sras-cov-2 recombinants et leurs utilisations WO2021220246A1 (fr)

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GB2006376.4 2020-04-30

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WO2022238882A1 (fr) 2021-05-10 2022-11-17 University Of Cape Town Ingénierie moléculaire et glyco intégrée de glycoprotéines virales complexes
WO2023101007A1 (fr) * 2021-12-03 2023-06-08 株式会社 アイロムグループ Vecteur d'expression d'antigène-protéine et son utilisation
WO2024105539A1 (fr) * 2022-11-15 2024-05-23 University Of Cape Town Constructions d'antigène de coronavirus bovin vectorisé lsdv recombinant

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CN111778271A (zh) * 2020-07-21 2020-10-16 梁建国 一种表达SARS-CoV-2 N蛋白的重组质粒、重组菌及构建方法和应用
CN113817028A (zh) * 2020-09-22 2021-12-21 青岛海洋生物医药研究院 多肽制剂
WO2022216895A1 (fr) * 2021-04-09 2022-10-13 University Of Florida Research Foundation, Incorporated Procédés, kits et approches pour vaccins viraux

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WO2018220595A1 (fr) 2017-06-02 2018-12-06 University Of Cape Town Co-expression de protéines chaperons humaines dans des plantes pour une expression accrue de polypeptides hétérologues
WO2019220403A2 (fr) 2018-05-17 2019-11-21 University Of Cape Town Gène homologue de superoxyde dismutase (sod) stabilisé et utilisations associées

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022238882A1 (fr) 2021-05-10 2022-11-17 University Of Cape Town Ingénierie moléculaire et glyco intégrée de glycoprotéines virales complexes
WO2023101007A1 (fr) * 2021-12-03 2023-06-08 株式会社 アイロムグループ Vecteur d'expression d'antigène-protéine et son utilisation
WO2024105539A1 (fr) * 2022-11-15 2024-05-23 University Of Cape Town Constructions d'antigène de coronavirus bovin vectorisé lsdv recombinant

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