WO2018175518A1 - Mini-protéines immunogènes présentant des épitopes de neutralisation du virus respiratoire syncytial (vrs) - Google Patents

Mini-protéines immunogènes présentant des épitopes de neutralisation du virus respiratoire syncytial (vrs) Download PDF

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Publication number
WO2018175518A1
WO2018175518A1 PCT/US2018/023463 US2018023463W WO2018175518A1 WO 2018175518 A1 WO2018175518 A1 WO 2018175518A1 US 2018023463 W US2018023463 W US 2018023463W WO 2018175518 A1 WO2018175518 A1 WO 2018175518A1
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polypeptide
rsv
multimer
subject
nucleic acid
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PCT/US2018/023463
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English (en)
Inventor
William Schief
Dan KULP
Xiaozhen HU
Sergey MENIS
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The Scripps Research Institute
International Aids Vaccine Initiative
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Publication of WO2018175518A1 publication Critical patent/WO2018175518A1/fr

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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
    • C07K14/08—RNA viruses
    • C07K14/115—Paramyxoviridae, e.g. parainfluenza virus
    • C07K14/135—Respiratory syncytial virus
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/64—Medicinal preparations containing antigens or antibodies characterised by the architecture of the carrier-antigen complex, e.g. repetition of carrier-antigen units
    • 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
    • C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
    • C12N2750/00011—Details
    • C12N2750/00034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • Respiratory Syncytial Vims is the leading cause of viral death in infants worldwide and also causes disease in tire elderly and immune-compromised.
  • the RSV-F protein is a trimeric glycoprotein that contains both neutralizing and non-neutralizing epitopes.
  • the development of a stable, minimal, monomeric domain containing potent neutralizing epitopes and minimizing non-neutralizing epitopes would offer an attractive alternative to the pre- fusion RSV F protein trimer that is currently being pursued by most in the field.
  • polypeptides comprising a first domain, wherein the first domain comprises the amino acid sequence of SEQ ID NO.l.
  • first domain comprises the amino acid sequence of SEQ ID NOS: 2-8.
  • the first domain is present in two or more copies.
  • the polypeptide further comprises
  • the multimerization domain comprises the amino acid sequence selected from the group consisting of SEQ ID NOS.9-28.
  • polypeptides comprising:
  • the multimerization domain comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 10 and 15-28.
  • the polypeptide further comprises an amino acid linker between the first domain and the multimerization domain, or between the multimerization domain and the RSV antigen.
  • the polypeptide comprises the amino acid sequence selected from the group consisting of SEQ ID NOS: 29-41.
  • multimers of the polypeptides of the discl osure comprising 2, 3, 4, 5, 6, 7, 8, or more copies of the polypeptides of the disclosure.
  • nucleic acids are provided encoding the polypeptide of any embodiment of the disclosure.
  • the nucleic acid comprises the sequence selected from the group consisting of SEQ ID NOS: 44-47.
  • recombinant expression vectors comprising the nucleic acids of the disclosure operativeiy linked to a suitable control sequence are provided.
  • recombinant host cells comprising the
  • compositions are provided that comprise
  • methods for treating a respiratory syncytial virus (RSV) infection comprising administering to a subject infected with RSV an amount effective to treat the infection of the polypeptide, the multimer, the nucleic acid, the recombinant expression vector, the recombinant host cell, or the pharmaceutical composition, of any embodiment of the disclosure.
  • RSV respiratory syncytial virus
  • methods for limiting development of an RSV infection comprising administering to a subject at risk of RSV infection an amount effective to limit development of an RSV infection of the polypeptide, the multimer, the nucleic acid, the recombinant expression vector, the recombinant host cell, or the pharmaceutical composition, of any embodiment of the disclosure.
  • methods for generating an immune response in a subject comprising administering to the subject an amount effective to generate an immune response of the polypeptide, the multimer, the nucleic acid, the recombinant expression vector, the recombinant host cell, or the pharmaceutical composition, of any embodiment of the disclosure.
  • methods for monitoring an RSV-induced disease in a subject and/or monitoring response of the subject to immunization by an RSV vaccine comprising contacting of the polypeptide, the multimer, the nucleic acid, the recombinant expression vector, the recombinant host cell, or the pharmaceutical composition, of any embodiment of the disclosure, with a bodily fluid from the subject and detecting RSV- binding antibodies in the bodily fluid of the subject.
  • the bodily fluid comprises serum or whole blood.
  • methods for detecting RSV binding antibodies comprising
  • the method further comprises isolating the RSV antibodies.
  • methods for producing RSV antibodies comprising
  • FIG. 1 Model of the RSV F glycoprotein and the engineered domain from the "top" of RSV-F (eFTop).
  • proteins or polypeptide are used in their broadest sense to refer to a sequence of subunit amino acids.
  • the proteins or polypeptides of the disclosure may comprise L-amino acids, D-amino acids (which are resistant to L-amino acid-specific proteases in vivo), or a combination of D- and L-amino acids.
  • the proteins or polypeptides described herein may be chemically synthesized or recombinantly expressed.
  • the disclosure provides polypeptides comprising a first domain, wherein the first domain comprises the amino acid sequence of SEQ ID NO: 1.
  • Polypeptides falling within the scope of SEQ ID NO: 1 include efTop mutations disclosed in the examples that follow, which can be used, for example, in fusion polypeptides of the disclosure, and are more effective candidates for treating RSV infection and generating a neutralizing anti-RSV immune response than currently used stabilized prefusion trimers.
  • amino acid residues are abbreviated as follows: alanine (Ala; A), asparagine (Asn; N), aspartic acid (Asp; D), arginine (Arg; R), cysteine (Cys; C), glutamic acid (Glu; E), glutamine (Gin; Q), glycine (Gly; G), histidine (His; H), isoleucine (He; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P ), serine (Ser; S), threonine (Tin; T), tryptophan (Tip; W), tyrosine (Tyr; Y), and valine (Vai; V).
  • the first domain comprises the amino acid sequence of SEQ ID NQS: 1-8.
  • the polypeptides of SEQ ID NOS:2-8 are described in the examples that follow.
  • polypeptides of the disclosure may comprise two or more (i.e.: 2, 3, 4, 5, or more) copies of the first domain.
  • the polypeptides of the disclosure may further comprise a multimerization domain.
  • Any suitable multimerization domain may be used that can result in a polypeptide multimer that can present multiple copies of the polypeptides of the disclosure to, for example, the immune system of a subject to which the polypeptides are administered.
  • the multimerization domain comprises the amino acid sequence selected from the group consisting of SEQ ID NOS:9-12.
  • RMKQIEDKIEEILSKIYHIENEIARIKKLIGER SEQ ID NO: 1 1
  • MKVKQLEDVVEELLSVNYHLENVVARLKKLVGER (SEQ ID NO: 12), which is a tetramerization motif having 4 helices curling around each other in helical manner.
  • a fusion with this multimerization domain may comprise fusing one copy of an EF- TOP polypeptide of the disclosure to the N- terminus of SEQ ID NO: 12 and a second copy of an EF-TOP polypeptide of the disclosure to the C- terminus of SEQ ID NO: 12.
  • the multimerization domain comprises the amino acid sequence selected from the group consisting of SEQ ID NOS: 13-28.
  • polypeptides comprising
  • the polypeptides of this aspect of the disclosure are fusion proteins that comprise a lumazine synthase mutation of the disclosure fused to an RSV antigen.
  • the polypeptides of this aspect of the disclosure can be used, for example, in the methods of the disclosure.
  • the RSV antigen may be any suitable RSV antigen, including but not limited to the RSV F protein, or an antigenic portion thereof.
  • the multimerization domain comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 10 and 15-28.
  • polypeptides of the disclosure may further comprise a linker between different domains within the polypeptide.
  • the polypeptides may further comprise an amino acid linker between the first domain and the multimerization domain, or between the multimerization domain and the one or more copies of the RSV antigen.
  • polypeptides of the disclosure may comprise the amino acid sequence selected from the group consisting of SEQ ID NOS: 29-
  • polypeptides may comprise the amino acid sequence selected from the group consisting of SEQ ID NOS: 29-31.
  • the disclosure provides multimers, comprising two or more copies (2, 3, 4, 5, 6, 7, 8, 10, 20, 30, 40, 50, 60, or more copies) of the polypeptides of the disclosure that include a multimerization domain.
  • the muitimer may be a self-assembling multimer and/or may be present on a surface, including but not limited to a particle or bead.
  • the multimer comprises eight or more copies of the polypeptide; in another specific embodiment, the multimer comprises 60 or more copies of the polypeptide.
  • the present disclosure provides isolated nucleic acids encoding a polypeptide of the present disclosure.
  • the isolated nucleic acid sequence may comprise RNA or DNA.
  • isolated nucleic acids are those that have been removed from their normal surrounding nucleic acid sequences in the genome or in cDNA sequences.
  • Such isolated nucleic acid sequences may comprise additional sequences useful for promoting expression and/or purification of the encoded protein, including but not limited to polyA sequences, modified Kozak sequences, and sequences encoding epitope tags, export signals, and secretory signals, nuclear localization signals, and plasma membrane localization signals. It will be apparent to those of skill in the art, based on the teachings herein, what nucleic acid sequences will encode the polypeptides of the disclosure. In various non-limiting
  • the nucleic acid comprises the sequence selected from the group consisting of SEQ ID NOS: 44-47, which show improved expression compared to other encoding nucleic acid sequences.
  • the present disclosure provides recombinant expression vectors comprising the isolated nucleic acid of any aspect of the disclosure operatively linked to a suitable control sequence.
  • “Recombinant expression vector” includes vectors that operatively link a nucleic acid coding region or gene to any control sequences capable of effecting expression of the gene product.
  • "Control sequences" operably linked to the nucleic acid sequences of the disclosure are nucleic acid sequences capable of effecting the expression of the nucleic acid molecules. The control sequences need not be contiguous with the nucleic acid sequences, so long as they function to direct the expression thereof.
  • intervening untranslated yet transcribed sequences can be present between a promoter sequence and the nucleic acid sequences and the promoter sequence can still be considered "operably linked" to the coding sequence.
  • Other such control sequences include, but are not limited to, polyadenylation signals, termination signals, and ribosome binding sites.
  • Such expression vectors can be of any type known in the art, including but not limited plasmid and viral-based expression vectors.
  • the present disclosure provides host cells that have been transfected with the recombinant expression vectors disclosed herein, wherein the host cells can be either prokaryotic or eukaryotic.
  • the cells can be transiently or stably transfected.
  • transfection of expression vectors into prokaryotic and eukaryotic cells can be accomplished via any technique known in the art, including but not limited to standard bacterial transformations, calcium phosphate co-precipitation, electroporation, or liposome mediated-, DEAE dextran mediated-, polycationic mediated-, or viral mediated transfection. (See, for example. Molecular Cloning: A Laboratory Manual (Sambrook, et ai., 1989, Cold Spring
  • a method of producing a polypeptide according to the disclosure is an additional part of the disclosure.
  • the method comprises the steps of (a) cuiturmg a host according to this aspect of the disclosure under conditions conducive to the expression of the polypeptide, and (b) optionally, recovering the expressed polypeptide.
  • the expressed polypeptide can be recovered from the cell free extract, but preferably they are recovered from the culture medium. Methods to recover polypeptide from cell free extracts or culture medium are well known to the man skilled in the art.
  • the present disclosure provides pharmaceutical compositions (such as a vaccine), comprising one or more polypeptides, multimers, nucleic acids, recombinant expression vectors, or host cells of the disclosure and a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions of the disclosure can be used, for example, in the methods of the disclosure described below.
  • the polypeptides may be the sole active agent in the pharmaceutical composition, or the composition may further comprise one or more other agents suitable for an intended use, including but not limited to adjuvants to stimulate the immune system generally and improve immune responses overall. Any suitable adjuvant can be used.
  • the present disclosure provides methods for treating and/or limiting an RSV infection, comprising administering to a subject in need thereof a therapeutically effective amount of one or more polypeptides of the disclosure, salts thereof, conjugates thereof, multimers thereof, nucleic acids of the disclosure (such as RNA), host cells or pharmaceutical compositions thereof, to treat and/or limit the RSV infection.
  • the method comprises eliciting an immune response in an individual having or at risk of an RSV infection, comprising administering to a subject in need thereof a therapeutically effective amount of one or more polypeptides of the disclosure, salts thereof, conjugates thereof, multimers thereof, nucleic acids of the disclosure (such as RNA), host cells or pharmaceutical compositions thereof, to generate an immune response.
  • RSV is a negative-sense, single-stranded RNA virus of the family
  • Paramyxoviridae that causes a respiratory disease, especially in children.
  • the therapeutic is administered to a subject already infected with the RSV, and/or who is suffering from symptoms (including but not limited to lower respiratory tract infections, upper respiratory tract infections, bronchiolitis, pneumonia, fever, listlessness, diminished appetite, recurrent wheezing, and asthma) indicating that the subject is likely to have been infected with the RSV.
  • symptoms including but not limited to lower respiratory tract infections, upper respiratory tract infections, bronchiolitis, pneumonia, fever, listlessness, diminished appetite, recurrent wheezing, and asthma.
  • treating means accomplishing one or more of the following: (a) reducing RSV titer in the subject; (b) limiting any increase of RSV titer in the subject; (c) reducing the severity of RSV symptoms; (d) limiting or preventing development of RSV symptoms after infection; (e) inhibiting worsening of RSV symptoms; (f) limiting or preventing recurrence of RSV symptoms in subjects that were previously symptomatic for RSV infection.
  • the therapeutic is used as a "therapeutic vaccines" to ameliorate the existing infection and/or provide prophylaxis against infection with additional RSV virus.
  • the therapeutic can also be administered prophylactically to a subject at risk of RSV infection to limit development of an RSV infection.
  • Groups at particularly high risk include children under age 18 (particularly infants 3 years or younger), adults over the age of 65, and individuals suffering from any type of immunodeficiency.
  • a “therapeutically effective amount” is an amount of the therapeutic effective for treating and'Or limiting RSV infection.
  • a suitable dosage range may, for instance, be 0.1 ug/kg- 100 mg/kg body weight; alternatively, it may be 0.5 ug/kg to 50 mg/kg; 1 ug/kg to 25 mg/kg. or 5 ug/kg to 10 mg/kg body weight.
  • the therapeutic can be delivered in a single bolus, or may be administered more than once (e.g., 2, 3, 4, 5, or more times) as determined by an attending physician.
  • the present disclosure provides methods for monitoring an RSV-induced disease in a subject and/or monitoring response of the subject to immunization by an RSV vaccine, comprising contacting a polypeptide, multimer, recombinant host cell, or pharmaceutical composition of the disclosure with a bodily fluid from the subject and detecting RSV-binding antibodies in the bodily fluid of the subject.
  • RSV-induced disease is intended any disease caused, directly or indirectly, by RSV.
  • the method comprises contacting a polypeptide, multimer, recombinant host cell, or pharmaceutical composition of the disclosure with an amount of bodily fluid (such as serum, whole blood, etc.) from the subject; and detecting RSV- binding antibodies in the bodily fluid of the subject.
  • the detection of the RSV binding antibodies allows the RSV disease in the subject to be monitored.
  • the detection of RSV binding antibody also allows the response of the subject to
  • Any suitable detection assay can be used, including but not limited to homogeneous and heterogeneous binding
  • immunoassays such as radioimmunoassays (RIA), ELISA, immunofluorescence, immunohistocliemistry, FACS, BIACORE and Western blot analyses.
  • the methods may be carried out in solution, or the polypeptide! s) of the disclosure may be bound or attached to a carrier or substrate, such as microtiter plates (ex: for ELISA), membranes and beads, etc.
  • a carrier or substrate such as microtiter plates (ex: for ELISA), membranes and beads, etc.
  • the polypeptides of the disclosure for use in this aspect may be conjugated to a detectable tag, to facilitate detection technique.
  • the present disclosure provides methods for detecting RSV binding antibodies, comprising contacting a polypeptide, multimer, recombinant host cell, or pharmaceutical composition of the disclosure with a composition comprising a candidate RSV binding antibody under conditions suitable for binding of RSV antibodies to the polypeptide, VLP, or composition; and
  • the methods are performed to determine if a candidate RSV binding antibody recognizes the RSV F epitope present in the polypeptides of the disclosure.
  • Any suitable composition may be used, including but not limited to bodily fluid samples (such as serum, whole blood, etc.) from a suitable subject (such as one who has been infected with RSV), naive libraries, modified libraries, and libraries produced directly from human donors exhibiting an RSV-specific immune response.
  • the assays are performed under conditions suitable for promoting binding of antibodies against the polypeptide, multimer, recombinant host cell, or pharmaceutical composition of the disclosure; such conditions can be determined by those of skill in the art based on the teachings herein. Any suitable detection assay can be used, such as those described above.
  • the polypeptides of the disclosure for use in this aspect may comprise a conjugate as disclosed above, to provide a tag useful for any detection technique suitable for a given assay.
  • the RSV F-binding antibodies are isolated using standard procedures.
  • the present disclosure provides methods for producing RSV antibodies, comprising
  • the antibodies can be used, for example, in RSV research.
  • the subject is preferably an animal typically used for antibody production, including but not limited to rodents, rabbits, goats, sheep, etc.
  • the antibodies can be either polyclonal or monoclonal antibodies.
  • the RSV-F is a trimeric glycoprotein that contains both neutralizing and non- neutralizing epitopes.
  • the development of a stable, minimal, monomeric domain containing potent neutralizing epitopes and minimizing non-neutralizing epitopes would offer an attractive alternative to the pre-fusion RSV F protein trimer that is currently being pursued by most in the field.
  • the design interventions to stabilize this domain in the absence of the rest of the RSV F glycoprotein included circular permutation, loop design, repacking and disulfide stapling.
  • eFTop- 10 and eFTop- 11 each contain 210 amino acids (not including an optional histag for purification), considerably smaller than the 492 amino acids in a single protomer of the RSV F glycoprotein trimer. eFTop- 10 and eFTop- 11 only differ in the design of an additional disulfide.
  • eFTop-11 is a monomer in solution as determined by SEC-MALS ( Figure 3A).
  • eFTop- 11 has a melting temperature of 75 degrees C according to Differential Scanning Calorimetry (DSC) ( Figure 3B) and a slightly higher melting temperature according to Circular Dichroism (CD) ( Figure 3C, left). CD also confirmed that eFTop- 11 maintains secondary structure to 75 degrees C ( Figure 3C, right).
  • the thermal stability of eFTop- 1 1 is a marked improvement from the published stabilized trimer known as RSVF-DSCAV1, for which we measure a melting temperature of 52 degrees C.
  • eFTop- 10 is also a monomer in solution according to SEC-MALS.
  • D25 IgG was captured on the sensor chip and monomeric eFTop-10 was analyte.
  • the affinity of eFTop-11 for D25 was also measured using the solution-based method KinExa.
  • eFTop-1 1 Multiple variants of eFTop-1 1 were designed using RosettaFixbb rM to remove void volumes within the core of eFTop- 11. Two such stabilized variants, eFTop- 11.1 and eFTop- 11.2, were discovered to be more stable than eFTop-1 1 while retaining similar antigenic profiles to eFTop-1 1.
  • the melting temperature of eFTop-1 1.1 was measured by DSC to be 87 degrees C. while the melting temperature of eFTop-11.2 was 78 degrees C.
  • the eFTop-11 originally designed as a monomer, w r as engineered via computational design and genetic fusion to create 3-mer, 4-mer and 8-mer multimers. These constructs were expressed in 293F cells and purified using standard Nickel and Size Exclusion methods. By SEC-MA LS, each construct was shown to have the correct molecular weight according to its intended multimeric state. The antigenic profiles of the constructs were tested and the results showed binding to D25, Motavizumab and Palivizumab.
  • the foui" Lumazine synthase fusions containing a form of eFTopl 1 with both stabilizing mutations (eFTop- 11.1) and with additional glycans (g4a, g4b), and also containing stabilizing mutations added to the lumazine sythase itself (“d41m3" mutations), and also containing modified codon usage for improved expression were:

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Abstract

L'invention concerne des polypeptides et leur utilisation pour traiter ou limiter une infection par le virus respiratoire syncytial.
PCT/US2018/023463 2017-03-22 2018-03-21 Mini-protéines immunogènes présentant des épitopes de neutralisation du virus respiratoire syncytial (vrs) WO2018175518A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2020132699A1 (fr) * 2018-12-21 2020-06-25 The Wistar Institute Of Anatomy And Biology Compositions comprenant des vaccins à auto-assemblage et leurs méthodes d'utilisation

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US8563002B2 (en) * 2007-12-24 2013-10-22 Glaxosmithkline Biologicals, S.A. Recombinant RSV antigens
US8580270B2 (en) * 2008-09-30 2013-11-12 University Of Massachusetts Respiratory synctial virus (RSV) sequences for protein expression and vaccines
US8846051B2 (en) * 2004-10-08 2014-09-30 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services, Centers For Disease Control And Prevention Modulation of replicative fitness by deoptimization of synonymous codons
WO2014160463A1 (fr) * 2013-03-13 2014-10-02 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Protéines f de rsv pré-fusion et leur utilisation
US20160303224A1 (en) * 2013-10-11 2016-10-20 The United States Of America, As Represented By The Secretary, Department Of Health And Human Epstein-barr virus vaccines

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US8846051B2 (en) * 2004-10-08 2014-09-30 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services, Centers For Disease Control And Prevention Modulation of replicative fitness by deoptimization of synonymous codons
US8563002B2 (en) * 2007-12-24 2013-10-22 Glaxosmithkline Biologicals, S.A. Recombinant RSV antigens
US8580270B2 (en) * 2008-09-30 2013-11-12 University Of Massachusetts Respiratory synctial virus (RSV) sequences for protein expression and vaccines
WO2014160463A1 (fr) * 2013-03-13 2014-10-02 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Protéines f de rsv pré-fusion et leur utilisation
US20160046675A1 (en) * 2013-03-13 2016-02-18 The USA, as represented by the Secretary, Departm- ent of Health and Human Service Prefusion rsv f proteins and their use
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020132699A1 (fr) * 2018-12-21 2020-06-25 The Wistar Institute Of Anatomy And Biology Compositions comprenant des vaccins à auto-assemblage et leurs méthodes d'utilisation

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