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WO2015048438A1 - Immunogènes du vih-1 - Google Patents

Immunogènes du vih-1 Download PDF

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Publication number
WO2015048438A1
WO2015048438A1 PCT/US2014/057708 US2014057708W WO2015048438A1 WO 2015048438 A1 WO2015048438 A1 WO 2015048438A1 US 2014057708 W US2014057708 W US 2014057708W WO 2015048438 A1 WO2015048438 A1 WO 2015048438A1
Authority
WO
WIPO (PCT)
Prior art keywords
hiv
composition
vector
immunogens
science
Prior art date
Application number
PCT/US2014/057708
Other languages
English (en)
Inventor
Barton F. Haynes
Feng Gao
Beatrice H. Hahn
George M. Shaw
Hua-Xin Liao
Original Assignee
Duke University
The Trustees Of The Univesity Of Pennsylvania
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Duke University, The Trustees Of The Univesity Of Pennsylvania filed Critical Duke University
Publication of WO2015048438A1 publication Critical patent/WO2015048438A1/fr

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Classifications

    • 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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/162—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0031—Rectum, anus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • 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
    • C12N2740/16034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • 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
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16122—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
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • the present invention relates, in general, to HIV-1 and, in particular, to HIV-1 immunogens and to methods of using such immunogens to induce the production of broadly neutralizing HIV-1 antibodies in a subject (e.g., a human).
  • BnAbs broadly neutralizing antibodies
  • CD4bs CD4 binding site
  • CD4bs BnAbs have extremely high levels of somatic
  • T/F transmitted/founder virus
  • the initial neutralizing antibody response to this virus arises approximately 3 months after transmission and is strain-specific (Richman et al, Proc. Natl. Acad. Sci. USA 100:4144-4149 (2003), Corti et al, PLoS One 5:e8805 (2010)).
  • This antibody response to the T/F virus drives viral escape, such that virus mutants become resistant to neutralization by autologous plasma (Richman et al, Proc. Natl. Acad. Sci. USA 100:4144-4149 (2003), Corti et al, PLoS One 5:e8805 (2010)).
  • BnAbs studied to date have only been isolated from individuals who were sampled during chronic infection (Walker et al, Science 326:285-289 (2009), Burton et al, Science 337: 183-186 (2012), Kwong and Mascola, Immunity 37:412-425 (2012), Wu et al, Science 329:856-861 (2010), Wu et al, Science 333: 1593-1602 (201 1), Zhou et al, Science 329:81 1-817 (2010), Bonsignori et al, J. Virol.
  • Vaccine strategies have been proposed that begin by targeting unmutated common ancestors (UCAs), the putative naive B cell receptors of BnAbs, with relevant Env immunogens to trigger antibody lineages with potential ultimately to develop breadth (Wu et al, Science 333: 1593-1602 (201 1), Haynes et al, Nat. Biotechnol. 30:423-433 (2012), Scheid et al, Nature 458:636-640 (2009), Chen et al, AIDS Res. Human Retroviral. 23: 1 1 (2008), Dimitrol, MAbs 2:347-356 (2010), Ma et al, PLoS Pathog.
  • UCAs unmutated common ancestors
  • the present invention results, at least in part, from studies that resulted in the isolation of HIV Envelope encoding sequences from an individual, CHI 754, who developed plasma HIV-1 neutralization breadth over a two to three year period.
  • the present invention relates to HIV-1. More specifically, the invention relates to HIV-1 immunogens and to methods of using such
  • the present invention results, at least in part, from studies that resulted in the isolation of Envelope gene sequences from an individual, CHI 754, who developed plasma HIV-1 neutralization breadth over a two to three year period.
  • the invention relates the Env gene sequences shown in the Sequence Listing and the encoded amino acid sequences, and the use thereof as immunogens.
  • the envelopes to be used as immunogens in accordance with the invention can be expressed as full gpl40, gpl45 with transmembrane portions, gpl20s, gpl20 resurfaced core proteins, gpl20 outer domain constructs, or other minimal gpl20 constructs.
  • immunization regimens can include sequential immunizations of Env constructs selected from those encoded by the sequences of the Sequence Listing, or can involve prime and boosts of combinations of Envs, or the administration of "swarms" of such sequences. Immunogenic fragments/subunits can also be used, as can encoding nucleic acid sequences.
  • the transmitted founder virus Env constructs can be used as primes, followed by a boost with the transmitted founder Env and sequential additions of Envs from progressively later times after transmission in patient CHI 754.
  • repetitive immunization can be effected with "swarms" of CHI 754 Envs (for example, including various combinations of the nucleic acid sequences in the Sequence Listing and encoded proteins) ranging from, for example, 2 to 40 Envs.
  • the present invention relates to a method of activating an appropriate naive B cell response in a subject (e.g., a human) by administering the CHI 754 T/F Env or Env submits that can include the gpl45 with a transmembrane portion, gp41 and gpl20, an uncleaved gpl40, a cleaved gpl40, a gpl20, a gpl20 subunit such as a resurfaced core (Wu X, Science 329:856-61 (2010)), an outerdomain, or a minimum epitope expressing only contact points of broadly neutralizing antibodies (Bnabs) with Env (the minimal epitope to avoid dominant Env non-neutralizing epitopes), followed by boosting with
  • CHI 754 Env variants e.g., see the Sequence Listing
  • DNA, RNA, protein or vectored immunogens can be used alone or in combination.
  • transmitted founder virus envelope is administered to the subject (e.g., human) as the priming envelope and then one or more of the sequential envelopes disclosed herein is administered as a boost in an amount and under conditions such that BnAbs are produced in the subject (e.g., human).
  • the subject e.g., human
  • one or more of the sequential envelopes disclosed herein is administered as a boost in an amount and under conditions such that BnAbs are produced in the subject (e.g., human).
  • 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17 or 18 envelopes (or subunits thereof) can be used with one prime and multiple boosts.
  • the present invention includes the specific envelope proteins disclosed herein (e.g., those encoded by the sequences in the Sequence Listing) and nucleic acids comprising nucleotide sequences encoding same (e.g., those in the Sequence Listing).
  • the envelope proteins (and subunits thereof) can be expressed, for example, in 293T cells, 293F cells or CHO cells (Liao et al, Virology 353:268-82 (2006)).
  • the envelope proteins can be expressed, for example, as gpl20 or gpl40 proteins and portions of the envelope proteins can be used as immunogens such as the resurfaced core protein design (RSC) (Wu et al, Science 329:856-861 (2010)); another possible design is an outer domain design (Lynch et al, J. Virol. 86:7588-95 (2012)).
  • RSC resurfaced core protein design
  • the invention includes immunogenic fragments/subunits of the envelope sequences disclosed herein, including fragments at least 6, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280 300, 320 or more amino acids in length, as well as nucleic acids comprising nucleotide sequences encoding such fragments and vectors containing same.
  • the invention provides variants of the sequences encoded by the sequences in the Sequence Listing, including variants that comprise a mutation which repairs a trypsin cleavage site, thereby preventing protein clipping during Env protein production in a cell line, e.g., a CHO cell line.
  • the envelopes can be formulated with appropriate carriers using standard techniques to yield compositions suitable for administration.
  • the compositions can include an adjuvant, such as, for example, alum, poly IC, MF- 59 or other squalene-based adjuvant, ASOIB or other liposomal based adjuvant suitable for protein immunization.
  • nucleic acid sequences encoding the immunogens can also be administered to a subject (e.g., a human) under conditions such that the immunogen is expressed in vivo and BnAbs are produced.
  • the DNA can be present as an insert in a vector, such as a rAdenoviral (Barouch, et al. Nature Med. 16: 319-23 (2010), recombinant mycobacterial (i.e., BCG or M smegmatis) (Yu et al. Clinical Vaccine Immunol. 14: 886-093 (2007); ibid 13: 1204-1 1 (2006), or recombinant vaccinia type of vector (Santra S.
  • Immunogens of the invention and nucleic acids (e.g., DNAs) encoding same, are suitable for use in generating an immune response (e.g., BnAbs) in a patient (e.g., a human patient) to HIV-1.
  • the mode of administration of the immunogen, or encoding sequence can vary with the particular immunogen, the patient and the effect sought, similarly, the dose administered.
  • the administration route is intramuscular or subcutaneous injection (intravenous and intraperitoneal can also be used).
  • the formulations can be administered via the intranasal route, or intrarectal ly or vaginally as a
  • immunogens and nucleic acids encoding same are suitable for use prophylactically, however, their administration to infected individuals may reduce viral load.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Virology (AREA)
  • Reproductive Health (AREA)
  • Dermatology (AREA)
  • Urology & Nephrology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gynecology & Obstetrics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Peptides Or Proteins (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

La présente invention concerne en général le VIH-1, et en particulier des immunogènes du VIH-1. Elle concerne des méthodes d'utilisation de tels immunogènes pour induire la production d'anticorps pouvant largement neutraliser le VIH-1 chez un sujet (par exemple, un humain)
PCT/US2014/057708 2013-09-28 2014-09-26 Immunogènes du vih-1 WO2015048438A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201361884014P 2013-09-28 2013-09-28
US61/884,014 2013-09-28

Publications (1)

Publication Number Publication Date
WO2015048438A1 true WO2015048438A1 (fr) 2015-04-02

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PCT/US2014/057708 WO2015048438A1 (fr) 2013-09-28 2014-09-26 Immunogènes du vih-1

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012040562A2 (fr) * 2010-09-24 2012-03-29 International Aids Vaccine Initiative Nouveaux anticorps à pouvoir de neutralisation du vih-1 étendu
WO2013006688A2 (fr) * 2011-07-05 2013-01-10 Duke University Immunogènes gp120 à extrémité n-terminale délétée

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012040562A2 (fr) * 2010-09-24 2012-03-29 International Aids Vaccine Initiative Nouveaux anticorps à pouvoir de neutralisation du vih-1 étendu
WO2013006688A2 (fr) * 2011-07-05 2013-01-10 Duke University Immunogènes gp120 à extrémité n-terminale délétée

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GRAY ET AL.: "The neutralization breadth of HIV-1 develops incrementally over four years and is associated with CD 4+ T cell decline and high viral load during acute infection", JOURNAL OF VIROLOGY, vol. 85, no. 10, 2011, pages 4828 - 4840 *
HUSSAIN ET AL.: "Broadly neutralizing antibody responses in a subset of HIV-1-infected individuals in Chennai, India : potential avenues for vaccine design", JOURNAL OF THE INTERNATIONAL ASSOCIATION OF PROVIDERS OF AIDS CARE (JIAPAC)., February 2013 (2013-02-01), pages 1 - 8 *
WALKER ET AL.: "Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target", SCIENCE, vol. 326, no. 5950, 2009, pages 285 - 289 *

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