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WO2015048517A1 - Mutants d'échappement - Google Patents

Mutants d'échappement Download PDF

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Publication number
WO2015048517A1
WO2015048517A1 PCT/US2014/057817 US2014057817W WO2015048517A1 WO 2015048517 A1 WO2015048517 A1 WO 2015048517A1 US 2014057817 W US2014057817 W US 2014057817W WO 2015048517 A1 WO2015048517 A1 WO 2015048517A1
Authority
WO
WIPO (PCT)
Prior art keywords
hiv
composition
vector
science
immunogens
Prior art date
Application number
PCT/US2014/057817
Other languages
English (en)
Inventor
Barton F. Haynes
Feng Gao
Bette T. Korber
Hua-Xin Liao
Original Assignee
Duke University
Los Alamos National Security, Llc
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, Los Alamos National Security, Llc filed Critical Duke University
Publication of WO2015048517A1 publication Critical patent/WO2015048517A1/fr

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Classifications

    • 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
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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 Induction of HIV-1 envelope (Env) broadly neutralizing antibodies (BnAbs) is a key goal of HIV- 1 vaccine development.
  • BnAbs can target conserved regions that include conformational glycans, the gp41 membrane proximal region, the V 1/V2 region, glycans-associated C3/V3 on gpl20, and the CD4 binding site (CD4bs) (Walker et al, Science 326:285-289 (2009), Walker et al, Nature 477:466-470 (201 1), 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), Sattentau and McMichael, F1000 Biol.
  • CD4bs BnAbs have extremely high levels of somatic mutation suggesting complex or prolonged maturation pathways (Kwong and Mascola, Immunity 37:412-425 (2012), Wu et al, Science 329:856-861 (2010), Wu et al, Science 333 : 1 593- 1602 (201 1 ), Zhou et al, Science 329:81 1 -817
  • Envs bind to UCAs of BnAbs targeting gp41 membrane proximal region (Ma et al, PLoS Pathog. 7:el 002200 (2001 ), Alam et al, J. Virol. 85: 1 1725-1 1731 (201 1 )), and to UCAs of some V1 V2 BnAb (Bonsignori et al, J. Virol.
  • 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)).
  • T/F Envs might be predisposed to binding the germline or unmutated common ancestor (UCA) of the observed BnAb in those rare patients that make BnAbs.
  • UCA common ancestor
  • 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 Retrovirol. 23: 1 1 (2008), Dimitrol, MAbs 2:347-356 (2010), Ma et al, PLoS Pathog.
  • UCAs unmutated common ancestors
  • Env immunogens to trigger antibody lineages with potential ultimately to develop breadth
  • the CH I 03 CD4bs BnAb clonal lineage was isolated from an African patient, CH505, who was followed from acute HIV-1 infection through BnAb development.
  • the studies show that the CHI 03 BnAb lineage is less mutated than most other CD4 binding site BnAbs, and may be first detectable by as early as 14 weeks after HIV- 1 infection.
  • Early autologous neutralization by antibodies in this lineage triggered virus escape, but rapid and extensive Env evolution in and near the epitope region preceded the acquisition of plasma antibody neutralization breadth defined as neutralization of heterologous viruses.
  • Analysis of the cocrystal structure of the CH I 03 Fab and a gpl20-core demonstrated a novel loop binding mode of antibody neutralization. (See International
  • the present invention relates to HIV- 1 . More specifically, the invention relates to HIV- 1 immunogens and compositions comprising same. The invention further relates to methods of inducing the production of broadly neutralizing HIV-1 antibodies in a subject (e.g., a human) and to compounds and compositions suitable for use in such methods.
  • a subject e.g., a human
  • Figure 1 Sequences of escape mutants.
  • the invention relates to the Env sequences shown in Figure 1 and to nucleic acids comprising nucleotide sequences encoding same.
  • the invention further relates to methods of using such amino acid and nucleic acids as immunogens.
  • the "escape mutants" of Figure 1 are Env sequences which were designed to capture virus sequences which are not recognized by the CHI 03 antibodies. The expectation is that adding these escape mutant antigen to the polyvalent vaccine described in International Applications PCT/US 13/00210 and
  • PCT/US2013/059515 would increase the breadth of immunogenicity and protection.
  • the envelopes to be used as immunogens in accordance with the invention can be expressed as full gp!40, gpl 45 with transmembrane portions, gp l 20s, gp! 20 resurfaced core proteins, gpl 20 outer domain constructs, or other minimal gp] 20 constructs.
  • immunization regimens can include sequential immunizations of Env constructs, including Envs selected from those included Fig. 1 , 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 CH0505, Further, repetitive immunization can be effected with "swarms" of CH05O5 Envs (for example, including various combinations of the sequences in Fig.1 and encoding nucleic acids) 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 T/F Env or Env subunits that can include the gpl 45 with a transmembrane portion, gp41 and gpl 20, an uncleaved gpl 40, a cleaved gpl 40, a gpl 20, a gpl 20 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 representatives of subsequently evolved Env variants either given in combination to mimic the high diversity observed in vivo during affinity maturation, or in series, using vaccine immunogens specifically selected to trigger the appropriate maturation pathway by high affinity binding to U
  • 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 and/or in International Application PCT/US 13/00210 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 and/or in International Application PCT/US 13/00210 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 in Fig. 1 ) and nucleic acids comprising nucleotide sequences encoding same.
  • the envelope proteins (and subunits thereof) can be expressed, for example, in 293T cells, 293F cells or CHO cells (Liao et al, Virology
  • 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 Fig. 1 , 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, ASO l B 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. Nature Med. 16: 324-8 (2010)).
  • 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 intrarectally or vaginally as a
  • a large panel of neutralizing antibodies has been tested against a large global panel of pseudotyped Envelopes.
  • Phylogenetically corrected amino acid signature patterns have been defined that are associated with either neutralization sensitivity or resistance.
  • Signatures have been defined for each of four major classes of neutralizing antibodies: CD4bs, VI V2 glycan (PG9-like) V3 glycan (PGT121 -like) and MPER.
  • 5 specific resistance signatures that were found for the CHAVI CD4bs neutralizing antibody CH I 03 were tested experimentally for impact through site-directed mutagenesis. 1 of the 5 signature sites was in a contact residue for this antibody, and could independently confer resistance, The other 4 were outside the epitope region.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne, en général, le VIH-1 et, en particulier, des immunogènes du VIH-1 et des procédés d'utilisation de tels immunogènes pour induire la production d'anticorps anti-VIH-1 largement neutralisants chez un sujet (par exemple, un humain).
PCT/US2014/057817 2013-09-28 2014-09-26 Mutants d'échappement WO2015048517A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201361884029P 2013-09-28 2013-09-28
US61/884,029 2013-09-28

Publications (1)

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WO2015048517A1 true WO2015048517A1 (fr) 2015-04-02

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110044994A1 (en) * 2009-03-17 2011-02-24 Po-Ying Chan-Hui Human immunodeficiency virus (hiv)-neutralizing antibodies
US20110262488A1 (en) * 2010-03-02 2011-10-27 Phogat Sanjay K Novel HIV-1 Envelope Glycoprotein
WO2013006688A2 (fr) * 2011-07-05 2013-01-10 Duke University Immunogènes gp120 à extrémité n-terminale délétée
US20130164316A1 (en) * 2010-05-07 2013-06-27 Los Alamos National Security, Llc Genetic signatures in hiv-1 subtype c envelope glycoproteins

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110044994A1 (en) * 2009-03-17 2011-02-24 Po-Ying Chan-Hui Human immunodeficiency virus (hiv)-neutralizing antibodies
US20110262488A1 (en) * 2010-03-02 2011-10-27 Phogat Sanjay K Novel HIV-1 Envelope Glycoprotein
US20130164316A1 (en) * 2010-05-07 2013-06-27 Los Alamos National Security, Llc Genetic signatures in hiv-1 subtype c envelope glycoproteins
WO2013006688A2 (fr) * 2011-07-05 2013-01-10 Duke University Immunogènes gp120 à extrémité n-terminale délétée

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE GENBANK 22 April 2013 (2013-04-22), accession no. GG24895.1 *

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