WO2004053100A2 - Polypeptides gp120 du virus de l'immunodeficience humaine mutants immunogenes, et leurs procedes d'utilisation - Google Patents

Polypeptides gp120 du virus de l'immunodeficience humaine mutants immunogenes, et leurs procedes d'utilisation Download PDF

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Publication number
WO2004053100A2
WO2004053100A2 PCT/US2003/039534 US0339534W WO2004053100A2 WO 2004053100 A2 WO2004053100 A2 WO 2004053100A2 US 0339534 W US0339534 W US 0339534W WO 2004053100 A2 WO2004053100 A2 WO 2004053100A2
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WIPO (PCT)
Prior art keywords
hiv
gpl20
amino acid
neutralizing
mutant
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PCT/US2003/039534
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English (en)
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WO2004053100A3 (fr
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Dennis R. Burton
Ian Wilson
Ralph Pantophlet
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The Scripps Research Institute
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Publication of WO2004053100A3 publication Critical patent/WO2004053100A3/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
    • 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
    • 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

Definitions

  • Anti-CD4bs mAbs typically neutralize TCLA viruses with moderate efficacy, but neutralize primary isolates of HIV-1 very weakly if at all (102). However, one mAb, bl2, which interacts with the CD4bs, does neutralize many primary and TCLA viruses very efficiently (22, 29, 53, 69). MAb bl2 and non-neutralizing anti-CD4bs mAbs typically have very similar binding affinities for monomeric gpl20 from a number of isolates (78, 80). The differences between bl2 and the other mAbs in neutralizing activity against TCLA viruses, therefore, have been associated with different affinities for the mature envelope trimer expressed on virions (35, 110, 116).
  • the invention provides immunogenic modified (mutant) HIV-1 gpl20 polypeptides, which can elicit an antibody response in a subject, particularly an antibody response characterized by the generation of neutralizing HIV-1 antibodies, including a much greater level of neutralizing antibody (as compared to non-neutralizing antibody) than that elicited by a wild-type gpl20 polypeptide.
  • the neutralizing antibody response is elicited in the absence of a non-neutralizing antibody response.
  • wild-type gpl20 polypeptide was modified by the substitution of at least one alanine for the wild-type amino acid residue(s).
  • variable loop deletions were made in the gp 120 molecule.
  • an immunogenic mutant HIV-1 gpl20 polypeptide can have Ql 14N, Ll 15T, S143T, E150N, and G152T substitutions and, if desired, can have one or more substitutions, e.g., H92N; K171N and Y173T; and/or I423N.
  • the present invention further relates to a method of reducing or preventing HIV infection in a subject.
  • a method which can be a prophylactic method, can be performed, for example, by administering an immunogenic mutant g l20 polypeptide of the invention to the subject under conditions that stimulate an HIV neutralizing antibody response in the subject.
  • Figure IB shows the location of mutations (colored blue) mapped onto the gpl20 core of HxB2. The view is from the perspective of CD4.
  • Monomeric gpl20 thus contains all of the antigenic determinants to elicit a broadly neutralizing antibody such as bl2.
  • a broadly neutralizing antibody such as bl2.
  • the use of monomeric g ⁇ l20 is jeopardized by the exposure of non-neutralizing epitopes that are normally occluded on oligomeric gpl20 or that reside in the variable regions, in particular the V2 and V3 loops (100, 103, 145).
  • These antigenic determinants are immunologically dominant over more conserved neutralizing epitopes (70, 86).
  • they may induce antibodies that interact with gpl20 in a manner that is not permitted on native envelope spikes.
  • HIV-1 gpl20 polypeptides provide potential immunogens useful, for example, as a component of an HIV-1 vaccine, and can serve as a basis for alternative approaches to the development of candidate vaccines against other viral pathogens.
  • mutant gpl20 molecule of the invention elicits a neutralizing human monoclonal antibody response similar to has the same (i.e., equivalent) ability to elicit a response including antibodies having specificity as a human monoclonal antibody such as bl2 by ascertaining whether the former or test antibodies prevent the bl2 antibody from binding to HIV.
  • Virus neutralization can be measured by a variety of in vitro and in vivo methodologies. Exemplary methods described herein for determining the capacity for neutralization are the in vitro assays that measure inhibition of HIV-induced syncytia formation, plaque assays and assays that measure the inhibition of output of core p24 antigen from a cell infected with HIV (see also the Examples section below).
  • one or a combination of mutations modifies the gpl20 polypeptide so as to generate a glycosylation site (e.g., an N-glycosylation site).
  • a glycosylation site e.g., an N-glycosylation site
  • Such mutations are exemplified by HIN-1 gpl20 comprising H92 ⁇ and N94T; Ql 14N and L115T; S143T; E150N and G152T; K171N and Y173T; Q246N; P313N and R315T; I423N and N425T; as well as combinations of such mutations that generate a glycosylation site (e.g., Ql 14N, Ll 15T, S143T, E150N, and G152T), any or all of which can further include a H92N, K171N, Y173T, and/or I423N substitution.
  • ADCC antibody-dependent cellular cytotoxicity
  • DRC complement-dependent cellular cytotoxicity
  • DRC complement-dependent cellular cytotoxicity
  • the effector functions may therefore be desirable in therapeutic applications.
  • Diagnostic assays include the ability to detect the presence of the immunoglobulin molecule. These assays rely on the cross-linking of red cells or beads in agglutinations, the activation of complement in plaque assays, or the antigenic properties of the Fc region of the heavy chain as detected by secondary antibodies in ELISA or RIA procedures to detect the presence of the immunoglobulin molecule. Such diagnostic assays can only be performed with the entire immunoglobulin molecule.
  • compositions of the present invention contain a physiologically tolerable carrier together with at least one species of gpl20 mutant or neutralizing antibodies as described herein, dissolved or dispersed therein as an active ingredient.
  • the therapeutic composition is not immunogenic for non-neutralizing antibodies when administered to a human patient for therapeutic purposes.
  • a representative patient for practicing the present passive immunotherapeutic methods is any human exhibiting symptoms of HIV-induced disease, including AIDS or related conditions believed to be caused by HIV infection, particularly HIV-1 infection, and humans at risk of HIV infection.
  • Patients at risk of infection by HIV include babies of HIV- infected pregnant mothers, recipients of transfusions known to contain HIV, users of HIV contaminated needles, individuals who have participated in high risk sexual activities with known HIV-infected individuals, and the like risk situations.
  • the passive immunization method comprises administering a composition comprising more than one species of human monoclonal antibody of this invention, preferably directed to non-competing epitopes or directed to distinct serotypes or strains of HIV, particularly HIV-1, so as to afford increased effectiveness of the passive immunotherapy.
  • the dosage ranges for the administration of the monoclonal antibodies of the invention are those large enough to produce the desired effect in which the symptoms of the HIV disease are ameliorated or the likelihood of infection decreased.
  • the dosage should not be so large as to cause adverse side effects, such as hyperviscosity syndromes, pulmonary edema, congestive heart failure, and the like.
  • the dosage will vary with the age, condition, sex and extent of the disease in the patient and can be determined by one of skill in the art.
  • the dosage can be adjusted by the individual physician in the event of any complication.
  • All tliree antibodies recognize discontinuous epitopes overlapping the CD4bs on HIV-l gpl20.
  • Tliree variable loop-deleted gpl20 mutants (Nl, ,V1/V2 and ,V3) were investigated. Deletion of the VI loop alone or together with the V2 loop had an adverse effect on the binding of CD4 and all three mAbs to g ⁇ l20, whereas deletion of the V3 loop decreased the binding affinity of CD4 and mAbs b6 and bl2, but not b3 (Table 1, below). Nineteen alanine substitutions in gpl20 reduced the affinity for CD4 and all three mAbs.
  • a small panel of recombinant gpl20 proteins with multiple alanine substitutions at these amino acid positions was generated to determine whether the unique differences in the effects observed with the single alanine mutations could be retained.
  • a plasmid was constructed encoding the gpl20 segment of a codon-optimized env gene of the primary isolate JR-FL, which is 94% identical in amino acid sequence to JR-CSF.
  • a tissue plasminogen activator leader sequence was placed upstream of the env gene to ensure secretion of g l20 into the culture media.
  • Four mutants (GDMR, DMR, DR and GM) were generated and tested on a panel of anti-CD4bs mAbs (Table 4, below).
  • amino acid residues of gpl20 that affect binding were systematically defined using the broadly neutralizing mAb bl2, CD4 and two non-neutralizing anti-CD4bs antibodies. Selected residues were changed to alanine because alanine generally does not significantly alter the main-chain conformation or impose extreme electrostatic or steric effects and so permits identification of amino acid side chains, which may be important for ligand binding.
  • antibody binding curves from ELISA data were generated, and the apparent antibody affinity for each gpl20 mutant was determined and related to that for wild-type gpl20.
  • Figure 4 (top panel) also shows that a number of mutations around the Phe43 cavity on gpl20 uniquely diminished bl2 binding, supporting recent results that residues comprising the antigen binding region, particularly those in the extended finger-like loop of the third complementarity determining region (CDR) of the heavy chain of Fab bl2, make crucial contacts with the residues close to the CD4 binding pocket on the gpl20 surface (90, 153).
  • CDR complementarity determining region
  • the substitutions in the stem region can lead to a repositioning of the VI /V2 loops, the effect of which is markedly different for monomeric and functional oligomeric gpl20; i.e., the substitutions lead to increased obstruction of the CD4bs for monomeric g l20, but have little effect for oligomeric gpl20.
  • These observations are pronounced of results obtained recently by Kolchinsky et al. (55, 56), in which mutant pseudovirions of the primary isolate ADA with an N ⁇ -K or Q substitution at position 197 become highly sensitive to neutralization by various anti-gpl20 mAbs (56).
  • plasmid pCMV-Tag4A-tpa R . FL gpi2 0w thas was described (94).
  • This plasmid which is derived from plasmid pCMV-Tag4A (Stratagene), contains a tissue plasminogen activator leader sequence immediately upstream of the env gene to ensure secretion of gpl20 envelope glycoprotein into the culture supernatant.
  • the env gene of HIV-1 JR-FL was obtained by PCR amplification using as template a plasmid (pSyngp 140 JR . PL ) encoding the codon-optimized gpl40 gene (2, 45) of this HIV isolate.
  • Site-directed mutagenesis to substitute wild-type residues for alanine and to incorporate N-glycosylation sequence motifs was performed using the QUIKCHANGE mutagenesis kit (Stratagene).
  • Assays were performed essentially as described (94). Glycoproteins were captured onto ELISA plate wells using the anti-C5 polyclonal antibody preparation, unless otherwise indicated. Antibodies against CD4-induced epitopes were tested in the absence of soluble CD4. MAb 2G12, or in some cases HIVIG, was used to ensure that similar amounts of envelope proteins were captured in each experiment. In general, plates were developed with p-nitrophenyl phosphate (Sigma) and absorbance measured at 405 nm.
  • P313 ⁇ a mutant, termed P313 ⁇ , was generated.
  • P313N/R315T an R315T substitution
  • Arg and Thr were substituted for Pro and Arg at positions 313 and 315, respectively, in the "tip" of the V3 loop (-Gly-Pro-Gly-Arg-Ala-Phe-; SEQ ID NO: 17) segment.
  • This N-glycosylation sequon ( ⁇ XT) permits the addition of a potential N-linked glycan at position 313.
  • N-glycosylation sequons were introduced individually at various positions in g ⁇ l20, primarily on the non-neutralizing face (143) and in the Nl and V2 loops, to determine the effect on bl2 binding.
  • the ⁇ XT glycosylation sequon (X is any amino acid except proline) was used because the asparagine in this motif is 2-fold more likely to be glycosylated than the asparagine in the NXS motif (124).
  • mutant GDMR was tested in ELISA with a selection of mAbs against various linear and discontinuous epitopes on gpl20. Only non-neutralizing or weakly neutralizing CD4bs mAbs were significantly affected by the alanine substitutions ( Figure 7). It is unclear whether this result correlates with how these antibodies interact with gpl20 and their lack of neutralizing potency.
  • incorporation of the glycosylation motif allows potential antibody epitopes to be masked due to the presence of the glycan. Whether the glycan indeed masks the entire loop is uncertain, since there are currently no antibodies available that are reactive with residues down- or upstream from the introduced glycosylation site in the V3 loop of JR-FL.
  • the second effect of replacing the proline and arginine residues is that this most likely eliminates or modifies the e-turn and e-type hairpin, which are characteristic of the apex of the V3 loop and confer immunodominance to the loop (40, 109). Lowering this predominant characteristic of the V3 loop may further increase the potential to obtain antibodies against epitopes on gpl20 that are normally only weakly immunogenic.
  • the extra glycans incorporated into the g ⁇ l20 mutants can reduce the overall flexibility of monomeric gpl20 and, therefore, further promote the induction of antibodies with neutralizing properties superior to those obtained with unmodified gpl20.
  • Variable-loop-deleted variants of the human immunodeficiency virus type 1 envelope glycoprotein can be stabilized by an intermolecular disulfide bond between the gpl20 and gp41 subunits. J. Virol. 74:5091-5100.
  • Human monoclonal antibody 2G12 defines a distinctive neutralization epitope on the g ⁇ l20 glycoprotein of human immunodeficiency virus type I. J. Virol. 70:1100-1108.
  • HIV-1 envelope glycoproteins fusogens, antigens, and immunogens. Science 280:1884-1888.

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Abstract

L'invention a trait à des polypeptides gp120 du VIH mutants immunogènes, qui présentent au moins une mutation et possèdent au moins un épitope qui se lie de manière spécifique à des anticorps non neutralisants. L'invention concerne également des procédés de production de tels anticorps neutralisant le VIH, qui font appel à de tels polypeptides gp120 mutants immunogènes. De plus, l'invention se rapporte à des méthodes permettant d'induire une réponse d'anticorps neutralisant le VIH chez un sujet.
PCT/US2003/039534 2002-12-11 2003-12-11 Polypeptides gp120 du virus de l'immunodeficience humaine mutants immunogenes, et leurs procedes d'utilisation WO2004053100A2 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006105993A2 (fr) * 2005-04-05 2006-10-12 Istituto Di Ricerche Di Biologia Molecolare P Angeletti Spa Procede permettant de proteger des sites fonctionnels ou des epitopes sur des proteines
WO2011028963A2 (fr) * 2009-09-03 2011-03-10 Biological Mimetics, Inc. Compositions immunogènes du vih
WO2014022475A2 (fr) * 2012-08-03 2014-02-06 Dana-Faber Cancer Institute, Inc. Compositions et méthodes de stabilisation par conformation de trimères de glycoprotéines de l'enveloppe du virus de l'immunodéficience chez le primate
WO2014165494A1 (fr) * 2013-04-02 2014-10-09 Duke University Production de glycoprotéines d'enveloppe du vih-1 par des techniques de recombinaison
WO2016062294A1 (fr) * 2014-10-24 2016-04-28 Versitech Limited Composés à motif d'adn et procédés pour induire des anticorps spécifiques et une immunité cellulaire
WO2020086483A1 (fr) * 2018-10-22 2020-04-30 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Protéine gp120 de recombinaison à délétion de la boucle v1
CN117568404A (zh) * 2024-01-16 2024-02-20 四川大学华西医院 多指（趾）相关的基因片段以及动物模型构建方法及应用

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US5585250A (en) * 1993-08-20 1996-12-17 The United States Of America As Represented By The Department Of Health & Human Services Dampening of an immunodominant epitope of an antigen for use in plant, animal and human compositions and immunotherapies
US5652138A (en) * 1992-09-30 1997-07-29 The Scripps Research Institute Human neutralizing monoclonal antibodies to human immunodeficiency virus
US5653985A (en) * 1990-03-09 1997-08-05 Chiron Corporation Purified gp120 composition retaining natural conformation
US5814458A (en) * 1988-09-13 1998-09-29 Chiron Corporation Immunoassay methods for the detection of HIV-1 antibodies employing envelope muteins containing hypervariable domain deletions
US6103238A (en) * 1992-03-13 2000-08-15 President And Fellows Of Harvard College Selectively deglycosylated human immunodeficiency virus type 1 envelope vaccines

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5814458A (en) * 1988-09-13 1998-09-29 Chiron Corporation Immunoassay methods for the detection of HIV-1 antibodies employing envelope muteins containing hypervariable domain deletions
US5653985A (en) * 1990-03-09 1997-08-05 Chiron Corporation Purified gp120 composition retaining natural conformation
US6103238A (en) * 1992-03-13 2000-08-15 President And Fellows Of Harvard College Selectively deglycosylated human immunodeficiency virus type 1 envelope vaccines
US5652138A (en) * 1992-09-30 1997-07-29 The Scripps Research Institute Human neutralizing monoclonal antibodies to human immunodeficiency virus
US5585250A (en) * 1993-08-20 1996-12-17 The United States Of America As Represented By The Department Of Health & Human Services Dampening of an immunodominant epitope of an antigen for use in plant, animal and human compositions and immunotherapies

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006105993A2 (fr) * 2005-04-05 2006-10-12 Istituto Di Ricerche Di Biologia Molecolare P Angeletti Spa Procede permettant de proteger des sites fonctionnels ou des epitopes sur des proteines
WO2006105993A3 (fr) * 2005-04-05 2007-03-29 Angeletti P Ist Richerche Bio Procede permettant de proteger des sites fonctionnels ou des epitopes sur des proteines
JP2008534640A (ja) * 2005-04-05 2008-08-28 イステイチユート・デイ・リチエルケ・デイ・ビオロジア・モレコラーレ・ピ・アンジエレツテイ・エツセ・ピー・アー タンパク質の機能部位またはエピトープの遮蔽方法
WO2011028963A2 (fr) * 2009-09-03 2011-03-10 Biological Mimetics, Inc. Compositions immunogènes du vih
WO2011028963A3 (fr) * 2009-09-03 2011-08-18 Biological Mimetics, Inc. Compositions immunogènes du vih
WO2014022475A3 (fr) * 2012-08-03 2014-04-17 Dana-Faber Cancer Institute, Inc. Compositions et méthodes de stabilisation par conformation de trimères de glycoprotéines de l'enveloppe du virus de l'immunodéficience chez le primate
WO2014022475A2 (fr) * 2012-08-03 2014-02-06 Dana-Faber Cancer Institute, Inc. Compositions et méthodes de stabilisation par conformation de trimères de glycoprotéines de l'enveloppe du virus de l'immunodéficience chez le primate
US11149069B2 (en) 2012-08-03 2021-10-19 Dana-Farber Cancer Institute, Inc. Compositions and methods for conformationally stabilizing primate immunodeficiency virus envelope glycoprotein trimers
WO2014165494A1 (fr) * 2013-04-02 2014-10-09 Duke University Production de glycoprotéines d'enveloppe du vih-1 par des techniques de recombinaison
WO2016062294A1 (fr) * 2014-10-24 2016-04-28 Versitech Limited Composés à motif d'adn et procédés pour induire des anticorps spécifiques et une immunité cellulaire
WO2020086483A1 (fr) * 2018-10-22 2020-04-30 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Protéine gp120 de recombinaison à délétion de la boucle v1
US20210340188A1 (en) * 2018-10-22 2021-11-04 The United States Of America, As Represented By The Secretary, Department Of Health And Human Servic Recombinant gp120 protein with v1-loop deletion
CN117568404A (zh) * 2024-01-16 2024-02-20 四川大学华西医院 多指（趾）相关的基因片段以及动物模型构建方法及应用
CN117568404B (zh) * 2024-01-16 2024-03-15 四川大学华西医院 多指（趾）相关的基因片段以及动物模型构建方法及应用

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