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WO1989007615A1 - Glycoproteines immunogeniques de cytomegalovirus humains - Google Patents

Glycoproteines immunogeniques de cytomegalovirus humains Download PDF

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Publication number
WO1989007615A1
WO1989007615A1 PCT/US1989/000318 US8900318W WO8907615A1 WO 1989007615 A1 WO1989007615 A1 WO 1989007615A1 US 8900318 W US8900318 W US 8900318W WO 8907615 A1 WO8907615 A1 WO 8907615A1
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Prior art keywords
glycoprotein
glycoproteins
gcii
molecular weight
galactosamine
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Ceased
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PCT/US1989/000318
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English (en)
Inventor
Bruce E. Kari
Richard C. Gehrz
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Childrens Hospital Inc
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Childrens Hospital Inc
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Publication of WO1989007615A1 publication Critical patent/WO1989007615A1/fr
Priority to KR1019890701929A priority Critical patent/KR900700509A/ko
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/081—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from DNA viruses
    • C07K16/085—Herpetoviridae, e.g. pseudorabies virus, Epstein-Barr virus
    • C07K16/089—Cytomegalovirus
    • 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
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/16011—Herpesviridae
    • C12N2710/16111—Cytomegalovirus, e.g. human herpesvirus 5
    • C12N2710/16122—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
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/16011—Herpesviridae
    • C12N2710/16111—Cytomegalovirus, e.g. human herpesvirus 5
    • C12N2710/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • HCMV glycoproteins appear to be involved in human immune recognition of the virus. This has been demonstrated by the reactivity of HCMV glycoproteins with human convalascent sera. (G. H. Farrar et al., 3. Gen. Virol., 65, 1991 (1984); B. Nowak et al., Virology, 132, 325 (1984)). Biochemical approaches have been used to try to determine the number and composition HCMV glycoproteins.
  • gCI HCMV glycoprotein complexes and their constituent glycoproteins
  • compositions of matter which are substantially-pure glycoprotein complexes or glycoproteins which can be derived from HCMV. These compounds are found only on the membrane envelope of the intact HCMV virion, where the glcyoproteins are associated via disulfide linkages into the glycoprotein complexes.
  • the glycoprotein complexes and their component glycoproteins are physically accessible to the immune system and to antibodies, and are capable of stimulating both humoral and cellular immunity in humans and in other mammals.
  • one embodiment of the present invention is directed to substantially-pure, immunogenic glycoprotein complexes, which are on the membrane envelope of HCMV, wherein said complexes comprise an about 50-52 kD glycoorotein which reacts with the monoclonal antibody produced by hybridoma IVI-10118.
  • Two of these complexes have a molecular weight of about 200 kD or about 93 kD.
  • these complexes will be referred to as gCII-200 and gCII-93, respectively.
  • a further embodiment of the present invention is a substantially-pure, irnmunogenic glycoprotein having a molecular weight of about 50-52 kD, wherein sai'i glycoprotein is on the membrane envelope of HCMV and is associated with other envelope glycoproteins by means of disulfide bonds, and wherein said glycoprotein reacts with the monoclonal antibody IVI-10118.
  • this complex will be referred to gp52(II).
  • the present invention also provides a vaccine comprising an amount of this glycoprotein which is effective to produce an immune response against HCMV in a mammal, when administered thereto, in combination with a pharmaceutically-effective vehicle such as a liquid carrier.
  • a pharmaceutically-effective vehicle such as a liquid carrier.
  • glycoorotein A of HCMV, see L. Pereira (U.S. Patent No. 4,689,225), the disclosure of which is incorporated by reference herein.
  • the present compositions are useful in the production of monoclonal antibodies, which in turn can be used to diagnose HCMV or to treat HCMV infections.
  • the present compositions are also useful to produce clonai populations of antigen-specific T-helper lymphocytes, which in turn can be used for HCMV therapy.
  • compositions of the present invention were extracteo from human cytomegalovirus with a nonionic detergent and seoarated by anion exchange high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • One comolex had a molecular weight of 93,000 and was designated as gCII-93.
  • Another related complex had a molecular weight greater than 200,000 and was designated as gCII-200.
  • Both complexes were immunoprecipitated with a monoclonal antibody (9E10).
  • glycoproteins were reduced, alkylated, and the individual glycoproteins were separated by gel-filtration HPLC.
  • the amino sugar content of these glycoproteins was compared to that of higher molecular weight glycoproteins obtained from gCII-200 and to a glycoprotein with a molecular weight of 93,000 (gp93(I)) from gCI.
  • Glycoproteins with molecular weights of 50-52,000 derived from both gCII-93 and gCII-200 contained similar amounts of galactosamine (GalN), glycosamine (GlcN) and sialic acid. Also, they both contained 2-3 times more GalN than any other glycoprotein from gCII-200 and 10 times more GalN than was detected in gp93(I). All glycoproteins from gCII-93 or gCII-200 also contained more sialic acid when compared to gp93(I). GalN in these glycoproteins was present in O- linked oligosaccharides.
  • gp52(II) appears to have a unique phenotype marked by a high amount of O-linked oligosaccharides.
  • the immunoprecipitated complexes were solubilized by heating them at 60°C for 5 min. in Tris buffer (pH 8) containing 4% SOS. After cooling, urea was added to a final concentration of 8 M and complexes reduced with 10 mM dithiothreitol (DTT) at room temperature for 4 hrs before adding iodoacetamide. Alkylation was allowed to proceed for 2 hrs at room temperature. Samples were dialyzed against 0.1% SDS and reduced in volume to 0.5 ml. Individual glycoproteins were separated by gel-filtration HPLC using coupled columns of TSK 3000 and 4000 (Toyo Soda, Japan). HPLC was done at a flow rate of 0.3 ml/min. using a buffer of 10 mM Tris (pH 7.8) containing 0.1% SDS. Eluate was monitored for radioactivity.
  • SDS-PAGE and fluorographv SDS-PAGE was done with 5-15% polyacrylamide slab gel gradients following the method of U. K. Laemmli, Nature, 227, 680 (1970). Tritium in gels was detected by fluorography using Enlighting (New England Nuclear Corp., Boston, MA).
  • Pronase digestion Pronase (Caibiochem) digestion was done at 60°C for 48 hrs as previously described by F. Dall'Olio et al., J. Virol., 56 , 127 (1985), with the exception that 0.1% SDS was used and enzyme was added twice to a final concentration of 0.3%.
  • Aft3r pronase digestion detergent was removed using Extracti-Gel D (Pierce Chem. Co., Rockford, IL).
  • G-50 column chromatograohy Chromatography of pronase glycopeptides was done using a Sephadex G-50 column (1 ⁇ 50 cm) equilibrated with 0.1 N acetic acid.
  • the void volume (Vo) was determined with blue dextran and the total included volume (Vt) with [ 3 H] glucosamine.
  • the elution volume of N-linked complex and high mannose glycopeptides was accomplished as previously described by S. Olofsson et al., 3. Gen. Virol., 64, 6735 (1983).
  • TLC Thin layer chromatography was carried out according to the methods of Dall'Olio et al., cited above, using silica gel 60 on plastic-backed plates from Merck.
  • the solvent system was ethanol: pyridine:1-butanol:acetic acid:water (100:10:10:3:30, v/v/v/v/v) to which 1% (w/v) potassium tetraborate was added (solvent B).
  • Radioactive hexosamines were detected by fluorography using Enhance spray (New
  • Non-radioactive standards were run in lanes aojacent to the unknowns. After development of TLC plates, lanes containing standards were cut from the piates and hexosamines detected with ninhydrin spray.
  • Peak 3UR contained gCI complexes, which were recognized by monoclonal antibody 4IC2. After reduction of disulfide bonds, gCI generated glycoproteins with molecular weights of 130,000, 93,000 and 50,000. Peak 2UR also contained a 93,000 molecular weight glycoprotein which was not disulfide-linked to other glycoproteins and was not immunoprecipitated by the monoclonal antibodies. This glycoprotein was not examined further.
  • Glycoprotein complexes gCII-93 and gCII-200 were immunoprecipitated with 9E10 and gCI was immunoprecipitated with 41C2. Immunoprecipitated complexes were solubilized in SDS, reduced with DTT, alkylated with iodoacteamide, and the individual glycoprcteins were separated by gel-filtration HPLC. By gel-filtration, we were able to obtain a 93,000 molecular weight glycoprotein (designated gp93 (I)) from gCI (Fig. 2A). Material from gCII-93 was resolved into two peaks (Fig. 2B).
  • a minor peak contained a 90,000 molecular weight glycoprotein, while a second major peak had a glycoprotein with a molecular weight of 50-52,000 (designated gp 52 (11-93)). Due to the small amount of the 90,000 molecular weight glycoprotein, only gp52 (11-93) was collected for further analysis.
  • gCII-200 resolved into at least 3 peaks (Fig. 2C).
  • the first peak contained material with a molecular weight greater than 200,000 (designated gp200 (11-200)); the second peak contained a smear of material ranging in molecular weight from 90,000 to 200,000 (designated gp90 (11-200)) (Fig. 2C).
  • the third peak was the most abundant when glycoproteins were labeled with [ 3 H]GlcN. This peak containing glycoproteins with molecular weights of 50-52,000 (designated gp52 (11-200)) (Fig. 2C).
  • glycoproteins were double labeled with [ 3 H] arginine and [ 14 C]GlcN.
  • Glycoprotein 93 (I) was examined for comparison.
  • the purified glycoproteins were digested with trypsin and fragments separated by gel-filtration HPLC. By this method, three major peptides were obtained from gp93 (I). All three contained carbohydrate, suggesting that gp93 (I) contains at least three glycosylation sites.
  • gp52 (11-93) and gp52 (11-200) two major fragments were obtained.
  • a second fragment had a molecular weight of approximately 10,000 ana contained little or no [ 14 C]GlCN. Smaller, less abundant peaks were also detected. With both glycoproteins, the most abundant of these eluted with arginine.
  • Radioactivity released by neuraminidase was bound to a Dowex 1 column in the formate form and was reieased by 2 N formate.
  • label eluting with 2 N formate co-migrated with authentic sialic acid with paper chromatography using solvent system A.
  • the amount of radioactivity released by neuraminidase was used to quantitate the amount of sialic acid in the various glycoproteins.
  • To quantitate the amount of GlcN and GalN, desialylated glycopeptides were subjected to strong acid hydrolysis and hexosamines separated by TLC.
  • glycopeptides from gp52 (11-93) and gp52 (11-200) were resolved into three peaks by G-50 chromatography.
  • the first peak eluted at the Vo. Material in this peak was collected and redigested with pronase for 24 hrs with no further degradation.
  • the glycopeptides eluting at the Vo may have contained closely spaced oligosaccharides on the peptide backbone which can prevent the action of pronase.
  • G-50 peak I from both gp52 (11-93) and gp52 (11-200) contained 72-75% GalN, the peak itself was more abundant in gp52 (11-200).
  • the second peak (G-50 peak 2) eluted with N-linked standards and contained
  • glycoproteins from gCII-93 and gCII-200 contained more GalN than gp93 (I).
  • gp52 from both gCII complexes contained two to three times more GalN than other glycoproteins from the same complexes.
  • glycopeptides obtained after mild alkaline borohvdride treatment Since glycoproteins from gCII-93 and gCII-200 contained high amounts of GalN, it was of interest to determine if the GalN was present in O-linked oligosaccharides. To determine this, the glycopeptides were subjected to the betaeiimination reaction which cleaves oligosaccharides which are O-glycosidically-linked to serine or threonine. N-acetylgalactosamine, which is usually present at the reducing end of the oligosaccharide, is converted to GalNAc-ol. Oligosaccharides obtained after beta-elimination were subjected to strong acid hydrolysis and hexosamines examined to demonstrate the conversion of GalN to GalN-ol.
  • This fast migrating material was most likely degradation products obtained by strong acid hydrolysis of GalN-ol.
  • the elution position of G-50 peak 2 was not affected by the beta-elimination reaction carried out on any glycoprotein from gCI, gCII-93 and gCII-200.
  • This peak contained GlcN, demonstrating that the oligosaccharides were N-linked.
  • the elution position of G-50 peak 3 from any glycoprptein from gCII-93 or gCII-200 was not affected by beta-elimination, but GalN in this peak was converted to GalN-ol. This suggested that the GalN in this peak was O-glysosidically linked. 5.
  • glycopeptides in G-50 peak 1 were resolved into three peaks. Of the applied radioactivity, 17% was not retained by the column. As determined by TLC, this peak contained only GalN, suggesting that some O-linked oligosaccharides were neutral and did not contain sialic acid. Peak 2 eluted at a salt concentration needed to elute a monosialylated oligosaccharide and contained 96% GalN. This suggested the presence of O-linked oligosaccharides containing a single sialic acid residue.
  • glycopeptides from G-50 peak 1 were retained by the DEAE column, indicating that they contained sialic acid. Therefore, glycopeptides were applied to a WGA column which has affinity for nonreducing terminal sialic acid and GlcNAc residues [K. Yamamoto et al., Biochemistry, 20, 5894 (1981)]. When this was done, 85% of the radioactivity bound to the column. Taken together, DEAE and WGA affinity chromatography suggest that these glycopeptides contain nonreducing terminal sialic acid residues. The portion which did not bind WGA would contain the neutral glycopeptides detected by DEAE chromatography. These glycopeptides were applied to a peanut lectin column which has strong affinity for the structure Gal-GalNAc [I. J .
  • glycoproteins gp52 (11-93) and gp52 (11-200) were collectively designated gp52 (II).
  • N-linked oligosaccharides All of the HCMV Towne strain glycoproteins which we isolated contained N-linked oligosaccharides. These were identified as N-linked by several criteria. First, they co-eluted with N-linked standards on gelfiltration and contained high amounts of GlcN. Moreover, GlcN was still detected after mild alkaline treatment and their elution position did not change. The N-linked oligosaccharides were not examined further. Very few viral glycoproteins have been characterized which contain high amounts of 0-linked oligosaccharides. Of the HCMV glycoproteins characterized, O-linked oligosaccharides were most abundant in gp52 (II).
  • gp52 (II) contains a cluster of hydroxyamino acids to which some of the O-linked oligosaccharides are bound. This is based on the observation that pronase resistant high molecular weight glycopeptides containing high amounts of GalN were always obtained. The nearly complete conversion of the GalN in this fragment to GalN-ol indicated that most of the GalN was at the reducing end of the oligosaccharide attached to either serine or theronine. Thus, this fragment would have to contain a number of hydroxamino acids.
  • the O-linked oligosaccharides of gp52 (II) appear to be terminated by at least Gal and sialic acid.
  • Neutral O-linked oligosaccharides were det ect ed by DEAE chromatography. Among the neutral oligosaccharides were those apparently terminated by Gal as determined by their affinity for peanut lectin. However, of the glycopeptides tested, most bound DEAE and required pretreatment with neuraminidase to bind peanut lectin. These results suggested that some 0-linked oligosaccharides were terminated with Gal, but in others, sialic acid was the terminal residue and Gal the penultimate. It is also possible, based on DEAE data, that some of the O-linked oligosaccharides contained more than 1 sialic acid residue.
  • Glycoproteins which normally contain O-linked oligosaccharides in this molecular weight range include the proteoglycans, immunoglobulin light chains and MN blood group glycoprotein. These oligosaccharides contain GalNAc, Gal, and 1 to 2 sialic acid residues. Sialic acid in most of these oligosaccharides is the nonreducing terminal monosaccharide while Gal is the penultimate. Thus, it seems that the enzymes involved in the synthesis of these oligosaccharides must be active in cells infected by HCMV.
  • the Invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

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Abstract

La présente invention a été décrite avec référence à divers modes de réalisation et techniques spécifiques et préférés. Il est toutefois clair que de nombreuses variations et modifications peuvent être apportées à la présente invention pour autant qu'elles en respectent l'esprit et les limites.
PCT/US1989/000318 1988-02-22 1989-01-25 Glycoproteines immunogeniques de cytomegalovirus humains Ceased WO1989007615A1 (fr)

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KR1019890701929A KR900700509A (ko) 1988-02-22 1989-10-21 인간 거대세포 바이러스의 면역원성 당단백질

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US158,389 1993-11-29

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990011302A1 (fr) * 1989-03-24 1990-10-04 University Of Iowa Research Foundation Sites de reconnaissance de cellules t et anticorps sur des glycoproteines
WO1996024378A3 (fr) * 1995-02-10 1996-11-14 Worcester Found Ex Biology Apport de composes exogenes
US5807557A (en) * 1994-07-25 1998-09-15 The Trustees Of The University Of Pennsylvania Soluble herpesvirus glycoprotein complex
US6156319A (en) * 1994-07-25 2000-12-05 The Trustees Of The University Of Pennsylvania Soluble herpesvirus glycoprotein complex vaccine

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4689225A (en) * 1984-11-02 1987-08-25 Institut Merieux Vaccine for cytomegalovirus

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5126130A (en) * 1986-11-24 1992-06-30 The Childrens Hospital Incorporated Monoclonal antibodies reactive with specific antigenic sites on human cytomegalovirus glycoprotein a

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4689225A (en) * 1984-11-02 1987-08-25 Institut Merieux Vaccine for cytomegalovirus

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
BRUCE KARI "J. Virology" Vol. 60, No. 2, 1986 "Characterization of Monoclonal Antibodies Reactive to Several Biochemically Distinct Human Cytomegalovirus Glycoprotein Complexes" pages 345-352. see Glycoproteins Reactive with the Monoclonal Antibodies, pages 350-351. *
GRAHAM H. FARRAR, "J. Gen. Virol." Vol. 67, 1986 "Characterization of Glyco-Protein Complexes Present in Human Cytomegalovirus Envelopes" page 1469-1473 see pages 1470-1471. *
K.S. KIM, "Journal of Virology" Vol. 20, No. 3. 1976 "Analysis of Structural Polypeptides of Purified Human Cytomegalovirus" pages 604-611, see table 2 on page 609. *
KATHERINE LAW, "J. of Medical Virology" Vol. 17, 1985 "A Murine Monoclonal Antibody Recognizing a Single Glycoprotein within a Human Cytomegalovirus Virion Envelope Glycoprotein Complex" pages 255-266 (note the Abstract and last paragraph, Preceeding Acknowledgements). *
See also references of EP0403541A4 *
TORU FURUKAWA, "Proceedings of the Society for Experimental Biology and Medicine" Vol. 175, 1984 "HCMV Envelope Antigens Induce Both Humoral and Cellular Immunity in Guinea Pigs" page 243-250. *
WILLIAM J. BRITT, "Virology" Vol. 135, 1984 "Neutralizing Antibodies Detect a Disulfied Linked Glycoprotein Complex within the Envelope of Human Cytomegalovirus" pages 369-378. (note the Abstract). *
WILLIAM J. BRITT, "Virus Research" Vol. 4, 1985 "Identification of a 65000 Dalton Virion Envelope Protein of Human Cytomegalovirus" pages 31-36 (note the Abstract) *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990011302A1 (fr) * 1989-03-24 1990-10-04 University Of Iowa Research Foundation Sites de reconnaissance de cellules t et anticorps sur des glycoproteines
US5807557A (en) * 1994-07-25 1998-09-15 The Trustees Of The University Of Pennsylvania Soluble herpesvirus glycoprotein complex
US6156319A (en) * 1994-07-25 2000-12-05 The Trustees Of The University Of Pennsylvania Soluble herpesvirus glycoprotein complex vaccine
US6541459B1 (en) 1994-07-25 2003-04-01 The Trustees Of The University Of Pennsylvania Soluble herpesvirus glycoprotein complex vaccine
WO1996024378A3 (fr) * 1995-02-10 1996-11-14 Worcester Found Ex Biology Apport de composes exogenes
US6335436B1 (en) 1995-02-10 2002-01-01 Hybridon, Inc. Oligonucleotides active against drug-resistant bacteria

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AU3283789A (en) 1989-09-06
KR900700509A (ko) 1990-08-13
JPH03502799A (ja) 1991-06-27
EP0403541A1 (fr) 1990-12-27
EP0403541A4 (en) 1991-01-09

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