EP1064357A1 - Procedes permettant d'ameliorer la presentation des antigenes par les cellules dendritiques - Google Patents

Procedes permettant d'ameliorer la presentation des antigenes par les cellules dendritiques

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Publication number
EP1064357A1
EP1064357A1 EP99914163A EP99914163A EP1064357A1 EP 1064357 A1 EP1064357 A1 EP 1064357A1 EP 99914163 A EP99914163 A EP 99914163A EP 99914163 A EP99914163 A EP 99914163A EP 1064357 A1 EP1064357 A1 EP 1064357A1
Authority
EP
European Patent Office
Prior art keywords
cell
protein
bacteria
peptide
bacterial
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP99914163A
Other languages
German (de)
English (en)
Inventor
Maria Rescigno
Giampiero Girolomoni
Silvia Corinti
Paola Ricciardi-Castagnoli
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ludwig Institute for Cancer Research Ltd
Biopolo SCARL
Ludwig Institute for Cancer Research New York
Original Assignee
Ludwig Institute for Cancer Research Ltd
Biopolo SCARL
Ludwig Institute for Cancer Research New York
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 Ludwig Institute for Cancer Research Ltd, Biopolo SCARL, Ludwig Institute for Cancer Research New York filed Critical Ludwig Institute for Cancer Research Ltd
Publication of EP1064357A1 publication Critical patent/EP1064357A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/315—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Streptococcus (G), e.g. Enterococci
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/76—Albumins
    • C07K14/77—Ovalbumin
    • 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
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0639—Dendritic cells, e.g. Langherhans cells in the epidermis
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • 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
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/05—Adjuvants
    • C12N2501/052—Lipopolysaccharides [LPS]
    • 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
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/20—Cytokines; Chemokines
    • C12N2501/22—Colony stimulating factors (G-CSF, GM-CSF)
    • 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
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/20—Cytokines; Chemokines
    • C12N2501/23—Interleukins [IL]

Definitions

  • This invention relates to the presentation of molecules so that an immune response
  • dendritic cells and bacteria which present relevant materials on their surface, and are internalized
  • dendritic cells which then process bacterial surface molecules to suitable antigens.
  • HLAs human leukocyte antigens
  • MHCs histocompatibihty complexes
  • T cell specific for a particular combination of an HLA molecule and a peptide. If a specific T cell specific for a particular combination of an HLA molecule and a peptide. If a specific T cell specific for a particular combination of an HLA molecule and a peptide. If a specific T cell specific for a particular combination of an HLA molecule and a peptide. If a specific T cell specific for a particular combination of an HLA molecule and a peptide. If a specific T cell specific for a particular combination of an HLA molecule and a peptide. If a specific T cell specific for a particular combination of an HLA molecule and a peptide. If a specific T cell specific for a particular combination of an HLA molecule and a peptide. If a specific T cell specific for a particular combination of an HLA molecule and a peptide. If a specific T cell specific for a particular combination of an HLA molecule and a peptide. If a specific T cell specific for
  • HLA binding peptides are processed into the HLA binding peptides. See, in this regard, Barinaga, Science 257 : 880 (1992); Fremont et al., Science 257: 919 (1992); Matsumuraet al., Science 257: 927 (1992); Latron et al., Science 257: 964 (1992).
  • TRAP tumor rejection antigens
  • Dendritic cells are antigen presenting cells which are crucial
  • tissues which interface with the environment such as the skin and mucosal surfaces
  • lymphoid organs where they serve as "sentinels" for incoming pathogens. See, e.g., Austyn, J.
  • DCs function, essentially, by capturing and processing antigens, and to "alert" the
  • DCs from peripheral tissues to secondary lymphoid organs. Upon activation, DCs produce
  • Class II molecules and costimulatory molecules become upregulated, and the DCs mature.
  • DCs Information on DCs generally can be found in, e.g. Thomson, et al, Dendritic Cells (Academic
  • CD4 + and CD8 + T cell responses in vivo. See, e.g., Paglia, et al.,
  • bacteria are potential inducers of DC activation. See, e.g.,
  • FIGS 1A-1G show FACS profiles of various surface markers after dendritic cells were incubated with either S. gordonii or latex beads. Filled histograms represent dendritic cells
  • histograms are isotypic controls.
  • FIGS. 2A and 2B depict 3 H- thymidine uptake by CTLs following their exposure to dendritic
  • FIGS 3 A, 3B and 3C summarize data which show that the presentation of antigen by dendritic
  • TEP transporter associated with antigen
  • TAP deficient line is tested with the full length, soluble OVA protein (open circles), or a peptide derived from it, referred to infra as SEQ ID NO:3 (dark circles).
  • FIGS 4A, 4B and 4C show results obtained when CD4 + cells specific for an antigen were
  • Figure 4A is a measurement of 3H-thymidine
  • figure 4B shows IFN-y production.
  • figure 4C increasing numbers of dendritic
  • Figures 5 A and 5B present data showing that phagocytosis is required for presentation of antigen.
  • DC cells were either treated with a drug (CCD) which inhibits phagocytosis, or were untreated. Tests using treated DC cells are represented by open squares
  • FIGs 6A and 6B summarize data from experiments designed to determine the mechanism of antigen presentation.
  • DCs were incubated with recombinant bacteria (dark circles)
  • Figures 7A and 7B present data regarding endocytic and phagocytic activities of DCs, when
  • Figure 8 shows results obtained using non-pathogenic S. typhimurium strain Aro A (open
  • MHC- Class I and antigenic peptide on their surfaces filled in squares and diamonds.
  • Dl is a homogenous, immature growth factor dependent long term dendritic cell line. It is
  • the DCs are grown in culture medium (IMDM), containing 10% heat inactivated fetal bovine serum, 100 U/ml penicillin, 100 mg/ml streptomycin, 2mM L-glutamine, and 50 ⁇ M
  • DCs were sampled (5xl0 5 cells/sample), pelleted via centrifugation (1200 rpm for 5 minutes), followed by two washes in cold, phosphate
  • Electron microscopy showed that the S. gordonii bacteria were internalized by DC via conventional phagocytosis. Bacteria were observed to be contacting the cell membrane of
  • LPS lipopolysaccharide
  • Example 1 or with 2 ⁇ m latex beads ( 100 beads per D 1 cell). Incubation conditions for the beads were the same as those used for the bacteria.
  • the cells were analyzed, via FACS, to determine the profile of cell surface molecules involved in DC activation and maturation.
  • the molecules were analyzed, via FACS, to determine the profile of cell surface molecules involved in DC activation and maturation.
  • MHC Class I molecule H-2D b MHC Class II molecule IA/Ed, CD80/B7.1,
  • CD40, CD 54/ICAM-I, CD86/B7.2, and VLA-4 The analysis was carried out using
  • the open histograms present the values obtained prior to stimulation, and the dashed
  • histogram an isotype control.
  • Dl cells stimulated with bacteria produced large amounts of TNF-alpha and 1L-6 (12 and 30ng/ml, respectively), and limited amounts of 1L-10
  • Dl cells were also incubated with the
  • D 1 cells were incubated with S. gordonii (10 bacteria per D 1 cell) for periods of time ranging from 1 to 36 hours, in medium described supra. Cells were then labeled
  • MHC-Class I synthesis was found to be induced very slowly, reaching its peak after about 18 hours, and was sustained for several hours thereafter.
  • monocyte derived DCs and noted upregulation of MHC molecule stimulus, but not stabilization of Class I molecules.
  • Newly synthesized MHC-Class II molecules in non-activated cells have a half life
  • MHC-Class I molecules present peptides derived from
  • foreign proteins could, in fact, serve as a stimulatory particulate antigen.
  • a recombinant strain of S. gordonii was prepared, using a host vector system referred to hereafter as GP1252. See Oggioni, et al., Gene 169:85-90 (1996), incorporated by reference.
  • the recombinant strain produced ovalbumin, or "OVA" hereafter.
  • OVA ovalbumin
  • a DNA sequence encoding amino acids 48-386 of OVA was prepared, using PCR primers: CTAGATCTGA CAGCACCAGG ACAC
  • the resulting amplification products were cloned into insertion vector pSMB55 which had been cut with restriction endonucleases Hind III and Bgl II, using standard methods.
  • the resulting construct produced a fusion protein of the OVA sequence and streptococcal protein M6.
  • the M6 protein is known as a fusion partner for surface expression of heterologous antigens in Gram-positive bacteria.
  • M6-OVA fusion protein in the recombinant GPI 252 strain was confirmed, via immunofluorescence, and Western blotting, using M6 and OVA specific rabbit polyclonal antibodies. See Pozzi, et al., Vaccine 12:1071-1081 (1994),
  • mice See Van Kaer, et al., Cell 71 : 1205- 1214 ( 1992), incorporated by reference.
  • the cells were purified from murine bone marrow after 14 days of culture, followed by positive selection with anti-CDl IC antibodies, coupled to magnetic microbeads. (Use of these cells permits the conclusions regarding TAP dependency, set out infra.)
  • the plated cells were then pulsed with either wild type S. gordonii. wild type
  • periods for the pulsing ranged from 2 hours to 16 hours, in the culture medium described supra,
  • Figures 2 A and 2B show that DCs processed and presented bacterial antigens with
  • the process of antigen presentation required at least 8 hours, because cells fixed before 8 hours of incubation presented no antigen.
  • Figure 3B is a comparison to 3 A, using the Dl
  • Examples 1-7 supra deal with murine DCs, and their ability to process bacteria presenting antigens on their surface.
  • human DCs were used.
  • the antigen under consideration is the C-fragment of tetanus toxin (TTFC), and the work was extended to show that CD4 + T cells were stimulated by DCs which had processed recombinant strains of bacteria presenting antigen on their surfaces.
  • TTFC C-fragment of tetanus toxin
  • PBMCs peripheral blood monocytes
  • PBMCs were isolated using standard density gradient centrifugation, and multistep Percoll gradients. The light density fraction cells were recovered, cultured at lxl 0 6
  • CD19 + cells with immunomagnetic beads coated with mAbs The resulting population was a
  • a recombinant strain of S. gordonii was prepared which expressed TTFC.
  • nucleotides 2844-4230 of the coding region for TTFC corresponded to nucleotides 2844-4230 of the coding region for TTFC, which
  • bacteria or soluble TTFC, at varying concentrations, in the complete medium described supra.
  • the T cells with which the DCs were cultured were CD4 + T cell clones specific
  • TTFC-specific CD4 + cells generated from PBMCs of healthy individuals, using standard methods. See Lanzavecchia, et al, supra. Analysis showed that these cells were CD4 + , CD8 " , TCR ⁇ / ⁇ + , TCR ⁇ / ⁇ ', CD 28 + , and secreted
  • CD4 + T cell clones and DCs derived from the same individual were mixed in these
  • bacteria were used, they were combined with DC at a bacteria to DC ratio of 50 to 1, which is
  • DCs exposed to recombinant bacteria were at least 10 2 times more effective than DCs pulsed with equal amounts of soluble antigen.
  • Immature DCs were incubated with live bacteria, at a bacteria to DC ratio of 50: 1 , and analyzed
  • the shortest time period tested was 2 hours, and at this point, bacteria were
  • the DCs were co-cultured for 3 days with 30,000 TTFC specific CD4 + cells, as are described
  • Figure 5 A shows the results using recombinant bacteria, and show that pretreatment inhibited presentation when recombinant bacteria were used, but did not inhibit presentation
  • soluble TTFC at 5ng/ml, which is an amount of TTFC comparable to the 50 bacteria (i); (iii) wild type bacteria, plus soluble TTFC (5ng/ml); (iv) LTA, i.e., lipoteichoic acid (10 ⁇ g/ml), plus
  • the DCs showed dramatic increases in molecules involved in antigen presentation, including both classes of MHC molecules, CD80 and CD86 (which are costimulatory molecules), and CD54. Both
  • CD40 and CD83 were also upregulated. In contrast, expression of CDla was consistently upregulated.
  • CD 115 which is the M-CSF receptor
  • the data show a marked downregulation of phagocytic and endocytic activity in
  • IL-l ⁇ TNF alpha
  • TGF- ⁇ TGF- ⁇
  • IL-6 IL-12
  • IL-10 IL-8
  • RANTES IP-10
  • MIG MIG
  • the DCs were also observed to release constitutively high amounts of IL-8 and low levels of IP-
  • DCs When incubated with bacteria, DCs increased secretion of IL-8 and IP- 10, as well as began to release RANTES and MIG in a dose dependent matter.
  • Aro A the Aro A strain transfected with a construct encoding amino acids 46-358 of ovalbumin
  • OVA-M and OVA-R D 1 cells were incubated with the bacteria, at the ratios described supra, for 3 hours
  • MHC-Class I and an OVA derived antigen were presented following contact of the Dl cells to the recombinant bacteria. In contrast, the non-pathogenic bacteria did not do so.
  • one aspect of the invention is a process for making a dendritic cell which presents a desired complex of an MHC molecule and a peptide antigen on its surface, by contacting a dendritic cell to a bacteria which expresses
  • a protein which comprises the relevant antigen under conditions which favor intemalization and processing of the bacteria by the dendritic cell, leading to presentation of the antigen in a
  • MHC refers to all major histocompatibihty complex molecules
  • HLAs Human leukocyte antigens
  • Bacteria refers to any type of bacteria which can be internalized
  • Exemplary of the bacteria which can be used in the invention are Salmonella typhimurium. Escherichia coli. Lactobacillus strains, Staphylococcus, such as S. aureus.
  • Pneumococcus such as unencapsulated Pneumococcus R6, Streptococcus, Lactococcus,
  • Mycobacterium such as M. smegmatis, Listeria, such as L. monocytogenes, and so forth. It has
  • the protein that the bacteria present may be a naturally occurring one, but preferably is not. Indeed, it is more preferable to use bacteria which have been treated such that they have been transformed with a nucleic acid molecule which encodes a protein that contains one or more antigenic sequences of interest. Examples of such sequences include sequences
  • antigens associated with cancer generally, such as p53
  • antigens viral antigens, antigens corresponding to bacterial proteins other than the bacteria used as the host, and so forth.
  • These coding sequences can also correspond to synthetic proteins
  • MHC typing is a fairly well known technique and, as has been
  • the art is familiar with many peptides presented by particular MHC or HLA molecules.
  • the transforming sequence may be one which encodes only HLA-A2 presented peptides.
  • constmcts are preferably prepared in the form of sequences which encode fusion proteins, a portion of which is a protein endogenous to the bacterial host. For example,
  • M6 protein can be used when the host bacteria is streptococcus and surface expression is desired, but the art will be familiar with other bacterial proteins both surface and cytoplasmic associated, which can be used in place of M6, depending upon the organism being used.
  • yet another feature of this invention is a method for improved generation of an immune response, such as T cells, B cells, cytokine production, etc., by contacting a sample capable of generating an immune response, such as peripheral blood, or any B cell or T cell containing sample, to a dendritic cell which has internalized a bacteria as described supra.
  • the dendritic cells which result from the intemalization are characterized by MHC Class I and MHC Class II molecules which have much longer half lives
  • dendritic cells are also a facet of this invention.
  • Also a part of this invention is a process for promoting maturation of dendritic
  • the key feature of the bacteria is the presentation of the relevant molecule on a cell surface. Hence, depending upon the type of DC used, the bacteria
  • non- viable bacteria may be used in the context of in vivo therapy.
  • S. gordonii. for example, is a non-pathogenic bacteria which is found in the oral cavity of humans.
  • Other non-pathogenic bacteria will be known to the skilled artisan.
  • dendritic cells to present relevant antigen can be increased via incubation with, e.g., LPS, LTA, or bacteria prior to contact with soluble antigen. Indeed, this
  • process is yet another feature of this invention, i.e., a process for improving the presentation of complexes of MHC molecules and peptides by dendritic cells, by contacting the dendritic cells in a first step, with an adjuvant like material, such as bacteria or LTA, followed by contact with a soluble antigen.
  • an adjuvant like material such as bacteria or LTA
  • Other adjuvant type materials will be known to the skilled artisan.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biomedical Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Zoology (AREA)
  • Biotechnology (AREA)
  • Biophysics (AREA)
  • Wood Science & Technology (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Cell Biology (AREA)
  • Hematology (AREA)
  • Microbiology (AREA)
  • Toxicology (AREA)
  • General Engineering & Computer Science (AREA)
  • Peptides Or Proteins (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

La présente invention concerne un procédé de préparation de cellules dendritiques qui présentent sur leur surface des complexes de peptides et de molécules de complexes majeurs d'histocompatibilité. Ce procédé consiste à mettre ces cellules dendritiques en contact avec des bactéries présentant sur leur surface ou dans leur cytosol une protéine, et qui incluent les séquences de peptides. Ces bactéries subissent de préférence une transformation les amenant à produire une protéine hétérologue s'exprimant sur leur surface.
EP99914163A 1998-03-20 1999-03-19 Procedes permettant d'ameliorer la presentation des antigenes par les cellules dendritiques Withdrawn EP1064357A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US7883298P 1998-03-20 1998-03-20
US78832P 1998-03-20
PCT/US1999/006627 WO1999047646A1 (fr) 1998-03-20 1999-03-19 Procedes permettant d'ameliorer la presentation des antigenes par les cellules dendritiques

Publications (1)

Publication Number Publication Date
EP1064357A1 true EP1064357A1 (fr) 2001-01-03

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EP99914163A Withdrawn EP1064357A1 (fr) 1998-03-20 1999-03-19 Procedes permettant d'ameliorer la presentation des antigenes par les cellules dendritiques

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EP (1) EP1064357A1 (fr)
AU (1) AU756911B2 (fr)
WO (1) WO1999047646A1 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU4700100A (en) 1999-05-06 2000-11-21 Wake Forest University Compositions and methods for identifying antigens which elicit an immune response
US7030228B1 (en) 1999-11-15 2006-04-18 Miltenyi Biotec Gmbh Antigen-binding fragments specific for dendritic cells, compositions and methods of use thereof antigens recognized thereby and cells obtained thereby
CA2434793A1 (fr) * 2001-01-15 2002-07-18 I.D.M. Immuno-Designed Molecules Composition auxiliaire pour la preparation de cellules dendritiques matures determinees
US7695725B2 (en) * 2003-02-06 2010-04-13 Aduro Biotech Modified free-living microbes, vaccine compositions and methods of use thereof
CA2515369C (fr) 2003-02-06 2015-03-31 Cerus Corporation Listeria attenuees en vue d'une entree dans des cellules non phagocytaires, vaccin comprenant ces listeria et techniques d'utilisation de celui-ci
WO2004084936A2 (fr) 2003-02-06 2004-10-07 Cerus Corporation Microbes modifies vivant en milieu naturel, compositions de vaccins, et procedes d'utilisation correspondants
US7842289B2 (en) 2003-12-24 2010-11-30 Aduro Biotech Recombinant nucleic acid molecules, expression cassettes, and bacteria, and methods of use thereof
EP1711598A4 (fr) * 2004-01-30 2009-04-08 Lifecord Inc Methode d'isolement et de culture de cellules souches multipotentes a partir de sang du cordon ombilical et procede pour induire leur differenciation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9947646A1 *

Also Published As

Publication number Publication date
AU756911B2 (en) 2003-01-23
WO1999047646A1 (fr) 1999-09-23
AU3206499A (en) 1999-10-11

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