EP1301624A2 - Preprocalcitonine utilisee comme precurseur d'antigene de rejet tumoral et ses utilisations - Google Patents

Preprocalcitonine utilisee comme precurseur d'antigene de rejet tumoral et ses utilisations

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Publication number
EP1301624A2
EP1301624A2 EP01927400A EP01927400A EP1301624A2 EP 1301624 A2 EP1301624 A2 EP 1301624A2 EP 01927400 A EP01927400 A EP 01927400A EP 01927400 A EP01927400 A EP 01927400A EP 1301624 A2 EP1301624 A2 EP 1301624A2
Authority
EP
European Patent Office
Prior art keywords
cells
cell
seq
nucleic acid
polypeptide
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Withdrawn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
EP01927400A
Other languages
German (de)
English (en)
Inventor
Hamid Echchakir
Fathia Mami-Chouaib
Isabelle Vergnon
Salem Chouaib
Jean François Uni. Catholique de Louvain BAURAIN
Pierre G. Uni. Catholique de Louvain COULIE
Thierry Boon-Falleur
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
Institut Gustave Roussy (IGR)
Institut National de la Sante et de la Recherche Medicale INSERM
Ludwig Institute for Cancer Research New York
Original Assignee
Ludwig Institute for Cancer Research Ltd
Institut Gustave Roussy (IGR)
Institut National de la Sante et de la Recherche Medicale INSERM
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, Institut Gustave Roussy (IGR), Institut National de la Sante et de la Recherche Medicale INSERM, Ludwig Institute for Cancer Research New York filed Critical Ludwig Institute for Cancer Research Ltd
Publication of EP1301624A2 publication Critical patent/EP1301624A2/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Withdrawn legal-status Critical Current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
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/585—Calcitonins
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • This invention relates to various therapeutic methodologies derived from the recognition that certain abnormal cells present complexes of human leukocyte antigens and peptides derived from preprocalcitonin protein on their surfaces. In addition, it relates to the ability to identify those individuals diagnosed with conditions characterized by cellular abnormalities whose abnormal cells present this complex, the presented peptides, and the ramifications thereof.
  • the process by which the mammalian immune system recognizes and reacts to foreign or alien materials is a complex one.
  • An important facet of the system is the T cell response. This response requires that T cells recognize and interact with complexes of cell surface molecules, referred to as human leukocyte antigens ("HLA”), or major histocompatibility complexes ("MHCs”), and peptides.
  • HLA human leukocyte antigens
  • MHCs major histocompatibility complexes
  • peptides are derived from large molecules which are processed by the cells which also present the HLA/MHC molecule. See in this regard Male et al., Advanced Immunology (J.P. Lipincott Company, 1987), especially chapters 6-10.
  • T cell and complexes of HLA/peptide are restricted, requiring a T cell specific for a particular combination of an HLA molecule and a peptide. If a specific T cell is not present, there is no T cell response even if its partner complex is present. Similarly, there is no response if the specific complex is absent, but the T cell is present. This mechanism is involved in the immune system's response to foreign materials, in autoimmune pathologies, and in responses to cellular abnormalities. Recently, much work has focused on the mechanisms by which proteins are processed into the HLA binding peptides.
  • One of the first molecules to be recognized as functioning as a tumor rejection antigen precursor was the enzyme tyrosinase. See, e.g., U.S. Patent No. 5,487,974. Others include the molecule referred to in the patent literature as "HOM-MEL 40," which was found to be identical to the known molecule SSX-2, and U.S. Patent No. 5,888,751, which teaches that the protein known as SCP-1 functions as a tumor rejection antigen precursor.
  • the lion's share of this work has used melanoma as the primary material for identifying tumor rejection antigen precursors.
  • the inventors have identified an additional tumor rejection antigen precursor from lung cancer cells.
  • This "TRAP” has been identified as the preprocalcitonin protein.
  • a large cell lung carcinoma was taken from a patient who had been typed as HLA-A2, A68, B7, B35, C4, C7 positive.
  • the cells were cultured under standard conditions, and a cell line, referred to hereafter as "IGR-Heu” was derived.
  • IGR-Heu a cell line, referred to hereafter as "IGR-Heu” was derived.
  • This is a non-small cell lung carcinoma (“NSCLC”) cell line. This line is used in examples presented infra.
  • a fresh tumor sample was taken from the same patient referred to supra, and was dissociated in DMEM medium containing ImM Hepes, 0.3U/ml DNAse, 0.5 U/ml collagenase, and 0.28 U/ml hyaluronidase. The suspension was frozen, and then thawed.
  • tumor infiltrating lymphocytes and tumor cells were isolated from the suspension, using standard techniques (Ficoll-Hypaque density gradient centrifugation). Tumor infiltrating lymphocytes were seeded at 10 4 cells/microwell, and then stimulated by adding irradiated, autologous tumor cells (3xl0 3 cells/well, 10000 rads), as well as irradiated, autologous EBV transformed B cells (4xl0 4 cells/well), in RPMI supplemented with 10% human AB serum, and recombinant IL-2.
  • autologous tumor cells 3xl0 3 cells/well, 10000 rads
  • EBV transformed B cells 4xl0 4 cells/well
  • lymphocytes were fed every 3 days with new medium and recombinant IL-2, and were restimulated every other week with irradiated tumor and EBV transformed B cells, as described supra. After 6 weeks, the lymphocytes were cloned via limiting dilution, and were stimulated with cells as described supra, in DMEM medium containing rIL-2 (100 U/ml) and 3% (v/v) of conditioned medium from PHA activated blood lymphocytes. One of the resulting T cell cloness was clone "161". All clones were amplified with the restimulation protocol supra, every week. The ability of clone 161 to lyse tumor cells was tested, and was confirmed.
  • CTL 161 recognized complexes of a peptide and an HLA-A2 molecule. This was determined by combining cells of clone 161 with autologous tumor cells, and monoclonal antibodies specific for HLA-A2. The mAbs abrogated the ability of CTL 161 to lyse target cells, indicating that the presenting molecule was HLA-A2.
  • This example describes the isolation of the DNA which encoded the protein processed to the antigen recognized by CTL 161.
  • RNA was isolated from the cell clone described in example 1, supra. This RNA was converted to cDNA, using oligo(dT) primer:
  • This primer contains a Notl site at its 5 ' end.
  • the degenerate 3 ' end of this primer favors annealing at the 5 ' end of the polyA tail of mRNA molecules, thus diminishing the proportion of cDNA clones containing long poly (A) stretches.
  • plasmid pCEP4 This plasmid contains EBV origin of replication oriP, as well as a sequence that encodes EBV nuclear antigen -1 (EBNA-1). This allows for episomal replication of plasmids which are transfected into mammalian clones.
  • the recombinant plasmids were electroporated into E. coli DH5 ⁇ , and selected with 50 ⁇ g/ml of ampicillin.
  • the resulting library was divided into 264 pools of about 100 cDNA clones, each of which was treated by amplifying and extracting the plasmid DNA.
  • cDNA clone 150 Eighty five pools were positive. One pool was subcloned, and one clone, referred to as "cDNA clone 150," was found to transfer expression of the relevant antigen into 293- EBNA cells. This clone was analyzed further.
  • the sequence of the cDNA clone referred to supra was secured following standard methods. Comparison to GENBANK revealed that the 956 base pair sequence is transcribed from the calcitonin / ⁇ -CGRP gene, identified in GENBANK as XI 5943.
  • the 956 base sequence, SEQ ID NO: 2 herein, contains a polyadenylation signal and a polyA sequence at its 3' end.
  • the calcitonin/ ⁇ CGRP gene encodes calcitonin, a calcium lowering hormone, as well as the neuropeptide ⁇ -CGRP. See Broad, et al, Nucl. Acids Res. 17:6999-7011 (1989). Both of these molecules are processed from precursor proteins encoded by the calcitonin / ⁇ CGRP mRNA. The transcripts are both generated from a common primary transcript, via tissue specific, alternative RNA processing events. See, Amara, et al, Nature 298: 240-244 (1982); Jonas, et al, Proc. Natl. Acad. Sci USA 82:1994-1998 (1985). The ⁇ CGRP molecule is encoded by a transcript that contains exons 1, 2, 3, 5 and 6, while calcitonin is encoded by a transcript containing exons 1-4.
  • Nucleotides 3-216 are a portion of intron 1, i.e. nucleotides 2085-2298 of X15943, with the exception of one change at position 13 of SEQ ID NO:2. This is T, whereas position 2095, the corresponding base in XI 5943, is A.
  • Nucleotides 217-311 correspond to exon 2 of X15943, nucleotides 312-452 to exon 3 of X15943, and nucleotides 453-947 to exon 4 of X15943.
  • ggtgtcatgg gcttccaaaa gt located at the 5' end of SEQ ID NO:2, and reverse primers, ctgaatggtg ctgcatgg ag (SEQ ID NO:4) gcactagtc ctgcaccag (SEQ ID NO: 5) gcaagtactc agattaccgc ac (SEQ ID NO: 6) tcgctggaca atatcccttttt c (SEQ ID NO:7) and gatcagcaca ttcagaagca gg (SEQ ID NO: 8) which are located at the 3' end, were used to generate PCR fragments, or "mini-genes," consisting of a portion of the nucleotide sequence of SEQ ID NO: 2, i.e., the portion including the primers and located in between them..
  • SEQ ID NO: 4 and one of SEQ ID NOS:5-8 were paired in a PCR reaction, which involved 3 minutes of incubation at 94°C, followed by 30 cycles of amplification, with a cycle being defined as 1 minute at 94°C, 2 minutes at 65°C, and 3 minutes at 72°C, followed by final elongation for 10 minutes at 72°C.
  • Template plasmids were diluted by diluting PCR products 100,000 fold, after which aliquots were used as templates for additional PCR amplification (again, 30 cycles). These PCR products were cloned into expression plasmid pcDNA3.1, using standard methods. The plasmids were then cofransfected, together with HLA-A2 cDNA clones as described supra, into 293-EBNA cells, using lypofectamine.
  • CTL 161 described supra, was added to the transfectants in the same manner as is described above, and TNF release was measured.
  • Calcitonin is normally expressed by the C cells of the thyroid, and at high levels in medullary thyroid carcinoma. (Edbrooke, et al, EMBO J 4:715-724 (1985)). It is also expressed ectopically in lung carcinoma (Edbrooke, et al, supra; Kelley, et al Cancer Res 81:19-25 (1994)). CGRP is expressed in neural cells (Rosenfeld, et al Science 225: 1315- 1320 (1984)).
  • Expression was determined by using primers: ggtgtcatgg gcttccaaaa gt (SEQ ID NO: 9) and tcctgcttct gaatgtgctg at (SEQ ID NO: 10) in a mixture which also contained 15.75 ⁇ l H 2 O, 2.5 ⁇ l of DNA polymerase buffer, 2 ⁇ l of dNTPs (10M each), 1 ⁇ l of each primer, 0.25 ⁇ l of Taq polymerase, and 2.5 ⁇ l of cDNA, which have been derived from 50ng of total RNA.
  • PCR was carried out for 5 minutes at 94°C, followed by 30 cycles, where a cycle is defined as 1 minute at 94°C, 2 minutes at 63°C, and 2 minutes at 72°C, followed by an elongation step of 10 minutes at 72°C.
  • Amplified DNA was assessed visually via agarose gels and ethidium bromide staining. The results are summarized as follows:
  • EXAMPLE 7 The peptide encoded by nucleic acids 292-403 of SEQ ID NO: 2 has amino acid sequence:
  • LHAAPFRSALESSPADPATLSEDEARLLLAALVQDYV (SEQ ID NO: 11). This sequence was screened using NTH algorithm "HLA binding predictions" found at http://bimas.drct.nih.gov/molbio/hla_bind/ which is based upon Parker, et al., J. Immunol 152: 163 (1994), both of winch are incorporated by reference. See Rammensee, "A Database of MHC Ligands And Peptide Motifs" at http://l 1342.296.221/ also incorporated by reference as well, to identify potential HLA binding peptides. These are set forth infra, with reference to the amino acids of SEQ ID NO: 11.:
  • peptides can be tested for binding to HLA molecules and stimulation of CTLs, in accordance with, e.g., Parker, et al, J., Immunol 152:163, and Ruppert, et al., Cell 74: 929- 937 (1993), incorporated by reference. Also see Van derBruggen, et al, Euro. J. Immunol 24: 3038-3043 (1994, incorporated by reference for an alternate way to do this. Also, it is known that alternate reading frames exist for tumor rejection antigen precursors, leading to the generation of entirely new famielies of relevant tumor rejection antigens. Se, e.g., Wang, et al., J. Immunol 161(7): 3598-606 91998)?
  • amino acid sequences for calcitonin SEQ ID NO: 12
  • CGRP SEQ ID NO: 13
  • amino acid sequences for calcitonin SEQ ID NO: 12
  • CGRP SEQ ID NO: 13
  • GRRRRDLQA were screened, leading to the following:
  • one aspect of the invention pertains to a method for determining cancer in a subject, by assaying a sample taken from the subject for expression of all or apart of the preprocalcitonin protein.
  • calcitonin is normally expressed by the C-cells of the thyroid, and is also found at high levels in medullary thyroid carcinoma, as well as being expressed ectopically in lung carcinoma.
  • ⁇ -CGRP is expressed in neural cells.
  • One of ordinary skill in the art can exclude these types of cells, if necessary, in order to determine if preprocalcitonin, calcitonin per se, or ⁇ - CGRP is expressed in the sample. For example, preprocalcitonin is not found in these cells, so expression of the molecules is indicative of cancer.
  • both calcitonin and ⁇ -CGRP are generated from a common transcript.
  • a transcript comprising at least nucleotides 292-403 of SEQ ID NO: 2 appears to be present in cancer cells, non small cell lung cancer cells in particular.
  • a further feature of this invention is the identification of nucleic acid molecules which comprise at least nucleotides 292-403 of SEQ ID NO: 2 and as many as all of the nucleotides of SEQ LD NO: 2, or nucleic acid molecules which hybridize thereto, under stringent conditions.
  • any one of these methodologies can also be used in progression/regression studies, simply by monitoring levels of the protein, its expression, and so forth using any or all of the methods set forth supra. It should be clear that these methodologies may also be used to track the efficacy of a therapeutic regime. Essentially, one can take a baseline value for the protein, proteins or peptides being tested, using any of the assays discussed supra, administer a given therapeutic agent, and then monitor levels of the "marker” thereafter, observing changes in levels as indicia of the efficacy of the regime.
  • tetrameric peptide structures such as structures based on the disclosures of Braud, et al., Nature 391 795-799 (1998); Airman, et al., Science 274: 94-96 (1996), and U.S. Patent application Serial No. 09/049,850, filed March 27, 1998, all of which are incorporated by reference.
  • preprocalcitonin protein as being implicated in pathological conditions such as cancer also suggests a number of therapeutic approaches to such conditions.
  • Antibodies can be produced which bind to the protein, suggesting their use as a vaccine.
  • a further embodiment of the invention is the treatment of conditions which are characterized by aberrant or abnormal levels of one or more preprocalcitonin proteins or peptides, via immunotherapeutic approaches.
  • One of these approaches is the administration of an amount of protein, or an immunogenic peptide derived from the protein in an amount sufficient to provoke or augment an immune response.
  • the protein or peptide may be combined with one or more of the known immune adjuvants, costimulatory molecules, or MHC helper binding peptides, such as saponins, GM-CSF, interleukins, LIF-3, emulsifying oils such as vitamin E, heat shock proteins and so forth. If the peptides are too small to generate a sufficient antibody response, they can be coupled to well-known conjugates used to stimulate responses.
  • the known immune adjuvants such as saponins, GM-CSF, interleukins, LIF-3, emulsifying oils such as vitamin E, heat shock proteins and so forth.
  • the immunotherapeutic approaches include administering an amount of inhibiting antibodies sufficient to inhibit the protein.
  • These antibodies may be, e.g., antibodies produced via any of the standard approaches elaborated upon supra.
  • T cell responses may also be elicited by using peptides derived from the proteins which then complex, non-covalently, with MHC molecules, thereby stimulating proliferation of cytolytic T cells against any such complexes in the subject. It is to be noted that the T cells may also be elicited in vitro using immune responsive cells such as dendritic cells, lymphocytes, or any other immune responsive cells, and then reperfused into the subject being treated.
  • immune responsive cells such as dendritic cells, lymphocytes, or any other immune responsive cells
  • T cells and/or antibodies can also be accomplished by administering cells, preferably treated to be rendered non-proliferative, which present relevant T cell or B cell epitopes for response.
  • the therapeutic approaches may also include gene therapies, wherein an antisense molecule, preferably from 10 to 100 nucleotides in length, is administered to the subject either "neat” or in a carrier, such as a liposome, to facilitate incorporation into a cell, followed by inhibition of expression of the protein.
  • an antisense molecule preferably from 10 to 100 nucleotides in length
  • a carrier such as a liposome
  • antisense sequences may also be incorporated into appropriate vaccines, such as in viral vectors (e.g., Vaccinia), bacterial constructs, such as variants of the well-known BCG vaccine, and so forth.
  • An additional DNA based therapeutic approach is the use of a vector which comprises one or more nucleotides sequences, preferably a plurality of these, each of which encodes an immunoreactive peptide derived from the expressed proteins.
  • a vector which comprises one or more nucleotides sequences, preferably a plurality of these, each of which encodes an immunoreactive peptide derived from the expressed proteins.
  • preprocalcitonin- 1 proteins per se one or more antigenic peptides derived therefrom, such as those presented supra, as well as so-called polytopic vaccines.
  • These include a plurality of antigenic peptides, such as those supra, united together, preferably by linker sequences. The resulting peptides may bind to either MHC-Class I or Class II molecules.
  • These proteins, peptides, or polytopic vaccines may be administered in combination with an appropriate adjuvant, costimulatory molecule, or binding helper peptide. They may also be administered in the form of genetic constructs which are designed to permit expression of the protein, the peptide, the polytopic structures, etc.
  • Peptides and polytopic structures can be expressed by so-called "minigenes” i.e., DNA molecules designed to express portions of the entire preprocalcitonin molecule, or the various portions of the molecules, linked together as described supra.
  • the amount of agent administered and the manner in which it is administered will vary, based on the condition being treated and the individual. Standard forms of administration, such as intravenous, intradermal, subcutaneous, oral, rectal and transdermal administration can be used.
  • the proteins and/or peptides may be combined with adjuvant and/or carriers such as a saponin, GM-CSF, one or more interleukin, vitamin E, LIF-3, one or more heat shock protein, etc.
  • vectors such as Vaccinia or adenovirus based vectors can be used. Any vector useful in eukaryotic transfection, such as in transfection of human cells, can be used. These vectors can be used to produce, e.g., cells such as dendritic cells which present relevant peptide/MH complexes on their surface. The cells can then be rendered non-proliferative prior to their administration, using standard methodologies.
  • Polytopes are groups of two or more potentially immunogenic or immune stimulating peptides, which can be joined together in various ways, to determine if this type of molecule will stimulate and/or provoke an immune response.
  • the Tam reference in particular shows that polytopes, when used in a mouse model, are useful in generating both antibody and protective immunity. Further, the reference shows that the polytopes, when digested, yield peptides which can be and are presented by MHCs. Tam shows this by showing recognition of individual epitopes processed from polytope 'strings' via CTLs. This approach can be used, e.g., in determining how many epitopes can be joined in a polytope and still provoke recognition and also to determine the efficacy of different combinations of epitopes. Different combinations may be 'tailor-made' for the patients expressing particular subsets of tumor rejection antigens.
  • polytopes can be introduced as polypeptide structures, or via the use of nucleic acid delivery systems.
  • the art has many different ways available to introduce DNA encoding an individual epitope, or a polytope such as is discussed supra. See, e.g., Allsopp et al., Eur J. Immunol. 26(8); 1951-1959 (1996), incorporated by reference.
  • Adenovirus, pox- virus, Ty- virus like particulars, plasmids, bacteria, etc. can be used.

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  • Health & Medical Sciences (AREA)
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Abstract

L'invention concerne l'identification d'un précurseur d'antigène de rejet tumoral. On a découvert que la protéine de préprocalcitonine fonctionnait comme un précurseur d'antigène de rejet tumoral, celle-ci étant traitée pour au moins un antigène de rejet tumoral. Des complexes d'antigène de rejet tumoral et une molécule MHC sont reconnus par des lymphocytes T cytolytiques, et sont lysés.
EP01927400A 2000-03-31 2001-03-14 Preprocalcitonine utilisee comme precurseur d'antigene de rejet tumoral et ses utilisations Withdrawn EP1301624A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US53956700A 2000-03-31 2000-03-31
US539567 2000-03-31
PCT/US2001/040288 WO2001075179A2 (fr) 2000-03-31 2001-03-14 Preprocalcitonine utilisee comme precurseur d'antigene de rejet tumoral et ses utilisations

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EP1301624A2 true EP1301624A2 (fr) 2003-04-16

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EP1793875B9 (fr) * 2004-06-16 2010-09-08 Affinergy, Inc. Biomateriaux interfaciaux favorisant l'adherence specifique de sunstances a analyser
EP2006384A1 (fr) * 2007-06-22 2008-12-24 Institut Gustave Roussy Epitopes d'antigènes dérivés de la préprocalcitonin
US20130046085A1 (en) * 2011-06-22 2013-02-21 Universidad De Sevilla Antibodies against n-procalcitonin
EP3115058A1 (fr) * 2015-07-09 2017-01-11 Institut Gustave Roussy Peptides immunogenes de preprocalcitonine

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AU662906B2 (en) * 1991-06-26 1995-09-21 F. Hoffmann-La Roche Ag Methods for detection of carcinoma metastases by nucleic acid amplification
DE19600875C1 (de) * 1996-01-12 1997-06-26 Brahms Diagnostica Gmbh Diagnostisches Verfahren zur Bestimmung der Ätiologie entzündlicher Prozesse
US5993811A (en) * 1997-02-03 1999-11-30 Biology Associates, Llc Method and compositions for preventing and treating the systemic inflammatory response syndrome including sepsis

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