WO2008119882A2 - Procédés de criblage - Google Patents

Procédés de criblage Download PDF

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Publication number
WO2008119882A2
WO2008119882A2 PCT/FI2008/050146 FI2008050146W WO2008119882A2 WO 2008119882 A2 WO2008119882 A2 WO 2008119882A2 FI 2008050146 W FI2008050146 W FI 2008050146W WO 2008119882 A2 WO2008119882 A2 WO 2008119882A2
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WIPO (PCT)
Prior art keywords
adam12
binding agent
adam
sample
seq
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Application number
PCT/FI2008/050146
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English (en)
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WO2008119882A8 (fr
WO2008119882A3 (fr
Inventor
Mikko SUONPÄÄ
Päivi ARONKYTÖ
Pertti Hurskainen
Outi Mulari
Jarkko Karvinen
Original Assignee
Wallac Oy
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Publication date
Application filed by Wallac Oy filed Critical Wallac Oy
Publication of WO2008119882A2 publication Critical patent/WO2008119882A2/fr
Publication of WO2008119882A3 publication Critical patent/WO2008119882A3/fr
Publication of WO2008119882A8 publication Critical patent/WO2008119882A8/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
    • 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
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6489—Metalloendopeptidases (3.4.24)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
    • G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
    • G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
    • G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
    • G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
    • G01N2333/96486—Metalloendopeptidases (3.4.24)

Definitions

  • the present invention relates to binding agents, preferably monoclonal antibody FAb fragments recognizing novel epitopes of ADAM12, useful for e.g. screening Down's syndrome in samples taken during the pregnancy.
  • ADAM12 an acronyme for A Disintegrin And Metalloprote- ase 12 is glycoprotein, which belongs to metzincin superfamily. It is synthe- sised in two forms ADAM12-L a 909 amino acid cell membrane bound form and ADAM12-S (hereinafter ADAM12), a 739 amino acid secreted form.
  • ADAM 12 is synthesized by the placenta and secreted throughout the pregnancy. ADAM 12 is a potentially important factor to screen for in prenatal diagnosis of Down syndrome during the first trimester, as the level of ADAM12 is reduced in maternal serum during the first trimester in Down syndrome and trisomy 18 pregnancies, as described by Laigaard et al, in Prenatal Diagnosis, 26 (2006). Furthermore, ADAM12 is reduced in the serum of women later developing preeclampsia. US patent publications 2005/025114 and 2006/0134654 disclose use of ADAM 12 as a marker in antibody based assays for diagnosing fetal chromosomal abnormalities and preeclampsia. In addition to placenta, many cancer cells express immunoreactive
  • ADAM 12 (Iba et al., (1999) Amer J Pathology, 154, 1489-1500). ADAM12 has also been found in the urine of breast cancer patients. International patent publication WO 2005/071387 discloses ADAM12 as a marker in antibody based assays for diagnosing cancers of epithelial origin and providing a prog- nosis thereof.
  • the present invention related to a novel, isolated epitope of human ADAM12, which is found in SEQ ID NO: 2, i.e., amino acids 360-660.
  • the epitope comprises the amino acid sequence SEQ ID NO: 3 and at least one amino acid sequence selected from the group consisting of:; SEQ ID NO: 4; SEQ ID NO: 5, SEQ ID NO: 6 and SEQ ID NO: 7.
  • the invention further relates to a binding agent that specifically binds to an epitope of ADAM12 according to the present invention.
  • the binding agent according to the present invention is a polyclonal or monoclonal antibody or a fragment thereof.
  • the invention also relates to a method for detecting ADAM 12 in a biological sample, wherein a sample, preferably a serum sample, obtained from a patient is provided and said sample is contacted with a binding agent according to the present invention and with another binding agent, preferably with the monoclonal antibodies, such as mAb 6E6, capable of binding ADAM12.
  • ADAM12 is detected by means of a label, either in one of the binding reagent itself or in the antigen.
  • one of the binding agents is immobilized on a solid support and the other binding agent is labeled.
  • the intensity of the signal produced by the bound labeled binding agent is proportional to the concentration of ADAM 12 in the sample.
  • the invention further relates to a method for prenatal screening of conditions related to ADAM 12, wherein a serum sample obtained from a woman during pregnancy, preferably during the first trimester, is provided and contacted with a binding agent according to the present invention.
  • the level of ADAM 12 in said serum sample is determined and compared to median levels of ADAM12 in serum.
  • An abnormal, e.g., a decreased, level of ADAM12 is indicative of said condition.
  • said conditions to be screened are fetal chromosomal anomalies e.g, Down's syndrome and trisomy 18, or preeclampsia, intrauterine growth retardation, fetal death, pre-term birth and low birth weight.
  • the invention further relates to a method for diagnosing other diseases where ADAM12 is abnormal e.g. cancers preferably breast cancer. In such cases the level of ADAM12 may be elevated.
  • the present invention relates to a kit for detecting ADAM 12, comprising a binding agent according to the present invention.
  • Figure 1 is a graph illustrating the instability of ADAM12 in serum samples when detected by monoclonal antibody 8F8, and
  • Figure 2 is a graph showing the sample stability in respect of ADAM12 when using Fab fragment FAb52.
  • a sandwich immunoassay based on two ADAM12-specific mono- clonal antibodies such as the ones described by Laigaard et al, could be useful for the detection of human ADAM12 in serum samples.
  • one monoclonal antibody such as clone 6E6 described by Laigaard et al
  • clone 8F8 described by Laigaard et al.
  • detection purposes with e.g., DELFIA Eu chelate.
  • ADAM 12 concentrations in maternal serum samples decreased markedly upon storage. Serum samples stored at +4°C for several days showed up to a 30% decrease in ADAM12 concentrations. Results were even more troublesome when serum samples were stored at room temperature (21 0 C), where the ADAM12 concentration showed a 60-70% decrease after storage of 7 days. As clinical samples taken at local hospitals or healthcare centers often are sent to central hospitals or laboratories for testing, either by mail or courier service, lability of ADAM 12 is a notable problem. The tem- perature during transportation of the samples may vary and can be about +20°C or higher for several days.
  • ADAM 12 concentrations which are largely dependent on the conditions during sample transportation. This fact makes such an assay unreliable and consequently unsuitable for diagnosis of dis- eases or prenatal screening of Down's syndrome in the clinics.
  • the known antibodies against ADAM 12, especially 8F8 seems to be sensitive to conformation changes in the target they have been raised against.
  • the present inventors set out to develop improved binding agents for use in immunoassay for detecting ADAM 12.
  • Such reagents should not be as sensi- tive to the possible conformation changes in the target, ADAM12.
  • binding agents for detecting ADAM12 in e.g. serum samples, which agents are less sensitive to the temperature dependent conformation changes of ADAM 12.
  • Suitable agents are any compound binding specifically to ADAM12 in a posi- tion which is not as sensitive to storage conditions of the target as prior art antibodies.
  • binding agents include polyclonal or monoclonal antibodies and fragments thereof, binding peptides, and aptamers.
  • binding agents useful in the present invention recognize different epitopes of ADAM 12 as compared to MAb 8F8.
  • ADAM 12 is to provide antibody fragments, such as a Fab, a Fv or a scFv fragment, especially Fab fragments.
  • antibody fragments such as a Fab, a Fv or a scFv fragment, especially Fab fragments.
  • Such fragments are highly preferred binding agents due to their smaller size and easy of production.
  • Fab fragments are usually more stable than Fv fragments, and were thus chosen as a working hypothesis when searching for improved ADAM12 binding agents.
  • Fab fragments are monovalent and consist of a heavy chain variable region and a light chain variable region. When so-called association domains are fused to C-terminus of a heavy chain variable region (for a review see Pluckthun and Pack, 1997) dimeric Fab fragments are formed.
  • Recombinant bivalent Fab fragments contain four self-associating domains (two per monomeric Fab fragment separated by a short flexible spacer sequence) which form a four-helix bundle. All four helices have the same amino acid sequence.
  • peptide tags such as 6xHis, StrepTag and Flag, may be incorporated to C-terminus for purification and possibly also for detection purposes. Avidity of these dimeric Fab fragments is about ten times higher than avidity of corresponding monomeric Fab fragments.
  • Antibody fragments may be produced by phage display methods. This concept was originally described for producing short peptides by Smith in 1985, and for producing functional antibody fragments in US Patent No. 6,248,416. A major advantage of phage display technology for producing Fab fragments is the ease and speed by which a large number of antigen specific fragments can be screened.
  • the starting point for selecting specific Fab fragments today is often a large antibody library comprising billions of clones.
  • ADAM12 Purified recombinant mature, full-length form of ADAM12 (GenBank accession number AF023477; SEQ ID NO. 1 ) was screened by panning against a human, highly variable monomeric Fab fragment library (Human Combinatorial Antibody Library, HuCAL; AbD Serotec) consisting of up to billions of Fab fragments in a phage library. Positive clones were identified as potentially antigen specific Fab fragments using ELISA where the fragments were reacted with recombinant ADAM12 coated onto a solid support. Bound Fab fragments were detected by enzyme labelled streptavidin.
  • HuCAL Human Combinatorial Antibody Library
  • the positive clones may be converted into clones producing dimeric Fab fragments to increase Fab avidity, expressed in bacteria, such as E.coli and purified.
  • the purification step may be performed by introducing pep- tide tags, such as StrepTag described by Skerra et al, in Biomolecular engineering, 16:79-86, 1999, into the Fab fragments, and using a streptavidin column for purification.
  • ADAM12 specific Fab fragments thus identified were further analyzed and epitope mapped, in order to identify novel epitopes of ADAM12, which are not sensitive to temperature dependent conformation change of ADAM 12 in serum samples.
  • Fab fragments may be mapped using synthetic peptide scanning. Chemical spot synthesis of short peptides, for example 20-mer peptides, overlapping by 15, may be performed on cellulose membranes using Fmoc chemistry or alternatively peptide libraries can be used as described by Valadon et al, in I. Immonol. Methods, 197:171-179, 1996.
  • Peptides are preferably synthesized so that they cover the entire target protein, i.e., human ADAM12.
  • Such a library e.g. membrane bound epitope library is then screened against Fab fragments raised against the target protein, ADAM 12.
  • Such fragments are labelled for detection purpose, preferable biotinylated.
  • labelled Fab fragments are detected.
  • the detection step may be performed by treating the membranes with horseradish peroxidase-conjugated streptavidin. Following washes the Fab fragments bound to the immobilized peptide epitopes are detected, e.g, as described in the examples, and corresponding peptide sequences are identi- fied as ADAM 12 epitopes.
  • a novel epitope was identified in the amino acid stretch defined by amino acids 360-660 (SEQ ID NO: 2), comprising at least one of the amino acid stretches defined by amino acids 445-475 (SEQ ID NO: 3), amino acids 560-580 (SEQ ID NO: 4), amino acids 625-645 (SEQ ID NO: 5), amino acids 650-660 (SEQ ID NO: 6) and amino acids 360-380 (SEQ ID NO: 7) was thus identified.
  • Amino acids 445-475 are in the disintegrin domain
  • amino acids 560-580, 625-645 and 650-660 are in the cysteine-rich domain
  • amino acids 360-380 are located in the metalloprotease domain of human ADAM 12.
  • Isolated immobilized epitopes according to the present invention may be used to screen for further binding agents, such as aptamers, which are ADAM12 specific and which detect ADAM12 in body fluids, such as serum, whole blood, blood spots, plasma, urine or amniotic fluid.
  • aptamers which are ADAM12 specific and which detect ADAM12 in body fluids, such as serum, whole blood, blood spots, plasma, urine or amniotic fluid.
  • Antibody fragments preferably Fab fragments, detecting the ADAM12 epitopes according to the present invention, are especially useful as binding agents in assays for determining ADAM12 concentrations in biological samples, due to their lower sensitivity to the temperature dependent conformation changes of ADAM 12 in samples during storage.
  • ADAM 12 specific binding agents such as antibody fragments, especially Fab fragments, which detect an epitope, comprising the amino acid sequence defined by amino acids 445-475 (SEQ ID NO: 3) and at least one amino acid sequence defined by amino acids 560-580 (SEQ ID NO: 4), amino acids 625-645 (SEQ ID NO: 5), amino acids 650-660 (SEQ ID NO: 6) and amino acids 360- 380 (SEQ ID NO: 7).
  • Binding agents are useful in assays for detecting ADAM12 in body fluid samples, such as serum, whole blood, blood spots, plasma, urine or amniotic fluid, and thus useful for e.g. prenatal diagnosis of Down's syndrome, trisomy 18 or preeclampsia, as they are not sensitive to the temperature dependent conformation changes of ADAM12, which is occurring in serum samples during storage.
  • An especially useful assay according to the present invention is a solid phase, two-site fluoroimmunometric assay based on the direct sandwich technique in which two binding agents, such as ADAM12-specific antibodies, or fragments thereof, are directed against two separate antigenic determinants on the ADAM12 molecule.
  • Calibrators, controls and samples containing ADAM 12 are reacted with a first, immobilized ADAM 12 specific monoclonal antibody, such as 6E6.
  • Bound ADAM 12 is detected with a second, labeled ADAM12-specific binding agent, such as a europium-labelled Fab fragment.
  • Enhancement Solution dissociates europium ions from the labelled antibodies into the solution where they form highly fluores- cent chelates with components of the Enhancement Solution. The fluorescence in each well is then measured. The europium fluorescence of each sample is proportional to the concentration of ADAM 12 in the sample.
  • said immobilizaed binding agent may be immobilized to any suitable solid support, such as reaction vials, microtitration plates, beads or slides.
  • said detection may be utilizing suitable labels known in the art, such as fluorescent labels, lanthanide chelates, enzymes, luminescent labels, chemilumi- nescent labels, phosphorescent labels or radioisotopes.
  • suitable labels known in the art, such as fluorescent labels, lanthanide chelates, enzymes, luminescent labels, chemilumi- nescent labels, phosphorescent labels or radioisotopes.
  • the detection of ADAM12 present in the sample to be tested may, in such an assay, be detected by TR- FRET or any other labeling system suitable for homogeneous assays known in the art.
  • the present invention further provides a kit for use in an assay according to the present invention, comprising ADAM12 specific binding agents according to the present invention, ADAM12 calibrators, assay buffers, reaction vials coated with an ADAM12 specific binding agent recognizing a second antigenic determinanta of ADAM 12.
  • the binding agents according to the present invention included in said kit are labeled for detection purposes, preferably by a Eu-label.
  • ADAM 12 immunoassay using MAbs A sandwich immunoassay based on two ADAM12-specific monoclonal antibodies was developed for the detection of human ' ADAM12 in serum samples.
  • One monoclonal antibody (clone 6E6) was coated on microtitration plates and the other (clone 8F8) was labelled with DELFIA Eu N1 chelate (PerkinElmer Cat n:o 1244-301) according to the manufacturer's instructions. Samples and calibrators were added in 25 ⁇ L to the plate followed by Eu- labelled monoclonal antibody in 100 ⁇ L (2 ⁇ g/ml) of DELFIA Assay Buffer (PerkinElmer Cat n:o 1244-106) .
  • ADAM 12 concentrations in maternal serum samples decreased markedly upon storage.
  • serum samples were stored at +4°C for 2 days and 7 days there was a 10% and 30% decrease in ADAM12 concentrations, respectively.
  • Results were even more troublesome when serum samples were stored at room temperature (21 "C).
  • Dimeric Fab fragments specific for human ADAM 12 obtained by screening against a commercially available library (AbD Serotec) were labelled with Europium chelates for use in ADAM12 assays. Labelling was performed at 4°C, pH 9.3, overnight.
  • Fab52 StrepTag was labelled at 0.9 mg/mL using a 25- fold molar excess of DELFIA Eu-NI-ITC chelate having a reactive isothiocy- anato group (product number AD0001 , PerkinElmer).
  • ADAM12 Fab fragments were mapped using synthetic peptide scanning. Spot synthesis of 20-mer peptides, overlapping by 15, was performed on cellulose membranes using Fmoc chemistry. Peptides covered the entire 739 amino acid sequence of human ADAM12 (SEQ ID NO: 1). After deprotection membranes were blocked with 0.1% casein in Tris-HCI buffered saline for 2 hours. Next membranes were incubated with biotinylated Fab fragments (10 ⁇ g/mL in the blocking buffer). After washing membranes were treated with horseradish peroxidase-conjugated streptavidin diluted in the blocking buffer. Following washes membranes were incubated in a luminol- based enhanced chemiluminescence detection mixture and exposed on X-ray film for various times (15 s to 2 min).
  • Fab fragments FAbI and FAb52 were found to bind to the following linear sequences in human ADAM12: Amino acids 445-475; Amino acids 560- 580; Amino acids 625-645; Amino acids 650-660: and Amino acids 360-380.
  • Amino acids 445-475 are in the disintegrin domain, amino acids 560-580, 625-645 and 650-660 are in the cysteine-rich domain, whereas amino acids 360-380 are located in the metalloprotease domain of human ADAM12.
  • TR-FRET Homogeneous time-resolved fluorescence resonance energy transfer
  • Requirements for TR-FRET include that emission peak of a lanthanide chelate overlaps excitation peak of a fluorescent label and distance between a lanthanide chelate and an acceptor is no longer than 10-15 nm.
  • emission peak of a lanthanide chelate overlaps excitation peak of a fluorescent label and distance between a lanthanide chelate and an acceptor is no longer than 10-15 nm.
  • suitable acceptors for a fluorescent Eu chelate include a fluorescent protein allophycocyanin (APC) and small- molecule fluorophores such as Hil_yte647, Alexa647 and Cy5. All these acceptors have an emission maximum at 650-680 nm.
  • Monoclonal antibody 6E6 was labelled with a fluorescent Eu chelate, LANCE Eu-WI 024-ITC chelate (PerkinEimer, catalog number AD0013) according to manufacturer's instructions. Labelling yield was 7 Eu-WI 024 che- lates per antibody.
  • Fab51 StrepTag was labelled with HiLyte647 N- hydroxysuccinimide ester (Anaspec) according to manufacturer's instructions giving 3 HiLyte molecules per Fab fragment. Immunoassays were performed in microtitration plates with a total volume of 200 ⁇ L.
  • Assay buffer was Tris-HCI based (50 mM, pH 7.8) containing 0.9% NaCI, 0.5% bovine serum albumin (BSA) and 0.05% bovine gamma-globulin.
  • First samples 50 ⁇ L s ⁇ rum or plasma, were added to wells followed by 150 ⁇ l_ assay buffer containing Eu- W1024-labelled monoclonal antibody 6E6 and HiLyte647-labelled Fab51.
  • Final concentrations for Eu-labelled 6E6 and Hil_yte647-labelled Fab were 200 ng/mL and 400 ng/mL.

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Abstract

La présente invention porte sur un nouvel épitope d'ADAM12 humain et sur des agents de liaison, de préférence des fragments Fab, se liant spécifiquement audit épitope. L'invention porte également sur un procédé pour détecter l'ADAM 12 dans un échantillon biologique à l'aide desdits agents de liaison, et sur des procédés de criblage prénatal et des procédés de diagnostic prénatal utilisant lesdits agents de liaison.
PCT/FI2008/050146 2007-03-30 2008-03-28 Procédés de criblage WO2008119882A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
FI20075209 2007-03-30
FI20075209 2007-03-30
US90748507P 2007-04-04 2007-04-04
US60/907,485 2007-04-04

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WO2008119882A2 true WO2008119882A2 (fr) 2008-10-09
WO2008119882A3 WO2008119882A3 (fr) 2008-11-20
WO2008119882A8 WO2008119882A8 (fr) 2009-07-30

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3938405A4 (fr) * 2019-03-20 2022-12-28 Javelin Oncology, Inc. Anticorps anti-adam12 et récepteurs antigéniques chimériques ainsi que compositions et méthodes les comprenant

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997009430A2 (fr) * 1995-09-05 1997-03-13 Celltech Therapeutics Limited Metalloproteinase humaine, ses variants et sequences d'adn codantes qui lui sont destinees
US20020147132A1 (en) * 1996-02-23 2002-10-10 Mochida Pharmaceutical Co., Ltd. Meltrins
EP1524523A1 (fr) * 2003-10-17 2005-04-20 Deutsches Krebsforschungszentrum Stiftung Des Öffentlichen Rechts Utilisation de ADAM 12 pour le diagnostic et le traitement de pré-éclampsie
WO2005071387A1 (fr) * 2004-01-09 2005-08-04 Children's Medical Center Coporation Methodes de diagnostic et de pronostic de cancers d'origine epitheliale
US20060134654A1 (en) * 2004-05-19 2006-06-22 Wewer Ulla M ADAM12, a novel marker for abnormal cell function

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997009430A2 (fr) * 1995-09-05 1997-03-13 Celltech Therapeutics Limited Metalloproteinase humaine, ses variants et sequences d'adn codantes qui lui sont destinees
US20020147132A1 (en) * 1996-02-23 2002-10-10 Mochida Pharmaceutical Co., Ltd. Meltrins
EP1524523A1 (fr) * 2003-10-17 2005-04-20 Deutsches Krebsforschungszentrum Stiftung Des Öffentlichen Rechts Utilisation de ADAM 12 pour le diagnostic et le traitement de pré-éclampsie
WO2005071387A1 (fr) * 2004-01-09 2005-08-04 Children's Medical Center Coporation Methodes de diagnostic et de pronostic de cancers d'origine epitheliale
US20060134654A1 (en) * 2004-05-19 2006-06-22 Wewer Ulla M ADAM12, a novel marker for abnormal cell function

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Title
CARL-MCGRATH STACY ET AL: "The disintegrin-metalloproteinases ADAM9, ADAM12, and ADAM15 are upregulated in gastric cancer" INTERNATIONAL JOURNAL OF ONCOLOGY, DEMETRIOS A. SPANDIDOS ED. & PUB, GR, vol. 26, no. 1, 1 January 2005 (2005-01-01), pages 17-24, XP009105604 ISSN: 1019-6439 *
IGARASHI ET AL: "Crystal structures of catrocollastatin/VAP2B reveal a dynamic, modular architecture of ADAM/adamalysin/reprolysin family proteins" FEBS LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 581, no. 13, 29 May 2007 (2007-05-29), pages 2416-2422, XP022086940 ISSN: 0014-5793 *
SEALS DARREN F ET AL: "The ADAMs family of metalloproteases: Multidomain proteins with multiple functions" GENES AND DEVELOPMENT, COLD SPRING HARBOR LABORATORY PRESS, PLAINVIEW, NY, US, vol. 17, no. 1, 1 January 2003 (2003-01-01), pages 7-30, XP002459610 ISSN: 0890-9369 *
YAMAMOTO S ET AL: "ADAM family proteins in the immune system" IMMUNOLOGY TODAY, ELSEVIER PUBLICATIONS, CAMBRIDGE, GB, vol. 20, no. 6, 1 June 1999 (1999-06-01), pages 278-284, XP004169720 ISSN: 0167-5699 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3938405A4 (fr) * 2019-03-20 2022-12-28 Javelin Oncology, Inc. Anticorps anti-adam12 et récepteurs antigéniques chimériques ainsi que compositions et méthodes les comprenant

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WO2008119882A3 (fr) 2008-11-20

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