EP1727832A2 - Antigen des pm-2 antikörpers und dessen verwendung - Google Patents

Antigen des pm-2 antikörpers und dessen verwendung

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Publication number
EP1727832A2
EP1727832A2 EP05735145A EP05735145A EP1727832A2 EP 1727832 A2 EP1727832 A2 EP 1727832A2 EP 05735145 A EP05735145 A EP 05735145A EP 05735145 A EP05735145 A EP 05735145A EP 1727832 A2 EP1727832 A2 EP 1727832A2
Authority
EP
European Patent Office
Prior art keywords
polypeptide according
cell
membrane glycoprotein
antigen
dsm
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Withdrawn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
EP05735145A
Other languages
German (de)
English (en)
French (fr)
Inventor
Heinz Vollmers
Frank Hensel
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.)
Patrys Ltd
Original Assignee
Oncomab GmbH
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Filing date
Publication date
Application filed by Oncomab GmbH filed Critical Oncomab GmbH
Publication of EP1727832A2 publication Critical patent/EP1727832A2/de
Withdrawn legal-status Critical Current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
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the invention relates to a polypeptide which is expressed as a membrane-bound protein on the cell surface, which is glycosylated at one or more sites (membrane glycoprotein) and whose amino acid sequence is partially or entirely that of the integrin binding protein p80 (accession # AJ 131720) or REV1 ( accession # AF206019).
  • the invention relates to the use of the polypeptide according to the invention in tumor treatment, tumor diagnosis and in tumor research.
  • Cancer patients are already at an advanced stage of the disease at the time of initial diagnosis.
  • the search for new anti-cancer agents also plays a major role, e.g. by inhibiting cell proliferation or by initiating
  • Apoptosis Apoptotic receptors on the cell surface, such as those of the NGF / TNF family, are predominantly expressed on lymphocytes, but are also found on various other cell types, which is why they are disadvantageously unsuitable for cancer therapy. NEN.
  • ligands and antibodies for these receptors have resulted in liver damage.
  • Tumor-specific receptors (antigens) with apoptotic function which are expressed on the cell surface of neoplastic cells, are therefore particularly important for cancer therapy. This applies in particular against the background that the identification and isolation of human monoclonal antibodies with an apoptotic effect is increasingly successful.
  • hybridoma technology has successfully isolated a series of tumor-specific IgM antibodies from the tissue of cancer patients and from the tissue of healthy donors.
  • two human monoclonal tumor-specific antibodies and their antigens have already been identified.
  • the human monoclonal antibody SC-1 specifically binds to the CD-55 receptor (Cancer Research, 1999 Oct. 15, 59 (20), 5299-5306, Hensel et. Al)
  • the human monoclonal PAM-1 antibody specifically binds to the CFR- 1 receptor binds (Oncol. Rep. 2004, Apr. 11 (4), 777-784, Brändlein et. Al).
  • Human monoclonal antibodies of this type are thought to play a major role in the treatment and diagnosis of cancer. Their importance for cancer therapy lies in the induction of apoptosis and / or inhibition of cell proliferation after specific binding to the corresponding antigens (receptors) on the surface of neoplastic cells.
  • Apoptosis is programmed cell death, i.e. H. Suicide of cells by fragmentation of the DNA, cell shrinkage and dilation of the endoplasmic reticulum, followed by cell fragmentation and the formation of membrane vesicles, the so-called apoptotic bodies. It is the most common cause of death for eukaryotic cells and occurs in embryogenesis, metamorphosis and tissue atrophy. As the physiological form of cell death, apoptosis guarantees a quick and clean removal of unnecessary cells without triggering inflammatory processes or tissue injuries as in the case of necrosis. Under pathological conditions, apoptosis also serves to remove malignant cells, such as cancer precursor cells. Apoptosis can be triggered by a wide variety of stimuli, such as cytotoxic T lymphocytes or cytokines such as tumor necrosis factor, glycocorticoids and antibodies.
  • stimuli such as cytotoxic T lymphocytes or cytokines such as tumor necrosis factor, glycocorticoids and antibodies.
  • Membrane glycoproteins have sugar residues (Glycokalix) on their extracellular side, which are either bound to the amide nitrogen of an asparagine side chain (/ -binding) or to the oxygen atom of a serine or threonine side chain (O-bond).
  • the sugar directly linked to the side chain is mostly N-acetylglucosamine or ⁇ / -acetylgalacatosamine.
  • Carbohydrates can form very diverse structures.
  • different monosaccharides can be linked to one another via one or more OH groups.
  • those on the C-1 atom connecting links have an ⁇ or ⁇ configuration. Using these different linkages, glycomembrane proteins can have extensive branches made up of oligosaccharides.
  • the carbohydrate structure (glycosylation pattern, glycocalyx) on the cell surface is of an informational nature for intercellular recognition.
  • the immune system uses the glycosylation pattern for recognition and adsorption to the target cell, the structural basis for the process of this
  • Integrins are proteins coupled to the surface of cells, the lipophilic part of which spans the cell wall (transmembrane proteins) and whose extracellular components are glycosylated (glycomembrane proteins). Through a process known as adhesion, integrins mediate the binding of cells to the extracellular matrix and to other cells. In addition to the amino acid sequence of the integrins and the three-dimensional protein structure, the structure of the sugars bound to the integrins is responsible for the selectivity of the binding. Integrins are heterodimers that are composed of one and one ⁇ subunit, with about 10 different ⁇ subunits and at least twice as many different ⁇ subunits. The resulting variability for the Integrine receptor type alone explains that the
  • integrins are particularly effective in signal transduction, i.e. in the transmission of information from extracellular signals to the inside of the cell and from the inside of the cell to the outside. Adhesion and subsequent signal transmission into the cell interior trigger intracellular processes that can lead to the restructuring of the cytoskeleton and the induction of signal cascades. Integrin binding proteins are the binding partners of the integrins in adhesion.
  • Cell adhesion processes have a regulatory effect on the expression pattern and thus on the specificity of the receptors themselves. Cell adhesion mechanisms are therefore important for cell growth, cell migration and differentiation, and they are particularly involved when cells lose their specialized forms and become cancer cells that can be metastasized.
  • neoplasm An abnormal tissue mass is called neoplasm or tumors, the growth of which is autonomous (regardless of growth factors), uncoordinated, aimless and progressive.
  • Tumors consist of two components. Firstly, the parenchyma cells, which are also called neoplastic cells, and the non-tumorous stroma, ie the connective tissue and the blood vessels.
  • a neoplastic cell is a cell that is subject to uncontrolled cell division or a cell that does not have an apoptosis mechanism. has mus.
  • a neoplastic cell in the sense of the invention can also have both disorders and can also be distinguished by the fact that its Zeil cycle deviates from the normal Zeil cycle.
  • the human REV-1 also known from the prior art
  • Protein (accession # AF206019) also has sequence homology to the antigen according to the invention, at least in sections.
  • a deoxycytidyl transferase activity is reported as a function of REV1. The deoxycytidyl transferase presumably catalyzes the binding of deoxycytidylate to the daughter DNA
  • REV1 is therefore not a membrane-bound protein and is located in the nucleus.
  • polypeptides with the same amino acid sequence can be present on the one hand as membrane-bound proteins and on the other hand as proteins in the cell nucleus shows that the post-translational modifications, such as glycosylation, play a major role with regard to the location and function of a polypeptide len and one cannot assume an identity of such proteins despite sequence homology.
  • the object of the invention is to identify and characterize an antigen to which the tumor-specific human monoclonal antibody PM-2 binds (DSM entry number: DSM ACC2600), and in the use of the antigen for tumor treatment and tumor diagnosis.
  • the PM-2 antibody (DE 102 30 516 A1) is a human monoclonal antibody with heavy and light chain molecules, each of which has an antibody-to-antibody constant and an antibody-to-antibody variable region or a functional fragment thereof, wherein at least one of the variable regions of the light chain substantially each in SEQ
  • the PM-2 antibody was produced using the hybridoma technique, the hybridoma cells (DSM ACC2600) being obtained by fusion of the hetero-myeloma cells HAB-1 and their subclones with P lymphocytes.
  • DSM ACC2600 the hybridoma cells
  • Lymphocytes were preferably taken from a lymphoid organ, the spleen or lymph nodes of a carcinoma patient.
  • the human monoclonal antibody PM-2 is characterized by the fact that after specific binding to the corresponding PM-2 antigen on the surface of a neoplastic cell in it
  • the invention teaches a glycomembrane protein with antigenic properties, which is characterized in that it is - expressed by neoplastic cells and not by non-neoplastic cells, and - as an antigen, the human monoclonal antibody PM-2 (DSM entry number: DSM ACC2600) binds specifically, and - ⁇ / -glycosidic and O-glycosidic is glycosylated.
  • the antigen of the invention is tumor specific, i.e. it is only expressed by neoplastic cells. Glycosylation, which is ⁇ / -glycosidic and O-glycosidic, is responsible for the specific binding of the human monoclonal antibody PM-2 (DSM entry number: DSM ACC2600) to the antigen according to the invention.
  • the fact that the p-80 protein integrin binds may provide an indication of the role that the antigen according to the invention plays in the development of tumors. Integrins are important as cell adhesion molecules in angiogenesis. Thus, the ⁇ Vß3 integrin is expressed by the endothelial cells of those vessels that supply tumors. It would be conceivable that the antigen according to the invention, which was detected in the epithelial cells of the blood vessels, also interacts with integrins and that its inhibition has an effect similar to the inhibition of angiogenesis. It is also known that integrins play an important role in the metastasis of tumor cells by reducing the adhesion of the over the blood streams made it possible for tumor cells to be transported into previously tumor-free tissue.
  • the / V-glycosidically bound glycostructures presumably play a special role for the specific binding of the antibody PM-2 according to the invention.
  • the precise analysis of the glycosylation sites is determined using software known to the person skilled in the art (software of the database of the "UK MRC Human Genome Mapping Project" http://www.hgmp.mrc.ac.uk/GenomeWeb/prot-anal.html).
  • REV1 has ⁇ / glycosylation in particular at the amino acid positions 810, 830, 927 and 1045.
  • the antigen identified with the help of the human monoclonal antibody is composed of one monomer or of several identical subunits.
  • the possibility that it is a homomer of two identical subunits (dimer) or is associated with other proteins could also explain that the molecular weight that can be indicated by means of immunoblot (Western plot) has hitherto varied within a wide range.
  • the cells expressing the protein have already been mentioned in connection with the characterization of the PM-2 antibody. Therefore, reference is made here to document DE 102 305 156 A1.
  • the hybridoma cell line, which produces the antibody PM-2 is under the Budapest Treaty on the international recognition of the
  • Carcinoma cells of the cell line BXPC3 (ATCC number CRL1687) are used because the antigen is particularly well expressed on their surface.
  • the antigen is expressed on the surface of epithelial cells in the tumor tissue.
  • the therapeutic potential of the antigen according to the invention which consists in that after the PM-2 antibody has bound to the antigen, apoptosis is induced in a neoplastic cell.
  • apoptosis is induced in a neoplastic cell.
  • due to the specific binding of the PM-2 antibody to the antigen on the surface of neoplastic cells inhibits their cell proliferation.
  • a method for isolating the antigen according to the invention was developed. After homogenization and solubilization in a detergent known to the person skilled in the art the antigen was purified by chromatography. Size exclusion chromatography is used in particular. In an improvement of the isolation process it is conceivable that the size exclusion chromatography is followed by a further step in the form of an anion exchange chromatography. This second purification step improves the purity of the isolated glycomembrane protein.
  • the antigen isolated in this way can be used to prepare a medicament using the customary pharmaceutical auxiliaries and carriers.
  • the purified antigen is administered in vivo in a physiological NaCl solution.
  • the purified glycomembrane protein is used as an antigen to identify specific binding ligands or adhesion peptides.
  • the polypeptides identified in this way correspond only in sections to the sequence of the human monoclonal antibody PM-2, but nevertheless in neoplastic
  • the adhesion peptides or ligands can be coupled to a radionucleotide, a cytotkin, a cytokine or a growth inhibitor.
  • the glycomembrane protein according to the invention is used as an antigen in the identification of active substances in the context of high-throughput screening. Such methods and their configurations are known to the person skilled in pharmaceutical research.
  • the use of the antigen according to the invention as a tumor marker is also provided within the scope of the invention.
  • the detection of the membrane glycoprotein according to the invention can be carried out on the surface of neoplastic cells with the aid of the PM-2 antibody. With the aid of the vector insert specified in sequence listing 1 and 2, it was possible, inter alia, to prove in an antisense experiment that the membrane glycoprotein according to the invention is the antigen for the specifically binding human monoclonal antibody PM-2.
  • the carcinoma cell line BXPC-3 (ATCC ⁇ number CRL1687) was used to obtain the receptor.
  • Western blot analysis also used the well-known gastric adenocarcinoma cell line 23132/87 (DSMZ entry number DSM201) (Hensel et al. 1999, Int.J. Cancer 81: 229-235).
  • the cells were grown to 80% confluency in RPMI-1640 (PAA, Vienna Austria) supplemented with 10% FCS and penicillin / streptomycin (1% for both). For the studies described, the cells were separated with trypsin / EDTA and washed twice with phosphate-buffered saline (PBS).
  • PBS phosphate-buffered saline
  • BXPC-3 implemented. Shown in abbreviated form, the connected tumor cells were washed twice with PBS, detached with a cell scraper and centrifuged, and dissolved in a hypotonic buffer (20 M HEPES, 3 mM KCI, 3mM MgCI 2 ). After a 15 min. Incubation time on ice and an ultrasound treatment for 5 min., The cores were pelleted by centrifugation at 10,000 g for 10 min. The supernatant was centrifuged for 30 min at 100,000 g in a swing-out rotor and the membrane was thereby pelletized.
  • a hypotonic buffer (20 M HEPES, 3 mM KCI, 3mM MgCI 2 .
  • the purification of the antigen was carried out with column chromatography using a Pharmazia (Freiburg, Germany) FPLC unit.
  • a Pharmazia Superdex 200 (XK 16/60) column was loaded with 5 mg of the membrane preparation and operated with a buffer A (100 mM Tris / Cl, pH 7.5.2 mM EDTA, 40 mM NaCl , 1% Triton X-100). Then the eluate was fractionated and examined for reactions with the antibody PM-2 by Western blot analysis. The positive fractions were placed on a MonoQ (5/5 column) using buffer A.
  • the bound proteins were washed out using a linear gradient using buffer B (100 mM Tris / Cl, pH 7.5.1 M NaCl, 2 mM EDTA, 1 M NaCl, 1% Triton X-100), fractionated and with Coomas- stained SDS-PAGE and Western blot analysis were examined.
  • buffer B 100 mM Tris / Cl, pH 7.5.1 M NaCl, 2 mM EDTA, 1 M NaCl, 1% Triton X-100
  • the amplification was carried out using the following cycle profile: 95 ° C., 2 min; subsequently 35 cycles at 94 ° C, 30 sec; 60 ° C, 30 sec; 72 ° C 60 sec. And finally 72 ° C, 4 min.
  • the cloning into the pCR script Amp SK (+) vector and the sequencing of the DNA was carried out as previously described (Hensel et al., 1999 Int.J. Cancer 81: 229-235).
  • the insert was cut out from the pCR script Amp SK (+) vector with appropriate restriction enzymes and subcloned into the pHook-2 vector (Invitrogen, Leek, Netherlands).
  • Clones were checked for successful cloning by sequencing. A clone was chosen in which the coding sequence was cloned in the antisense direction to the promoter. This clone was amplified and vectors for antisense transfection isolated.
  • the transfection of the cell line BXPC-3 with pHook2-anti PM-2-R was completed with a prime factor reagent (PQLab, Er Weg, Germany) according to the supplier manual.
  • the plasmid DNA was diluted to 10 ⁇ g / ml and the prime factor reagent was added 1:10 to a serum-free growth medium.
  • the diluted plasmid DNA (450 ⁇ l), the diluted primer factor reagent supplement (90 ⁇ l) and the serum-free growth medium (460 ⁇ l) were mixed and incubated at room temperature.
  • 60 ml cell culture dishes (70% confluent) were washed twice with the Washed rum-free growth medium and then added the prime factor / DNA mixture dropwise.
  • the cells were incubated for 18 hours at 37 ° C. and 7% CO 2 , then the serum-free growth medium was replaced by a growth medium with 10% FCS and the cells were incubated for a further 24 hours before the expression of the receptor protein was examined.
  • cytospins Digestion with N-glycosidase on cytospins
  • the cells used were detached from the base of their culture bottles using trypsin / EDTA and then incubated for 1 h in RPMI-1640 medium + 10% FCS at 4 ° C. Then cytospin preparations were made with the cells. The cytospins were dried at RT overnight. After drying, the cells were fixed with 100% acetone for 10 min and washed three times with PBS. The fixed cells were then digested with 5 mU / ml N-glycosidase (in 100 ⁇ l phosphate buffer, pH 7.0) in the incubator at 37 ° C. for 3 hours.
  • cytospin preparations were then washed three times with PBS and immediately the immunohistochemical staining with the various antibodies pern fed. Cytospins that were only incubated with phosphate buffer or cytospins that were subjected to normal immunohistochemical staining without glycosidase treatment served as a negative control. The coloring was carried out as described. The finished staining was then evaluated microscopically and the results documented with a photo system and an Olympus microscope.
  • cytospins Digestion with O-glycosidase on cytospins
  • the cells were trypsinized and reconstituted for 1 h in culture medium on ice.
  • the cells were incubated with 20 ⁇ U / ml O-glycosidase (in 100 ⁇ l phosphate buffer, pH 6.8) at 37 ° C. for 3 h.
  • O-glycosidase in 100 ⁇ l phosphate buffer, pH 6.8
  • the cells were extracted, washed and diluted to 1 ⁇ 10 6 cells per ml. 1 ml of the cell solution was centrifuged at 1,500 g for 5 min. The antibody diluted to 40 ⁇ g / ml with complete RPMI is added to a final volume of 1 ml and incubated on ice for 90 min. Then they will
  • the cytospins are prepared, air-dried at room temperature and, as described above, fixed in acetone. Then the cytospins are blocked for 15 min with PBS / BSA (0.1%) and incubated for 30 min with 10 ⁇ g / ml primary antibody and then washed three times. The incubation with the secondary antibodies and the staining is carried out as described above.
  • FIG. 1 shows the influence of glycosidase digestion on the antibody binding of PM-2 on the cell surface of the pancreatic carcinoma cells BXPC-3. After digestion, the cytospins were stained immunohistochemically with the positive control CAM keratin (A, C, E) and with PM-2 (B, D, F).
  • Pictures A and B in Fig. 1 show the controls after incubation of the cells in glycosidase buffer without enzyme.
  • Pictures C and D show the effects of the / V-glycosidase incubation on the binding of the antibody PM-2 to the pancreatic carcinoma cells. After digestion with the enzyme ⁇ / -Glycosidase, the antibody PM-
  • FIG. 1E and F show the effects of the O-glycosidase incubation on the binding of the antibody PM-2. While the positive control CAM keratin in image E shows no change in color, it is shown after digestion with the enzyme O-glycosidase that the cells can no longer be stained with the antibody PM-2. This suggests that in addition to ⁇ / -bonded sugars, at least one O-glycosidically bound determinant of the antigen was also responsible for the specific binding of the PM-2 antibody.
  • Fig. 2 shows the influence of antisense transfection on stains with antibodies PM-2 and living cell staining (magnification 200x).
  • the right column of FIG. 2 shows the cells of the BXPC-3 cell line stained with the PM-2. Untransfected cells are shown in the top row. The middle row shows the one with the empty one
  • FIG. 3 shows the immunospecific detection of the antigen expressed in BXPC-3 cells and in 23132/87 cells with the aid of the PM-2 antibody.
  • Example 4 Determination of the JV glycosylation sites
  • glycosylation points indicated in FIGS. 4a and 4b and 5a and 5b were determined using the software of the database of the “UK MRC Human Genome Mapping Project” (http://www.hgmp.mrc.ac.uk/GenomeWeb/prot-anal .html) determined.
  • FIG. 6 shows the result of the mass spectroscopic analysis of a selected from an SDS gel using the PM-2 antibody
  • Protein band A sequence comparison of the peptide sections No. 2, No. 3, No. 4 and No. 6 determined with the aid of the mass spectrometer has sequence homology to the p-80 protein and to the REV1 protein.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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  • Genetics & Genomics (AREA)
  • Gastroenterology & Hepatology (AREA)
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  • Toxicology (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Peptides Or Proteins (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
EP05735145A 2004-03-25 2005-03-10 Antigen des pm-2 antikörpers und dessen verwendung Withdrawn EP1727832A2 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004015179A DE102004015179A1 (de) 2004-03-25 2004-03-25 Antigen des PM-2 Antikörpers und dessen Verwendung
PCT/DE2005/000455 WO2005092922A2 (de) 2004-03-25 2005-03-10 Antigen des pm-2 antikörpers und dessen verwendung

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EP1727832A2 true EP1727832A2 (de) 2006-12-06

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US (1) US20080281083A1 (ja)
EP (1) EP1727832A2 (ja)
JP (1) JP2008502321A (ja)
DE (2) DE102004015179A1 (ja)
WO (1) WO2005092922A2 (ja)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2322559A3 (en) 2002-07-04 2011-08-03 Patrys Limited Neoplasm specific antibodies and uses thereof
DE10311248A1 (de) 2003-03-14 2004-09-30 Müller-Hermelink, Hans Konrad, Prof. Dr. Humaner monoklonaler Antikörper
DE10353175A1 (de) 2003-11-14 2005-06-16 Müller-Hermelink, Hans Konrad, Prof. Dr. Humaner monoklonaler Antikörper mit fettsenkender Wirkung
EP1531162A1 (en) 2003-11-14 2005-05-18 Heinz Vollmers Adenocarcinoma specific antibody SAM-6, and uses thereof
EP2234640A1 (en) * 2007-12-21 2010-10-06 Patrys Limited Pm-2 antibodies and methods for treating metastasis

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US5374548A (en) * 1986-05-02 1994-12-20 Genentech, Inc. Methods and compositions for the attachment of proteins to liposomes using a glycophospholipid anchor
DE4107154A1 (de) * 1990-10-11 1992-04-16 Boehringer Mannheim Gmbh Monoklonale antikoerper gegen melanom
US5639863A (en) * 1994-06-21 1997-06-17 Dan; Michael D. Human monoclonal antibodies specific to cell cycle independent glioma surface antigen
GB9822115D0 (en) * 1998-10-09 1998-12-02 King S College London Treatment of inflammatory disease
US7049132B1 (en) * 1999-06-28 2006-05-23 University Of Southern California Stress-responsive induction of a therapeutic agent and methods of use
US6677442B1 (en) * 1999-10-29 2004-01-13 University Of Kentucky Research Foundation Nucleic acid encoding human REV1 protein
AU2002325164B2 (en) * 2001-07-24 2008-12-04 Debiovision Inc. Receptor, the use thereof, and mouse antibodies
DE10230516A1 (de) * 2002-07-06 2004-01-15 Müller-Hermelink, Hans Konrad, Prof. Dr. Humaner monoklonaler Antikörper
WO2005001052A2 (en) * 2003-06-06 2005-01-06 University Of Massachusetts Modulation of apoptosis

Non-Patent Citations (1)

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Title
See references of WO2005092922A2 *

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DE102004015179A1 (de) 2005-10-13
WO2005092922A3 (de) 2006-07-27
WO2005092922A2 (de) 2005-10-06
JP2008502321A (ja) 2008-01-31
DE112005001260A5 (de) 2007-05-31
US20080281083A1 (en) 2008-11-13

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