WO2008002285A1 - Anticorps igy contre la transcriptase inverse de la télomérase humaine - Google Patents

Anticorps igy contre la transcriptase inverse de la télomérase humaine Download PDF

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Publication number
WO2008002285A1
WO2008002285A1 PCT/US2006/024750 US2006024750W WO2008002285A1 WO 2008002285 A1 WO2008002285 A1 WO 2008002285A1 US 2006024750 W US2006024750 W US 2006024750W WO 2008002285 A1 WO2008002285 A1 WO 2008002285A1
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antibody
htert
igy
specifically binds
antibodies
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PCT/US2006/024750
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English (en)
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Yan Xiao
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Science Applications International Corporation
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    • 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
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
    • C07K2317/11—Immunoglobulins specific features characterized by their source of isolation or production isolated from eggs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/23—Immunoglobulins specific features characterized by taxonomic origin from birds

Definitions

  • the invention relates to IgY antibodies to human telomerase reverse transcriptase (hTERT) and their therapeutic and diagnostic uses.
  • telomere length is determined by telomerase, an RNA-dependent DNA polymerase. When active, telomerase lengthens one chain of the telomere repeating sequence and maintains the length of the telomere.
  • Human telomerase is a complex which comprises two structural units: human telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT).
  • hTR is an RNA molecule that forms the template for extending a strand of the telomere DNA.
  • hTERT is an enzyme subunit that catalyzes the template-dependent polymerization reaction.
  • telomere length shortens with each division.
  • the telomeres of cancer cells do not shorten even with repeated cell division.
  • Cancer cells unlike most normal cells, express telomerase (Shay et ah, Eur. J. Cancer 33, 787, 1997).
  • the expression of telomerase activity in cancer cells is regulated by hTERT (Nakamura et ah, Science 277, 955, 1997; Nakayama et ah, Nature Genetics 18, 65, 1998).
  • hTERT Nemura et ah, Science 277, 955, 1997; Nakayama et ah, Nature Genetics 18, 65, 1998.
  • One embodiment of the invention is a preparation comprising an IgY antibody which specifically binds to human telomerase reverse transcriptase (hTERT).
  • the antibody can be, for example, a polyclonal antibody, a monoclonal antibody, an Fab fragment, an F(ab')2 fragment, a single chain antibody, a minibody, a diabody, a Kappa body, or a Janusin.
  • Some IgY antibodies specifically bind, for example, to an hTERT epitope comprising the amino acid sequence SEQ ID NO:2.
  • Other antibodies specifically bind to an hTERT epitope comprising the amino acid sequence SEQ ID NO:3.
  • the preparation can comprise a pharmaceutically acceptable vehicle.
  • Another embodiment of the invention is a method of detecting hTERT.
  • a biological sample is contacted with an IgY antibody which specifically binds to hTERT. Binding of the IgY antibody to hTERT is detected.
  • the biological sample can comprise cancer cells.
  • the antibody can be, for example, a polyclonal antibody, a monoclonal antibody, an Fab fragment, an F(ab') 2 fragment, a single chain antibody, a minibody, a diabody, a Kappa body, or a Janusin.
  • Some IgY antibodies specifically bind, for example, to an hTERT epitope comprising the amino acid sequence SEQ ID NO:2.
  • Other antibodies specifically bind to an hTERT epitope comprising the amino acid sequence SEQ ID NO:3.
  • Various means can be used to detect binding of the IgY antibody to hTERT, such as a quantum dot detection system.
  • Yet another embodiment of the invention is a method of reducing hTERT reverse transcriptase activity.
  • hTERT is contacted with an IgY antibody which specifically binds to hTERT, thereby reducing hTERT reverse transcriptase activity.
  • the hTERT can be in a cell, and cell can be in vitro or in vivo.
  • the cell can be in a patient who has a cancer.
  • the antibody can be, for example, a polyclonal antibody, a monoclonal antibody, an Fab fragment, an F(ab') 2 fragment, a single chain antibody, a minibody, a diabody, a Kappa body, or a Janusin.
  • Some IgY antibodies specifically bind, for example, to an hTERT epitope comprising the amino acid sequence SEQ ID NO:2.
  • Other antibodies specifically bind to an hTERT epitope comprising the amino acid sequence SEQ ID NO:3.
  • FIG. 1 Photomicrographs showing immunohistochemical detection of hTERT by chicken polyclonal IgY antibodies and mammalian IgG antibodies.
  • FIG. IA Human telomerase detection with IgY antibodies in high telomerase-expressing (A549, left) and control cells (IMR-90, right).
  • FIG. IB Human telomerase detection with mammalian IgG antibodies in high telomerase-expressing cells (A549, left) and cells that express telomerase at very low levels (IMR-90, right).
  • FIG. 2 Deconvolution image processing planes (top four panels, left and right) of cells for telomerase expression in high telomerase-expressing cells (A549, left stack) and very low-telomerase expressing cells (IMR-90, right stack). The total in-focus fluorescence is represented on the bottom grids for high telomerase expressing cells (A549, left bottom) and control cells (IMR-90, right bottom). These are the same cell images as in FIG. IA.
  • FIG. 3 Bar graph showing results of quantum dot imaging of antibody-hTERT binding using IgY and IgG antibodies in high telomerase expressing cells (A549) and control cells (IMR-90).
  • FIG. 4 Telomerase in Western blots as detected by IgM (top panel), IgG (second from top), and IgY (third from top). The lowest panel shows the ⁇ -actin control. See Example 5.
  • FIG. 5 Histogram comparing the relative affinity for hTERT of three antibodies (IgY, IgG, IgM) in a layered peptide array assay (see Example 7). DETAILED DESCRIPTION OF THE INVENTION
  • the invention provides immunoglobulin Y (IgY) antibodies which specifically bind to human telomerase reverse transcriptase (hTERT).
  • IgY antibody as used herein includes intact polyclonal or monoclonal IgY molecules; IgY fragments, such as monomelic and dimeric Fab, F ⁇ b) 2 , scFv, and Fv; and non-naturally occurring molecules such as diabodies, mmibodies, Kappa bodies, Janusins, and the like.
  • Naturally occurring IgY antibodies are produced in egg-laying non-mammalian vertebrates (e.g., chickens, ducks, geese, snakes, urodele amphibians).
  • IgY antibodies provide significant advantages when compared with previously generated mammalian antibodies with specificity for hTERT.
  • IgY antibodies do not react with rheumafactors, human Fc receptors, bacterial Fc receptors, or human anti-mouse IgG antibodies, which makes them very safe for therapeutic use.
  • IgY antibodies of the invention in particular are surprisingly more sensitive than commercially available mammalian hTERT antibodies and can be used, inter alia, in early cancer diagnostic test platforms and as therapeutic agents for treating cancer and benign proliferative diseases in which hTERT is expressed.
  • IgY antibodies of the invention comprise an hTERT binding site and specifically bind to hTERT.
  • "hTERT binding sites" as used herein include hTERT binding sites which naturally occur in the variable portion of IgY antibodies. hTERT binding sites also include binding sites which differ from naturally occurring hTERT binding sites by between 1 and 15 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) conservative amino acid substitutions and which specifically bind to hTERT.
  • an IgY antibody which specifically binds to hTERT provides a detection signal at least 5-, 10-, or 20-fold higher than a detection signal provided with a non-hTERT human antigen when used in an immunochemical assay.
  • IgY antibodies which specifically bind to hTERT do not detect other human proteins in immunochemical assays and can immunoprecipitate hTERT from solution.
  • Preferred IgY antibodies of the invention reduce hTERT reverse transcriptase activity (e.g., by 10, 20, 25, 30, 40, 50, 60, 70, 75, 80, 90, or 100%). Enzyme activity can be measured as described in Soldateschi et al, J. Biotechnol. 118, 370-78, 2005
  • High affinity IgY antibodies are preferred, such as those which bind to hTERT with at least 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-fold higher affinity than an IgG or IgM hTERT antibody.
  • the affinity of IgY antibody binding to hTERT can be assayed using any method known in the art, including technologies such as layered peptide arrays (see Example 7) and surface plasmon resonance (Day et al, Protein Science 11, 1017-25, 2002; Sjolander & Urbaniczky, Anal. Chem. 63, 2338-45, 1991; Szabo et al, Curr. Opin. Struct. Biol. 5, 699-705, 1995).
  • Polyclonal IgY antibodies of the invention can be produced in egg-laying non- mammalian vertebrates, such as fowl ⁇ e.g., chickens, ducks, geese), snakes, or urodele amphibians ⁇ e.g., axolotls, newts), after immunizing the animal with an hTERT epitope or a nucleic acid molecule encoding an hTERT epitope ⁇ see, e.g., Romito et al, Biotechniques Sep;31(3):670, 672, 674-75, 2001).
  • Preferred hTERT epitopes include amino acids 165-348 (SEQ ID NO:2) and amino acids 227-338 (SEQ ID NO:3). Amino acids 165-348 are exposed on the outer surface of hTERT and, compared with the rest of the hTERT protein, have lower homology with TERT proteins of other species. Full-length hTERT (SEQ ID NO:1) also can be used as an immunogen.
  • One method of producing IgY polyclonal antibodies in chickens is described in Example 1, below.
  • Monoclonal IgY antibodies ⁇ e.g., full-length, scFv, Fv) can be prepared using any technique which provides for the production of antibody molecules by continuous cell lines in culture. These techniques include, but are not limited to, the hybridoma technique, the human B-cell hybridoma technique, and the EBV-hybridoma technique. See Roberge et al, Science 269, 202-204, 1995; Kohler et al, Nature 256, 495-497, 1985; Kozbor et al., J. Immunol. Methods 81, 31-42, 1985; Cote et al., Proc. Natl. Acad. Sd.
  • Single chain antibodies can be generated by chain shuffling from random combinatorial IgY libraries. Takeda et al., Nature 314, 452-454, 1985.
  • Single-chain antibodies also can be constructed using a DNA amplification method, such as PCR, using hybridoma cDNA as a template.
  • Single-chain antibodies can be mono- or bispecific, and can be bivalent or tetravalent. Construction of tetravalent, bispecific single-chain antibodies is well known in the art.
  • a nucleotide sequence encoding a single-chain antibody can be constructed using manual or automated nucleotide synthesis, cloned into an expression construct using standard recombinant DNA methods, and introduced into a cell to express the coding sequence.
  • single-chain antibodies can be produced directly using, for example, filamentous phage technology. Burton et al, Proc. Natl Acad.
  • IgY antibodies of the invention can be purified from any cell which expresses the antibodies, including host cells which have been transfected with IgY antibody- encoding nucleic acid molecules.
  • the host cells are cultured under conditions suitable for expression of the IgY antibodies. Appropriate host cells and culture conditions can ⁇ selected from the wide variety known in the art.
  • Purified IgY antibodies are separated from other compounds that normally associate with the antibody in the cell, such as certain proteins, carbohydrates, or lipids. Purification methods include, but are not limited to, size exclusion chromatography, ammonium sulfate fractionation, ion exchange chromatography, affinity chromatography, and preparative gel electrophoresis.
  • a preparation of purified IgY antibodies is at least 80% pure; preferably, the preparations are 90%, 95%, or 99% pure. Purity of the preparations can be assessed by any means known in the art, such as SDS-polyacrylamide gel electrophoresis.
  • a preparation of purified IgY antibodies of the invention can contain more than one type of IgY antibody which specifically binds to hTERT.
  • Any IgY antibody of the invention also can be produced using chemical methods to synthesize its amino acid sequence, such as by direct peptide synthesis using solid- phase techniques (Merrifield, J. Am. Chem. Soc. 85, 2149-54, 1963; Roberge et al., Science 269,. 202-04, 1995). Protein synthesis can be performed using manual techniques or by automation. Automated synthesis can be achieved, for example, using Applied Biosystems 43 IA Peptide Synthesizer (Perkin Elmer).
  • fragments of IgY antibodies can be separately synthesized and combined using chemical methods to produce a full-length molecule.
  • the newly synthesized molecules can be substantially purified by preparative high performance liquid chromatography (e.g., Creighton, PROTEINS: STRUCTURES AND MOLECULAR PRINCIPLES, WH Freeman and Co., New York, N.Y., 1983).
  • the composition of a synthetic polypeptide can be confirmed by amino acid analysis or sequencing (e.g., using Edman degradation).
  • IgY antibodies of the invention can be used diagnostically, to detect telomerase- expressing cells in a biological sample.
  • biological samples include, but are not limited to, samples of blood or other body fluid (e.g., body fluid urine, sputum, etc.) or solid tissue (e.g., surgical biopsies, forensic samples), cell lines, and primary cell cultures.
  • Any detection methods known in the art can be used to detect binding of IgY antibodies to hTERT. These methods include, but are not limited to, Western blots, ELISAs, radioimmunoassays, immunohistochemical assays, immunoprecipitation, and other immunochemical assays known in the art. Detection can be qualitative or quantitative. In some embodiments, binding of IgY antibodies to hTERT is detected using streptavidin-conjugated semiconductor nanocrystals as described in Example 4. Use of such "quantum dot" detection systems readily permits quantitative immunohistochemistry staining.
  • Preferred methods of the invention include detection and quantification of hTERT- antibody binding using quantum dot detection systems; z-plane fluorescence image capture using three dimensional-deconvolution microscopy (e.g., Chamgoulov & MacAulay, Cell Oncol. 26, 319-27, 2004; Hollars & Dunn, Biophys. J. 75, 342-53, 1998); high-throughput, automated robotic slide processing; and affinity estimates using quantitative, massively parallel, high-throughput analysis of peptide antigen- antibody interactions using a layered peptide array (LPA) technology (Gannot et ah, J. MoI. Diagn. 7, 427-36, 2005).
  • LPA layered peptide array
  • Methods of detecting hTERT using IgY antibodies according to the invention provide more information than, for example, telomere repeat amplification protocol (TRAP) and RT-PCR assays, in which cell structure is destroyed.
  • assays of the invention can detect telomerase expressed in very small cell populations, including in a single cell.
  • Preferred IgY antibodies of the invention reduce hTERT reverse transcriptase activity and can be provided in a pharmaceutical composition to treat cancer and other proliferative diseases in which hTERT is expressed in a mammal, preferably a human.
  • an IgY antibody of the invention can be conjugated to a T-cell epitope, a toxin, or a radionuclide-binding peptide or protein to bring a killing function close to the cancer cells.
  • Cancers which can be treated include, but are not limited to, blood cancers ⁇ e.g., leukemias, lymphomas) and cancers of solid tissues (e.g., bladder, bone, brain, breast, cervix, colon, esophagus, kidney, liver, lung, pancreas, prostate, stomach).
  • blood cancers e.g., leukemias, lymphomas
  • solid tissues e.g., bladder, bone, brain, breast, cervix, colon, esophagus, kidney, liver, lung, pancreas, prostate, stomach.
  • compositions comprising IgY antibodies of the invention.
  • Aqueous isotonic solutions such as saline or corresponding plasma protein solutions, are readily available and can be used to prepare ready-to-use solutions for parenteral injection or infusion.
  • Pharmaceutical compositions can be stored as lyophylisates or dry preparations, which can be reconstituted with a known injectable solution before use.
  • a pharmaceutical composition can be supplemented with known carrier substances or/and additives (e.g., serum albumin, dextrose, sodium bisulfite, EDTA, etc.).
  • Pharmaceutical compositions of the invention typically comprise a pharmaceutically acceptable vehicle, such as an inert diluent.
  • compositions of the invention can be administered by different routes known to those skilled in the art.
  • the intravenous, intravascular, intramuscular, intraarterial, intraperitoneal, oral, intranodal, or intrathecal routes can be used.
  • More localized application can be effected subcutaneously, intracutaneously, intracardially, intralobally, intramedullarly, intrapulmonarily, or directly in or near the tissue to be treated.
  • compositions may be administered once or several times, for example on a daily basis for several days, weeks or months, and in different dosages.
  • Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 5O (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 /ED 50 .
  • Antibodies which exhibit large therapeutic indices are preferred.
  • Appropriate doses preferably lie within a range of circulating antibody concentrations which includes the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Doses can range from 1 ng/kg to 100 mg/kg and will depend on age, condition, sex and extent of the disease in the patient. For example, doses can vary from 5 ⁇ g/kg to about 50 ⁇ g/kg, about 50 ⁇ g/kg to about 5 mg/kg, about 100 ⁇ g/kg to about 500 ⁇ g/kg, and about 200 ⁇ g/kg to about 250 ⁇ g /kg of patient body weight.
  • telomerase GeneBank No. NP_003210.1; SEQ ID NO:1
  • amino acids 165-348 SEQ ID NO:2
  • CFA Complete Freund's Adjuvant
  • Booster inoculations were performed at 2-3 weeks interval with 100 ⁇ g antigen in Incomplete Freund's Adjuvant (IFA) for three inoculation cycles.
  • Antibodies were isolated from eggs collected after a second boost with polyethylene glycol (PEG) (Poison et al., Immunol. Cornmun. 9, 475-93, 1980). Eggs were collected after second boost. Antibodies were isolated from egg yolk using polyethylene glycol (PEG) precipitation method (Poison et al, Immunol. Commun. 9, 475-93, 1980). The antibodies were purified by affinity chromatography using the polypeptide immunogen as the affinity ligand.
  • PEG polyethylene glycol
  • A549 cells have high telomerase levels.
  • IMR-90 cells have low telomerase levels. Telomerase activity and transcript levels in these cell lines were determined by TRAP and RT-PCR assays, respectively (Atha et al, Electrophoresis. 24, 109-14, 2003; Jakupciak et al, Clinical Chemistry 51, 1-9, 2005).
  • Immunohistochemistry substrates were prepared by two methods. In one method, fixed monolayers were pre-blocked with 5% low-fat dry milk in PBS, 2O 0 C, for 20 minutes, slides were incubated manually with primary antibody (1:300 dilution), biotin-labeled secondary antibody (1:300 dilution), and detection reagents (streptavidin-Qdot605, Qdot Corporation/Invitrogen). In the other method (high-throughput), slides were prepared robotically (primary, secondary antibodies, and washes) with a Ventana BENCHMARK ® XT workstation (Ventana, Arlington, Arizona ) (Bankfalvi et al., Int J Oncol. 25, 929-3, 2004).
  • IgY antibodies were detected by biotin-labeled anti-IgY antibodies followed by semiconductor nanocrystal fluorophore streptavidin conjugates (Qdot Corporation).
  • the imaging system for three-dimensional analysis of fluorescence signals from quantum dots, deconvolution of z-plane (depth) images, and integration of the signal are described in Xiao et al., Nature Methods 2, 723, 2005.
  • Semiconductor nanocrystal fluorophores (quantum dots 605) signals were visualized on an Olympus BH2 RCFA microscope equipped with Qdot605 filters (Chroma Technology, Inc., E460SPUV exciter, 475CXRU dichroic, D605/40 emitter).
  • the blots were incubated with primary antibodies (1:1000 dilution) overnight at 4 0 C at antibody concentrations of 0.5, 1, 2, 4, 8, and 16 ⁇ g/ml. The blots were then washed and incubated with horseradish peroxidase-conjugated secondary antibodies (1:1000 dilution; goat anti-chicken IgY, GenWay Biotech, Inc., No. GAYFC-HRP; or goat anti-mouse IgG + IgM, Abeam, No. ab6006) for 1 hour at room temperature. After washing with TWEEN ® -PBS, bound antibody was visualized by SIGMAFJSr ⁇ DAB tablet sets (No. D-4293).
  • telomeres were used to detect telomerase in A549 cells (high telomerase expression) and IMR-90 cells (controls).
  • Mouse anti-human telomerase IgM antibodies were from Novus Biologicals (NB 100-297,); the antigen was full-length recombinant human telomerase protein produced in insect cells.
  • IgG2a was obtained from Novocastra (NCL-hTERT); the antigen was a synthetic peptide corresponding to residues 173-320 near the N-terminus of human telomerase.
  • Antibody details are summarized below:
  • the polyclonal IgY antibodies detected epitopes exclusively within the cell nucleus in high telomerase-expressing A549 cells (FIG. IA, left) but not in the control IMR-90 cells (FIG. IA, right).
  • Deconvolution of separate representative stack images of telomerase signals in A549 cells (left) and IMR-90 cells (right) is shown in FIG. 2. Cumulative stack fluorescence is shown on the orientation grids in the lowermost panels of FIG. 2.
  • the nuclear signal in the A549 cells was heterogeneous. Under similar conditions, the mammalian IgG (FIG. IB, left and right) detected a much lower signal in A549 cells.
  • the telomerase-specific IgM elicited almost no detectable signal in A549 cells.
  • Example 4 Western blots were made to determine whether the antibodies tested in Example 4 detected the appropriate sized-target proteins in telomerase expressing cells, but not in control cells.
  • chicken IgY isotype antibody abl3822 specific for human beta-actin was obtained (Abeam) and used at a 1:1000 dilution. The results are shown in FIG. 4.
  • the affinity of the mammalian monoclonal IgG antibody for telomerase was about 30% greater than the affinity of the polyclonal IgY antibodies.
  • the IgY antibodies provided a significantly better signal except at 8 ⁇ g/mL (at this concentration, the IgG and IgY signal had overlapping standard errors). In most cases, the IgY signal was about 30% greater than the signal obtained with the IgG antibody. In this experiment, consistent with immunohistochemistry data, the IgM signal was weak or absent.

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Abstract

Les anticorps IgY qui se lient spécifiquement à la transcriptase inverse de la télomérase humaine (hTERT) peuvent être utilisés pour détecter l'hTERT et ainsi diagnostiquer un cancer. Des préparations des anticorps peuvent être utilisées pour diminuer l'activité de la transcriptase inverse hTERT dans des essais in vitro et peuvent être utilisés en tant que thérapies in vivo pour traiter un cancer.
PCT/US2006/024750 2006-06-26 2006-06-26 Anticorps igy contre la transcriptase inverse de la télomérase humaine WO2008002285A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110212454A1 (en) * 2010-02-26 2011-09-01 Geron Corporation Assay for Telomerase Activity
WO2012147918A1 (fr) * 2011-04-28 2012-11-01 株式会社医学生物学研究所 Anticorps monoclonal pour transcriptase inverse de télomérase humaine
US10765853B2 (en) 2014-12-22 2020-09-08 Cook Medicai Technologies LLC Hemostatic valve system

Citations (2)

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Publication number Priority date Publication date Assignee Title
GB2317891A (en) * 1996-10-01 1998-04-08 Geron Corp hTRT, the reverse transcriptase subunit of human telomerase
WO1998041235A1 (fr) * 1997-03-20 1998-09-24 Immunsystem Ims Ab Utilisation d'anticorps aviaires

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2317891A (en) * 1996-10-01 1998-04-08 Geron Corp hTRT, the reverse transcriptase subunit of human telomerase
WO1998041235A1 (fr) * 1997-03-20 1998-09-24 Immunsystem Ims Ab Utilisation d'anticorps aviaires

Non-Patent Citations (2)

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Title
SCHADE R ET AL: "CHICKEN EGG YOLK ANTIBODIES (IGY-TECHNOLOGY): A REVIEW OF PROGRESS IN PRODUCTION AND USE IN RESEARCH AND HUMAN AND VETERINARY MEDICINE", ATLA. ALTERNATIVES TO LABORATORY ANIMALS, LONDON, GB, vol. 33, no. 2, April 2005 (2005-04-01), pages 129 - 154, XP009057556, ISSN: 0261-1929 *
SHAY J W ET AL: "A Survey of Telomerase Activity in Human Cancer", EUROPEAN JOURNAL OF CANCER, PERGAMON PRESS, OXFORD, GB, vol. 33, no. 5, April 1997 (1997-04-01), pages 787 - 791, XP004282534, ISSN: 0959-8049 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110212454A1 (en) * 2010-02-26 2011-09-01 Geron Corporation Assay for Telomerase Activity
US9249452B2 (en) * 2010-02-26 2016-02-02 Zhu Zhen Pirot Method of detecting and assaying telomerase activity of telomerase bound by anti-telomerase antibodies
WO2012147918A1 (fr) * 2011-04-28 2012-11-01 株式会社医学生物学研究所 Anticorps monoclonal pour transcriptase inverse de télomérase humaine
US10765853B2 (en) 2014-12-22 2020-09-08 Cook Medicai Technologies LLC Hemostatic valve system

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