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WO1986002364A1 - Anticorps monoclonaux et leur utilisation - Google Patents

Anticorps monoclonaux et leur utilisation Download PDF

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Publication number
WO1986002364A1
WO1986002364A1 PCT/GB1985/000475 GB8500475W WO8602364A1 WO 1986002364 A1 WO1986002364 A1 WO 1986002364A1 GB 8500475 W GB8500475 W GB 8500475W WO 8602364 A1 WO8602364 A1 WO 8602364A1
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WO
WIPO (PCT)
Prior art keywords
herpes
monoclonal antibody
antigen
antibody
labeled
Prior art date
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PCT/GB1985/000475
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English (en)
Inventor
Bruce William Wright
Peter John Cox
Alice Margaret Noyes
Danny Widdows
Patricia Winder
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Technology Licence Company Limited
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 Technology Licence Company Limited filed Critical Technology Licence Company Limited
Publication of WO1986002364A1 publication Critical patent/WO1986002364A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/081—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from DNA viruses
    • C07K16/085—Herpetoviridae, e.g. pseudorabies virus, Epstein-Barr virus
    • C07K16/087—Herpes simplex virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • monoclonal antibodies specific for the antigens or species of Herpes are desired which when used will rapidly diagnose the presence of such organisms in specimens.
  • Herpes species have been made among the Herpes species. Some of the representative members include Herpes . zoster. Herpes simplex, and Herpes hominis (inc. Types I and II) .
  • Herpes hominis (specifically Type II), as it is one of the best known species.
  • Herpes hominjs Type II is a virus in the western world with a widespread, often chronic recurrence, and genitally transmitted infection characterized by recurrent painful blisters of the genital region. It may be transmitted in the newborn child with often devastating results, including retardation and death.
  • Present methods of detec ⁇ tion include clinical signs (insensitive), culture (slow and costly), or clinical signs and direct
  • isotopic and nonisotopic immunoassays have been utilized in conjunction with monoclonal antibodies to test for the pres ⁇ ence of an antigenic substance.
  • agglutination, immuno-fluorescent, chemilum- inescent or fluorescent immunoassay, immuno- electron microscopy, radiometric assay systems, radio immunoassays, and enzyme-linked immunoassays are the most common techniques used with the monoclonal antibodies. Other techniques include bioluminescent, fluorescence polarization, and photon-counting immunoassays.
  • the enzyme-linked immunoassay procedure EIA
  • the enzyme-linked monoclonal antibody can then be used in the known enzyme-linked immunosor- bent assay procedure to determine the presence of an antigenic substance.
  • the serotype of the infecting organism can be determined, and appropriate treatment can then be initiated to rapidly and efficiently eliminate the disease.
  • the present invention provides novel mono ⁇ clonal antibodies for use in accurately and rapidly diagnosing samples for the presence of Herpes antigens and/or organisms.
  • the present invention com ⁇ prises monoclonal antibodies specific for an antigen or species of Herpes; in particular, the antigens or species of Herpes hominus, spe ⁇ cifically Type II, which applicant has further divided into four subgroups: E . hominus Type 11(1), H_. hominus Type 11(2), H_. ' hominus Type 11(3), and HL hominus Type 11(4); Herpes simplex; and Herpes zoster, as well as a monoclonal anti ⁇ body broadly cross-reactive with an antigen for each species of the genus Herpes.
  • the invention also comprises labeled mono ⁇ clonal antibodies for use in diagnosing the presence of the Herpes antigens, each comprising a monoclonal antibody against one of the above- mentioned antigens to Herpes or to a particular species thereof and linked thereto an appro ⁇ priate label.
  • the label can be chosen from the group consisting of a radioactive isotope, enzyme, fluorescent compound, chemilumines- cent compound, bioluminescent compound, ferromag ⁇ netic atom, or particle, or any other label.
  • the invention further comprises the process for diagnosing the presence of Herpes anti ⁇ gens or organisms in a specimen comprising con ⁇ tacting said specimen with the labeled monoclonal antibody in an appropriate immunoassay procedure.
  • the invention is also directed to a therapeutic composition
  • a therapeutic composition comprising a mono ⁇ clonal antibody for an antigen of Herpes and a carrier or diluent, as well as kits contain ⁇ ing at least one labeled monoclonal antibody to an antigen of a Herpes.
  • the monoclonal antibodies of the present invention are prepared by fusing spleen cells, from a mammal which ' has been immunized agaiast the particular Herpes antigen, with an appropri ⁇ ate myeloma cell line, preferably NSO (uncloned), P3NS1-Ag4/1, or Sp2/0 Agl4.
  • the resultant product is then cultured in a standard HAT (hypoxanthine, aminopterin, and thymidine) medium. Screening tests for the specific monoclonal antibodies are employed utilizing immunoassay techniques which will be described below.
  • the immunized spleen cells may be derived from any mammal, such as primates, humans, rodents (i.e., mice, rats, and rabbits), bovine, ovine, canine, or the like, but the present invention will be described in connection with mice.
  • the mouse is first immunized by injection of the particular Herpes antigen chosen generally for a period of approximately eleven weeks. When the mouse shows sufficient antibody produc- tion against the antigen, as determined by conven ⁇ tional assay, it is given a booster injection of the appropriate Herpes antigen, and then killed so that the immunized spleen may be remov ⁇ ed. The fusion can then be carried out utilizing immunized spleen cells and an appropriate myeloma cell line.
  • the fused cells yielding an antibody which give a positive response to the presence of the particular Herpes antigen are removed and cloned utilizing any of the standard methods.
  • the monoclonal antibodies from the clones are then tested against standard antigens to determine their specificity for the particular Herpes antigen.
  • the . monoclonal antibody selected, which is specific for the particular Herpes antigen or species, is then bound to an appropri ⁇ ate libel.
  • Amounts of antibody sufficient for labeling and subsequent commercial production are produced by the known techniques, such as by batch or continuous tissue culture or culture in vivo in mammals, such as mice.
  • the monoclonal antibodies may be labeled with a multitude of different labels, such as enzymes, fluorescent compounds, luminescent compounds, radioactive compounds, ferromagnetic labels, and the like.
  • labels such as enzymes, fluorescent compounds, luminescent compounds, radioactive compounds, ferromagnetic labels, and the like.
  • the present invention will be described with reference to the use of an enzyme labeled monoclonal antibody.
  • Some of the enzymes utilized as labels are alkaline phosphatase, glucose oxidase, galactosidase, peroxidase, or urease, and the like.
  • Such linkage with enzymes can be accomplished by any one of the conventional and known methods, such as the Staphylococcal Protein A method, the glutaraldehyde method, the benzoquinone method, or the periodate method.
  • EIA enzyme- linked immunosorbent assay
  • a nonlabeled antigen and a specific antibody are combined with identical fluorescently labeled antigen. Both labeled and unlabeled antigen compete for antibody binding sites. The amount of labeled antigen bound to the antibody is dependent upon, and therefore a measurement of, the concentration of nonlabeled antigen.
  • Examples of this particular type of fluorescent- i munoassay would include heterogenous systems such as Enzyme-Linked Fluorescent Immunoassay, or homogeneous systems such as the Substrate Labeled Fluorescent Immunoassay. The most suit- able fluorescent probe, and the one most widely used is fluorescein. While fluorescein can be subject to considerable interference from scattering, sensitivity can be increased by the use of a fluorometer optimized for the probe utilized in the particular assay and in which the effect of scattering can be minimized.
  • Fluorescence polarization In fluorescence polarization, a labeled sample is excited with polarized light and the degree of polarization of the emitted light is measured. As the antigen binds to the antibody its rotation slows down and the degree of polari- zation increases. Fluorescence polarization is simple, quick, and precise. However, at the present time its sensitivity is limited to the micromole per liter range and upper nano- mole per liter range with respect to antigens in biological samples.
  • Luminescence is the emission of light by an atom or molecule as an electron is transferred to the ground state from a higher energy state.
  • the free energy of a chemical reaction provides the energy required to produce an inter ⁇ mediate reaction or product in an electronically excited state. Subsequent decay back to the ground state is accompanied by emission of light.
  • Bioluminescence is the name given to a special form of chemiluminescenre found in biological systems, in which a catalytic protein or enzyme, such as luciferase, increases the efficiency of the luminescent reaction.
  • the best known chemiluminescent substance is luminol.
  • a further aspect of the present invention is a therapeutic composition
  • a therapeutic composition comprising one or more of the monoclonal antibodies to the particular Herpes antigen or species, as well as a pharmacologically acceptable carrier or diluent.
  • Such compositions can be used to treat humans and/or animals afflicted with some form of Herpes infections and they are used in amounts effective to cure; an amount which will vary widely dependent upon the individual being treated and the severity of the infection.
  • One or more of the monoclonal antibodies can be assembled into a diagnostic kit for use in diagnosing for the presence of an antigen, antigens, or species of Herpes in various speci ⁇ mens.
  • a rapid diagnostic method requiring limited technical skill could be widely used to screen pregnant mothers and all persons with genital lesions, as well as infants suspected of neonatal infections.
  • the broadly cross-reactive monoclonal antibody which can identify the genus Herpes alone or as part of a kit containing antibodies that can identify other bacterial genera or species of Herpes and/or other bacteria.
  • kits In the past there have been difficulties in developing rapid kits because of undesirable cross-reactions of specimens with antiserum.
  • the use of monoclonal antibodies can eliminate these problems and provide highly specific and rapid tests for diagnosis.
  • a rapid and precise kit could replace or augment existing tests and permit early direct therapy using precise antibiotics. Avoiding multiple antibiotics or more expensive or hazardous antibiotics would represent substantial patient and hospital sav ⁇ ings.
  • a kit can be used on an out-patient basis. At present the lack of a rapid test giving "same day" answers may delay the initiation of treatment until the patient has developed more severe symptoms or may require the initiation of more costly therapy in a sick patient. A test that would return results within an hour or two would be a substantial convenience to patients.
  • kit could be included as a component in a comprehensive line of compatible immunoassay reagents sold to reference laboratories to detect the species and serotypes of Herpes.
  • kits comprising at least one labeled monoclonal antibody against a particular Herpes antigen or species, as well as any appropriate stains, counterstains , or reagents.
  • Specific antigens to be detected in this kit include the antigens of Herpes hominus (specifically Type II, which applicant has further divided into four subgroups) ; Herpes simplex; and Herpes zoster.
  • Monoclonal diagnostics which detect the presence of Herpes antigens can also be used in periodic testing of water sources, food sup ⁇ plies and food processing operations.
  • the present invention describes * the use of the labeled monoclonal antibodies to determine the presence of a standard antigen
  • the invention can have many applications in diagnosing the presence of . antigens by determining whether specimens such as urine, blood, stool, water, milk, and the like contain the particular Herpes antigen. More particularly, the invention could be utilized as a public health and safety diagnos ⁇ tic aid, whereby specimens such as water or food could be tested for possible contamina ⁇ tion.
  • API Analytical Profile Index (ref. Ayerst Labs)
  • DMEM Dulbecco's Modified Eagles Medium
  • FCS Foetal Calf Serum
  • PBS phosphate-buffered saline pfu - plaque-forming units
  • % T refers to vaccine concentration measured in a 1 cm light path
  • Monoclonal antibodies of the present invention are prepared generally according to the method of Koehler and Milstein, Eur. J. Immunol. 6_, (1975) 292.
  • EXAMPLE 1 A. Animal Immunisation
  • mice are injected with prepared Herpes hominis Type II antigen. They are given intraperitoneal and/or intravenous injections (0.05 ml 80% T vaccine) of vaccine prepared as above. The mice are bled approximately six days after the last injection and the serum tested for antibodies by assay. A conventional assay used for this serum titer testing is the enzyme-linked immunosorbent assay system. When the mice show ai tibody production after this regimen, generally a positive titer of at least 10,000, a mouse is selected as a fusion donor and given a booster injection (0.02 ml 80% T vaccine) intravenously, three days prior to splenectomy. B.
  • Cell Fusion Spleen cells from the immune mice are harvested three days after boosting, by conventional techniques.
  • the donor mouse selected is killed and surface-sterilised by immersion in 70% ethyl alcohol.
  • the spleen is then removed and immersed in approximately 2.5 ml DMEM to which has been added 3% FCS.
  • the spleen is then gently homogenised in a LUX homogenising tube until all cells have been released from the membrane, and the cells are washed in 5 ml 3% FCS-DMEM.
  • the cellular debris is then allowed to settle and the spleen cell suspension placed in a 10 ml centrifuge tube.
  • the debris is then rewashed in 5 ml 3% FCS-DMEM. 50 ml suspension are then made in 3% FCS-DMEM.
  • the myeloma cell line used is NSO (uncloned) , obtained from the MRC Laboratory of Molecular Biology in Cambridge, England.
  • the myeloma cells are in the log growth phase, and rapidly dividing.
  • Each cell line is washed using, as tissue culture medium, DMEM containing 3% FCS.
  • the spleen cells are then spun down at the same time that a relevant volume of myeloma cells are spun down (room temperature for 7 minutes at 600 g) , and each resultant pellet is then separately resuspended in 10 ml 3% FCS-DMEM.
  • 0.1 ml of the suspension is diluted to 1 ml and a haemacytometer with phase microscope is used.
  • 0.1 ml of the suspension is diluted to 1 ml with Methyl Violet-citric acid solution, and a haemacytometer and light microscope are used to count the. stained nuclei of the cells.
  • 1 x 10 8 Spleen cells are then mixed with 5 x 107 myeloma cells, the mixture washed in serum-free DMEM hig in glucose, and centrifuged, and all the liquid removed.
  • the resultant cell pellet is placed in a 37°C water-bath.
  • each well contains 1.0 ml of the standard HAT medium (hypoxanthine, aminopterin and thymidine) and a feeder layer of Balb/c
  • the wells are kept undisturbed, and cultured at 37°C in 9% CO- air at approximately 100% humidity.
  • the wells are analysed for growth, utilising the conventional inverted microscope procedure, after about 5 to 10 days.
  • screening tests for the specific monoclonal antibody are made utilising the conventional enzyme immunoassay screening method described below. Somewhere around 10 days to 14 days after fusion, sufficient antibody against .the antigen may develop in at least one well.
  • the monoclonal antibodies from the clones are screened by the standard techniques for binding to the antigen, prepared as in the immunisation, and for specificity in a test battery of Herpes hominis Types I and II.
  • the EIA immunoassay noted above may be used.
  • DMEM-10% FCS was used to support growth in mid-log phase, to 1 litre volume. The culture was then allowed to overgrow, to allow maximum antibody production. The culture was then centrifuged at 1200 g for approximately 10 minutes, the cells discarded and the antibody-rich supernatant collected.
  • TRIS buffered supernatant was applied at a flow rate of 1 ml/min to a 1 ml column of Protein A-S.epharose, previously equilibrated with 0.1M TRIS buffer, pH 8.2. The column was then washed with 40 ml of 0.1M TRIS buffer.
  • the monoclonal antibody was eluted with citrate buffer (0.1M sodium " citrate, pH 3.5) into sufficient- 1M TRIS buffer, pH 9.0, to raise the pH immediately to about 7.5.
  • the eluate was dialysed in PBS, pH 7.4, at 4 C, and stored at -20 C.
  • the monoclonal antibody specific against the antigen, prepared as above, is linked to an enzyme, viz. highly-purified alkaline phosphatase.
  • alkaline phosphatase (Sigma Type VII-T) were dialysed against 2 x 500 ml of 0.25 M sodium phosphate buffer, pH 6.0, at +4 C. 18 mg p-benzoquinone were dissolved in 0.6 ml warm AR ethanol, and added to the dialysed. alkaline phosphatase. The benzoquinone/alkaline phosphatase mixture was left in the dark at room temperature for 1 hour. Unreacted benzoquinone and reaction by-products were then removed and the buffer exchanged by gel filtration on a Pharmacia PD-10 (Sephadex G-25M) column previously equilibrated in 0.15M sodiu chloride.
  • the benzoquinone-activated alkaline phosphatase thus produced was sufficient for six 1.5 mg antibody conjugations.
  • Monoclonal antibody was dialysed against 2 x 500 ml of 0.15M sodium chloride at +4 C. Dialysed antibody was added to 4 mg of benzoquinone- activated alkaline phosphatase and immediately followed by sufficient 1M sodium bicarbonate to give a final concentration of 0.1M.
  • the conjugation mixture was left in the dark at +4 C for 48 hours. Sufficientl 1M lysine was then added to give a final concentration of 0.1M. After 2 hours in the dark at room temperature, the conjugate was dialysed against 2 x 1000 ml PBS + 0.02% sodium azide at +4 C. An equal volume of glycerol was added. The conjugate was sterile-filtered through a 0.22 ⁇ m membrane filter into .a sterile amber vial, and stored at +4 C.
  • Example i The general procedure of Example i was followed in each of 5 cases, with the following differences: Herpes simplex virus type 1 was used in the antigen in Examples 2 and 3, Herpes simplex virus type 2 in Examples 4 and 5, and Herpes simplex virus (common antigen) in Example 6. All these antigens were obtained from Cambridge University; their strain titles are HSVl, HSV2 and HSV . They were prepared by growth in baby hamster kidney cells; the preparation sequence in Example 6 involved harvesting, disruption etc.
  • the animal immunisation step in Examples 2 and 3 comprised 10 5 pfu subcutaneously, 105 pfu ip after 3 weeks and 10 pfu iv after a further 4 weeks.
  • Example 6 L ear and 10 pfu iv after 2 weeks.
  • immunised mice were supplied.
  • I Inn Example 4 1.25 x 10 spleen cells were used for fusion.
  • Antibody production in Example 6 was conducted as follows:
  • Balb/c mice were primed with pristane for at least 7 days, and were then injected with 10 cells of the monoclonal antibody-producing cell line. Ascitic fluid was harvested when the mice were swollen with fluid but still alive. The fluid was centrifuged at 1200 g for approximately 10 minutes, the cells discarded and the antibody-rich ascites collected and stored at -20 C.
  • Antibody purification in Example 6 was conducted as follows: Balb/c mice were primed with pristane for at least 7 days, and were then injected -with 10 cells of the monoclonal antibody-producing cell line. Ascitic fluid was harvested when the mice were swollen.with fluid but still alive. The fluid was centrifuged at 1200 g for approximately 10 minutes, the cells discarded and the antibody-rich ascites collected and stored at -20 C.
  • Antibody conjugation in Examples 3 to 6 was conducted as follows: monoclonal antibody was dialysed with alkaline phosphatase (Sigma Type VII-T) , against 2 x 1000 ml of phosphate buffered saline (PBS), pH 7.4 at +4 C. After dialysis the volume was made up to 2.5 ml with PBS and 25 ⁇ l of a 20% glutaraldehyde in PBS solution added. The conjugation mixture was left at room temperature for 1.5 hours. After this time glutaraldehyde was removed by gel filtration on a Pharmacia PD-10 (Sephadex G-25M) column, previously equilibrated in PBS. The conjugate was eluted with 3.5 ml PBS.
  • the conjugate was then dialysed vs 2 x 2000 ml of TRIS buffer (50 mM TRIS, 1 mM magnesium chloride, pH 8.0 + 0.02% sodium azide) at +4 C.
  • TRIS buffer 50 mM TRIS, 1 mM magnesium chloride, pH 8.0 + 0.02% sodium azide
  • To the dialysed conjugate was added 1/lOth its own volume of 10% BSA in TRIS buffer.
  • the conjugate was then sterile filtered through a 0.22 ⁇ m membrane filter into a sterile amber vial and stored at +4 C.
  • the antibody of Example 2 was specific to HSV type 1 gD glycoprotein, of Example 3 to type 1 gC, of Examples 4 and 5 to 2gC, and of Example 6 to types 1 and 2.
  • the antibodies were negative to other organisms, specifically E .
  • Example 4 coli, Salmonella and Klebsiella (Examples 2, 3, 4 and 6), Shigella (Examples 2, 3 and 6), Pseudomonas (Examples 4 and 6) and Enterobacter (Example 4) .
  • Example 7 The general procedure of Example 1 may be followed to produce a monoclonal antibody broadly cross-reactive with an antigen of all types of the Herpes virus.
  • Tests using the present invention are superior to existing tests, based on the following advantages: (i) greater accuracy; (ii) same day results, within an hour or two; (iii) reduction in amount of skilled labour required to administer laboratory procedures, resulting in reduced labour costs; (iv) reduction in laboratory time and space used in connection with tests, resulting in reduced overhead expenses; and (v) improved therapy based upon early, precise diagnosis.

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Abstract

Anticorps monoclonaux pour le genre Herpès, anticorps marqués, compositions et kits les contenant, et leur utilisation pour le diagnostic et le traitement d'antigènes.
PCT/GB1985/000475 1984-10-19 1985-10-16 Anticorps monoclonaux et leur utilisation WO1986002364A1 (fr)

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GB848426467A GB8426467D0 (en) 1984-10-19 1984-10-19 Monoclonal antibodies
GB8426467 1984-10-19

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0321249A2 (fr) * 1987-12-15 1989-06-21 Toa Nenryo Kogyo Kabushiki Kaisha Agent et procédé de diagnostic d'une infection par le virus varicella zoster
US5444041A (en) * 1991-04-19 1995-08-22 Ibah, Inc. Convertible microemulsion formulations
US12281151B2 (en) 2018-06-29 2025-04-22 City Of Hope CD6 targeted chimeric antigen receptors for treatment of certain autoimmune disorders

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US5877016A (en) 1994-03-18 1999-03-02 Genentech, Inc. Human trk receptors and neurotrophic factor inhibitors
EP1941905A1 (fr) 1998-03-27 2008-07-09 Genentech, Inc. Synergie d'anticorps APO-2 ligand-anti-her-2
US7288390B2 (en) 2000-08-07 2007-10-30 Centocor, Inc. Anti-dual integrin antibodies, compositions, methods and uses
CA2420325A1 (fr) 2000-08-25 2002-02-28 Basf Plant Science Gmbh Polynucleotides vegetaux codant de nouvelles proteases prenyle
AU2003213729A1 (en) 2002-03-05 2003-09-22 Board Of Regents, The University Of Texas System Biospecific contrast agents
US20150017671A1 (en) 2004-04-16 2015-01-15 Yaping Shou Methods for detecting lp-pla2 activity and inhibition of lp-pla2 activity
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HUE030134T2 (en) 2007-10-16 2017-04-28 Zymogenetics Inc Combination of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and anti-CD20 agents for the treatment of autoimmune diseases
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US20140283157A1 (en) 2013-03-15 2014-09-18 Diadexus, Inc. Lipoprotein-associated phospholipase a2 antibody compositions and methods of use
WO2016057488A1 (fr) 2014-10-06 2016-04-14 Dana-Farber Cancer Institute, Inc. Anticorps humanisés anti-récepteur de la chimiokine cc4 (ccr4) et leurs procédés d'utilisation

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EP0084013A2 (fr) * 1982-01-13 1983-07-20 Universite Pierre Et Marie Curie Lignées cellulaires hybrides murines anti-herpès, procédé d'obtention, anticorps monoclonaux anti-herpès non neutralisants, applications biologiques
US4430437A (en) * 1980-08-27 1984-02-07 The United States Of America As Represented By The Department Of Health And Human Services Test methods employing monoclonal antibodies against Herpes simplex virus types 1 and 2 nucleocapsids proteins
EP0100955A2 (fr) * 1982-07-26 1984-02-22 Amf Incorporated Anticorps monoclonaux immunoglobuline M et procédé pour leur préparation
US4461829A (en) * 1981-09-14 1984-07-24 Miles Laboratories, Inc. Homogeneous specific binding assay element and lyophilization production method

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US4430437A (en) * 1980-08-27 1984-02-07 The United States Of America As Represented By The Department Of Health And Human Services Test methods employing monoclonal antibodies against Herpes simplex virus types 1 and 2 nucleocapsids proteins
US4461829A (en) * 1981-09-14 1984-07-24 Miles Laboratories, Inc. Homogeneous specific binding assay element and lyophilization production method
EP0084013A2 (fr) * 1982-01-13 1983-07-20 Universite Pierre Et Marie Curie Lignées cellulaires hybrides murines anti-herpès, procédé d'obtention, anticorps monoclonaux anti-herpès non neutralisants, applications biologiques
EP0100955A2 (fr) * 1982-07-26 1984-02-22 Amf Incorporated Anticorps monoclonaux immunoglobuline M et procédé pour leur préparation

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CHEMICAL ABSTRACTS, Volume 99, No. 21, 21 November 1983, Columbus, Ohio, (US) T. OKUNO et al.: "Synthesis and Processing of Glycoproteins of Varicella-Zoster Virus (VZV) as Studied with Monoclonal Antibodies to VZV Antigens", see page 352, Abstract No. 172586f & Virology 1983, 129 (2), 357-68 *
Clinical Chemistry, Volume 28, No. 7, July 1982, Washington, D.C. (US) E.D. SEVIER: "The use of Monoclonal Antibodies for Detection and Diagnosis of Venereal Disease", see page 1535, left-hand column, Abstract *
Infection and Immunity, Volume 34, No. 1, October 1981, Washington, D.C., (US) R.D. DIX et al.: "Use of Monoclonal Antibody Directed against Herpes Simplex Virus Glycoproteins to Protect Mice against Acute Virus-Induced Neurological Disease", see pages 192-199, page 192, Abstract *
M. SPROSSIG et al.: "Mikrobiologisches Vademekum", 1972, VEB Gustav Fischer Verlag, Jena, see page 265, section 2.5.3.2.1, the title *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0321249A2 (fr) * 1987-12-15 1989-06-21 Toa Nenryo Kogyo Kabushiki Kaisha Agent et procédé de diagnostic d'une infection par le virus varicella zoster
EP0321249A3 (fr) * 1987-12-15 1991-05-15 Toa Nenryo Kogyo Kabushiki Kaisha Agent et procédé de diagnostic d'une infection par le virus varicella zoster
US5444041A (en) * 1991-04-19 1995-08-22 Ibah, Inc. Convertible microemulsion formulations
US12281151B2 (en) 2018-06-29 2025-04-22 City Of Hope CD6 targeted chimeric antigen receptors for treatment of certain autoimmune disorders

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EP0203089A1 (fr) 1986-12-03

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