[go: up one dir, main page]

WO1997017374A1 - Ligands de recombinaison pour l'antigene cd30 de la membrane cellulaire humaine - Google Patents

Ligands de recombinaison pour l'antigene cd30 de la membrane cellulaire humaine Download PDF

Info

Publication number
WO1997017374A1
WO1997017374A1 PCT/EP1996/004765 EP9604765W WO9717374A1 WO 1997017374 A1 WO1997017374 A1 WO 1997017374A1 EP 9604765 W EP9604765 W EP 9604765W WO 9717374 A1 WO9717374 A1 WO 9717374A1
Authority
WO
WIPO (PCT)
Prior art keywords
ligands
seq
recombinant
sequences
fragments
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.)
Ceased
Application number
PCT/EP1996/004765
Other languages
German (de)
English (en)
Inventor
Andreas Ziegler
Harald Stein
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.)
Medac Gesellschaft fuer Klinische Spezialpraeparate mbH
Original Assignee
Medac Gesellschaft fuer Klinische Spezialpraeparate mbH
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 Medac Gesellschaft fuer Klinische Spezialpraeparate mbH filed Critical Medac Gesellschaft fuer Klinische Spezialpraeparate mbH
Priority to AU74971/96A priority Critical patent/AU7497196A/en
Publication of WO1997017374A1 publication Critical patent/WO1997017374A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to novel recombinant DNA molecules which code for variable immunoglobulin chains or fragments thereof which have specificity for the human cell membrane antigen CD30.
  • the invention further relates to expression vectors which contain these DNA molecules, and to host cells transformed therewith which are capable of producing the novel ligands.
  • a method for the production of ligands of the specified specificity using the transformed host cells, the resulting ligands and diagnostic and pharmaceutical preparations containing them are provided.
  • the CD30 antigen is a glycoprotein with a molecular mass of 120 kD when determined by SDS electrophoresis.
  • the special thing about the CD30 antigen is that it is normally only present in the organism on very few activated T-cell and B-cell blasts and only in low density on these (Stein et al., "Identification of Hodgkin and Sternberg-Reed cells as a unigue cell type derived from a newly detected small cell population ", Int. J. Cancer, 30, pp.
  • Ber-H2 a new monoclonal antibody of the Ki-1 family for the detection of Hodgkin's disease in formaldehyde-fixed tissue sections (A2.13) ", in: Leucocyte Typing III, White Cell Differentiation Antigens, AJ McMichael, ed., Oxford University Press, Oxford - New York - Tokyo, pp. 574-575, 1987), but it is expressed in a much higher concentration in a number of lymphoproliferative processes and in embryonic carcinomas.
  • the strong CD30-positive malignant lymphomas primarily include Hodgkin's lymphomas, anaplastic large cell lymphoma and the acute form of adult T-cell leukemia.
  • CD30 molecule Because of the extremely rare occurrence of the CD30 molecule in the normal organism and the high expression of this molecule on the tumor cells of the above-mentioned lymphomas and the embryonic carcinoma, as well as on activated T H 2 blasts, one is due to the expression of the CD30 molecule Establishing diagnostics and therapy an important strategy for the detection and treatment of the named diseases.
  • CD30-positive forms of cancer The primary diagnosis of CD30-positive forms of cancer is currently carried out immunohistologically, with only antibodies from the mouse such as Ber-H2 currently being used as antibodies.
  • This reagent is a monoclonal antibody directed against the CD30 molecule, which was briefly described in 1987 and in 1989 in detail by the inventors' working group (Schwarting et al., "Ber-H2: a new anti-Ki -1 (CD30) monoclonal antibody directed at a formol-resistant epitope ", Blood, 74, pp. 1678-1689, 1989).
  • the spread diagnosis of the tumor diseases mentioned is generally carried out by means of computer tomography, sonography and / or lymphography.
  • the non-invasive spreading diagnosis mentioned has the disadvantage that only relatively large tumor masses can be identified, but smaller tumors or metastases cannot be detected.
  • the surgical spreading diagnosis, which is therefore often used additionally, is very stressful for the patient and limited to certain body cavities (eg, abdominal cavity).
  • the currently only medically accepted and therefore used standard therapy for CD30-positive tumors is carried out with non-specific radio and / or chemotherapy.
  • the first follow rate is approximately 60-70%, there has been no curative concept for therapy failures so far.
  • the monoclonal antibody Ber-H2 was conjugated with plant poisons and experimentally used to treat patients with Hodgkin's disease in the terminal phase of the disease (Falini et al., "Response of refractory Hodgkin's disease to monoclonal anti-CD30 immunotoxin", Lancet, 339, p 1195-1196, 1992).
  • the four treated patients showed a tumor mass reduction of 50% to almost 100% within 10 days. In all cases, however, tumor masses reappeared at the old and / or new locations after different times. Repetition of the immunotoxin application was not possible because the patients treated in this way had formed antibodies against the mouse antibody Ber-H2 without exception.
  • variable regions of the heavy (V H ) and light (V L ) chain of a mouse antibody to the corresponding constant regions C H and C L of a human antibody molecule.
  • This manipulation largely eliminates the areas of the antibody molecule that are immunogenic for humans, while the specificity of the original mouse antibody in the chimeric molecule is usually retained.
  • the object of the present invention is therefore to provide new CD30-specific substances with reduced immunogenicity. Furthermore, the instability of the cell line Ber-H2 can be improved in terms of monoclonal antibody production.
  • recombinant DNA molecules which code for variable immunoglobulin chains or fragments thereof, which have specificity for the human cell membrane antigen CD30, the recombinant DNA molecules being sequences in accordance with one or more of the SEQ ID NOS : 1, 3, 4 and / or 6 or their fragments or syngeneic or allelic variants thereof, which are preferably operatively linked in whole or in part. It is further preferred that these sequences or their fragments or syngeneic or allelic variants thereof are operatively linked to DNA sequences which code for constant parts of a human or animal immunoglobulin molecule.
  • sequences, fragments and variants which are derived from the same or homologous gene and for the immunoglobulin chains or fragments thereof according to the invention encode.
  • the recombinant DNA molecules each comprise one or more of the hypervariable regions (which are also referred to as CDR for "complementarity determining residences") which are contained in SEQ ID NOS: 1 or 3 or in SEQ ID NOS: 4 or 6 specified sequences or syngeneic or allelic variants thereof.
  • the sequences given in SEQ ID NOS: 1, 3, 4 and / or 6 or their fragments or syngeneic or allelic variants thereof can be operatively linked to DNA sequences which code for toxic proteins or enzymes.
  • expression vectors which contain one or more of the recombinant DNA molecules mentioned in operative linkage with expression control sequences and are preferably suitable for expression in procaryte and / or eukaryote host cells.
  • the invention furthermore provides host cells which are transfected with the expression vectors mentioned, prokaryote or eukaryote cells being suitable, the ones obtained from the DSM (German Collection of Microorganisms and Cell Cultures GmbH) on August 8, 1995 under the Access number DSM ACC2224 according to the provisions of the Budapest Treaty, eukaryotic cell CH-BerH2 is preferred.
  • DSM German Collection of Microorganisms and Cell Cultures GmbH
  • a method for the production of ligands for the human cell membrane antigen CD30 in which one of the host cells mentioned is cultivated in a suitable nutrient medium, then the cells are separated from the medium and the ligands as expression products from or from the medium isolated from the cytoplasm of the host cells.
  • the ligands are then preferably purified and formulated with conventional auxiliaries and carriers to give pharmaceutical or diagnostic preparations.
  • recombinant ligands for the human cell membrane antigen CD30 comprise at least the amino acid sequences or fragments or allelic variants thereof given in SEQ ID NOS: 2 and / or 5.
  • These ligands preferably each comprise one or more of the hypervariable CDR regions of the amino acid sequences or syngeneic or allelic variants indicated in SEQ ID NOS: 2 and / or 5 the same.
  • 2 and / or 5 amino acid sequences or fragments or allelic variants thereof given in SEQ ID NOS: are linked to one another.
  • these sequences or fragments or all variants thereof can preferably be linked to constant parts of a human or animal immunoglobulin molecule.
  • the recombinant ligands mentioned above are linked peptically or via linker molecules to toxic proteins or to enzymes or proenzymes, the toxins preferably being in the form of ribosome-inactivating proteins and the enzymes preferably being selected from the group of the phosphodiesterases are.
  • the above-mentioned recombinant ligands are linked covalently or conjugated directly or via linker molecules to photoactivatable compounds or to radioactive isotopes, the latter preferably from the group consisting of indium, iodine, yttrium, technetium, Rhenium, copper and lutetium are selected.
  • the linkage can take place, for example, using chelating agents or via photochemical activation processes (cf. WO 94/04189).
  • diagnostic or pharmaceutical preparations which preferably contain one or more of the above-mentioned ligands or those produced by the process according to the invention, optionally in combination with conventional carriers and diluents.
  • common carriers are water, physiological saline, alcohols, polyethylene glycols, glycerol esters, gelatin, carbohydrates such as lactose and starch, calcium carbonate, magnesium stearate, talc.
  • Usual additives are, for example, preservatives, lubricants, wetting agents and emulsifiers, colorants, taste correctives and flavorings.
  • the choice of carriers and additives depends on whether the preparations according to the invention are to be administered enterally, parenterally or locally. Examples of the invention Future dosage forms are solutions, dragees, capsules, tablets, injection and infusion solutions as well as transdermal patches.
  • preparations are preferably used for the diagnosis and / or treatment of forms of cancer such as, in particular, Hodgkin's disease, in which the human cell membrane antigen CD30 is expressed on cells which are important for the disease.
  • V L J variable region of the light
  • V H DJ heavy chains
  • the cytoplasmic RNA was first isolated from cultured cells of the mouse myeloma hybrid line which produce the antibody Ber-H2. Then, with the help of the reverse transcriptase, a cDNA synthesis of V L J and V H DJ was carried out, the oligonucleotides used below being complementary to the 5 'end of the constant regions of the L and H chains :
  • oligonucleotides konLl or konHl already used for cDNA synthesis were used as 3 'primers.
  • the cDNAs were amplified with the 3'-oligonucleotides konL2 or konH2 given below and with the anchor primer indicated at the 5 'end, each of which carried overhanging restriction sites:
  • the fragments obtained were cloned into commercially available sequencing vectors (e.g. using the vector pGEM -HZf (+) from Promega, Heidelberg).
  • the sequence analyzes showed that the V gene segment of the light chain of the mAb Ber-H2 was recombined with the J 2 gene segment and that of the heavy chain with the J 3 gene segment.
  • 5 'primer sequences could be determined and synthesized in a further step, which are in the untranslated region of the respective gene. Since the intron sequences of all J-minigens are known and accessible via gene banks, 3 'primer sequences which lie in the non-coding region of the DNA of the mouse myeloma hybrid line could also be derived therefrom. In this way it was possible to clone this genomic DNA in a directed manner after PCR amplification without changing the original gene structure (5'-UTR - exon 1 - intron-exon 2 - J-intron).
  • V L J or V H DJ PCR products were then first cloned into suitable sequencing vectors and the "insert" regions of three clones were completely sequenced. In parallel, the PCR products were called Reference sequenced directly. After checking the correct reading frame and the absence of stop codons within the cloned DNA, a clone which was homologous to the PCR products was recloned into the corresponding expression vectors (pUHW ⁇ l or pUHW k ). These vectors contained the sequences coding for the constant parts of a human antibody, a murine / human intron hybrid, a selection marker, and the mouse promoter and enhancer elements required for efficient expression.
  • the advantage of the DNA sequences according to the invention or their products set out here compared to the prior art is, on the one hand, in the far lower immunogenicity in the human body and, on the other hand, in their diverse manipulation possibilities, which are based on the knowledge of the DNA sequences result. For example, it is possible to produce a protein with CD30 specificity in bacteria or insect cells at a much lower cost. than in conventional cell culture. Knowledge of the sequences also enables coupling to other DNA sequences which code for activating or toxic proteins, enzymes or ligands from defense cells. Furthermore, fragments of the total sequences, such as isolated hypervariable regions, can be used for the synthesis of corresponding protein fragments.
  • the pelleted cytoplasmic RNA was obtained, dissolved in distilled water, by PIC extraction (50% by volume phenol, 48% by volume CHC1 3 , 2% by volume .-% isoamyl alcohol) purified and precipitated with ethanol. The precipitates were stored at -80 ° C until further processing.
  • RNA corresponding volume of the precipitate obtained in Example 1 was used for cDNA synthesis.
  • the Precipitate was centrifuged at 14,000 rpm at 4 ° C. for 15 minutes, washed with 300 ⁇ l of 70% ethanol, and the RNA was dissolved in 15 ⁇ l of H 2 O.
  • the mixture was subsequently denatured for 20 minutes at 45 ° C. with 375 ⁇ l DMSO, precipitated with ethanol and, after 15 minutes of centrifugation at 4 ° C. and 14,000 rpm and after washing with 70% ethanol, dissolved in 5 ⁇ RT buffer.
  • the reaction mixture for the reverse transcriptase contained 1 mM each of the four dNTP's, 1 ⁇ g c ⁇ or c ⁇ primer, 1000 units MMLV reverse transcriptase (BRL), 20 ⁇ Ci [ 32 P] dCTP, 2 units RNAse Block 2 ( Stratagene) and H 2 0 up to a final volume of 100 ⁇ l.
  • the mixture was incubated at 37 ° C. for 90 minutes and then the RNA was treated with 50 ⁇ g RNAse at 42 ° C. for 30 minutes.
  • the approach for the subsequent "tailing" reaction of the cDNA contained 1 mM dGTP, 100 mM Na cacodylate, 1 mM ⁇ -mercaptoethanol, 1 mM CoCl 2 , 2 ⁇ g BSA, 33 units terminal deoxynucleotide transferase (BRL), 5 ⁇ l cDNA and water up to a final volume of 20 ⁇ l.
  • the reaction was carried out at 37 ° C. for 60 minutes. After PIC extraction, ethanol precipitation and washing of the nucleic acid according to Example 1, the DNA obtained, after dissolving in 20 ⁇ l of water and producing a series of dilutions, was fed to the subsequent PCR method.
  • the DNA from Example 2 was amplified in a first PCR reaction with the aid of a poly-C anchor primer (AN-Poly-C) and the corresponding 3'c primer (konLl or konHl) Letter c refers to the constant range.
  • the reaction mixture contained 10 ng of the primer AN-poly-C-oligo, 100 ng anchor primer, 100 ng konLl- or konHl-oligo, 2 ⁇ l lOx PCR buffer (2 mM dNTP's, 10 mM MgCl 2 , 100 mM Tris-HCl , 500 mM KC1, pH 8.4), 2 units of Taq polymerase, 5 ⁇ l cDNA and water to a final volume of 20 ⁇ l.
  • the reaction was carried out according to the following PCR program: 5 minutes 94 ° C, 5 cycles of 1 minute 94 ° C, 2 minutes 42 ° C, 1 minute 72 ° C, 30 cycles of 1 minute 94 ° C, 1 minute 42 ° C, 1 minute 72 ° C and 10 minutes 72 ° C.
  • the DNA molecules obtained in this way were applied to an agarose gel and separated electrophoretically.
  • the bands corresponding to V ⁇ and V ⁇ were cut out and eluted in 100 ⁇ l of H 2 012 hours at 4 ° C.
  • both the vector pGEM®-HZf (+) (Promega, Heidel ⁇ berg) and the cDNA obtained were incubated with the restriction enzymes EcoRI and Sall for 1 hour at 37 ° C.
  • the vector and cDNA were up an agarose or polyacrylamide gel, then transferred to an NA-45 membrane (Schleicher & Schull, Dassel) and eluted for 30 minutes at 65 ° C. with IM NaCI in 1 ⁇ TE.
  • the eluates were precipitated according to Example 1 with ethanol, centrifuged, washed and dissolved in H 2 0. The subsequent ligation reaction took place at 16 ° C. for 12 hours, the mixture containing 2 units of T4 DNA ligase (New England Biolabs, Boston, USA), 1 mM ATP and 5 ⁇ ligase buffer and the molar ratio of Plasmid to cDNA was 1: 2. The ligation mixture was then mixed with 200 ⁇ l bacterial suspension for the transformation of competent E.
  • coli bacteria (XL 1 blue) and first for 30 minutes at 0 ° C., then for 2 minutes at 42 ° C., then for 5 minutes at 0 ° C and finally after the addition of 1 ml LB medium for 1 hour at 37 ° C in a shaker.
  • 200 ⁇ l of the mixture were plated on agar plates containing antibiotics and incubated at 37 ° C. overnight.
  • the resulting individual colonies were then inoculated in LB ampicillin medium and incubated overnight at 37 ° C. in a shaker.
  • a plasmid preparation was then carried out with the bacterial culture obtained in this way and the cloning success was checked after restriction digestion and subsequent application of the mixture to an agarose gel.
  • the positive clones were then alkaline denatured for 30 minutes at 37 ° C. with 0.2N NaOH. After ethanol precipitation, centrifugation and washing of the precipitate according to Example 1, the DNA was dissolved and an aliquot was loaded onto an agarose gel for quantity estimation.
  • the cloned cDNA and the genomic DNA were sequenced using the method of Sanger (F. Sanger, S. Nicklen and
  • primer sequences were determined and synthesized in a second step in order to amplify the genomic DNA.
  • 5 'oligonucleotides given below
  • the primers also contained the restriction sites necessary for cloning in expression vectors.
  • the genomic DNA was amplified using these primers.
  • the PCR reaction (5 ⁇ l 10 ⁇ PCR buffer (1.5 mM MgCl 2 , 200 mM dNTP's, 500 mM KC1, 100 mM Tris-HCl, pH 8.3), 2.5 units Taq polymerase (Perkin Bucket, Kochlingen), 5 ⁇ M primer each, 5 ⁇ l genomic DNA from a dilution series, ad 50 ⁇ l H 2 0) was carried out with the following program: 5 minutes 95 ° C, 26 cycles of 1 minute 94 ° C, 2 minutes 55 ° C, 2 minutes 72 ° C, 7 minutes 72 ° C.
  • VJ or VDJ PCR products were first cloned into sequencing vectors (pGEM ®
  • Example 5 as well as the expression vectors pUHW ⁇ and pUHW ⁇ l
  • the prepared plasmids for light and heavy chains were used for the stable transfection with the restriction enzymes EcoRI or
  • the antibiotic G418 was initially added to the medium 48 hours after sowing in a concentration of 800 ⁇ g / ml, although the concentration was increased to 1200 ⁇ g / ml after 12 days. After 15 days, primary cultures whose culture supernatants reacted with L428KS cells in indirect immunofluorescence could be identified. These transfectants were cloned, recloned and supernatants were again analyzed for L428KS cells using a flow cytometer. Individual supernatants were also examined against CD30-negative cells, for example the cell line KG-1, and as expected no reaction could be detected.
  • MOLECULE TYPE DNA (genomic)
  • MOLECULE TYPE DNA (genomic)
  • microorganism referred to under I was received by this internal depository on (date of first deposit) and an application for the conversion of this first deposit into a deposit according to the Budapest Treaty was received on (date of receipt of the request for conversion)

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Peptides Or Proteins (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

L'invention concerne de nouvelles molécules d'ADN de recombinaison ou des parties de ces molécules qui assurent le codage de chaînes d'immunoglobine variables ou de fragments de ces chaînes et ont une spécificité pour la molécule membranaire CD30 de l'homme. De plus, on prépare des vecteurs d'expression contenant ces molécules d'ADN, ainsi que des cellules hôtes transformées par ces vecteurs en mesure de produire les nouveaux ligands. L'invention concerne également un procédé de production de ligands de la spécificité indiquée impliquant l'utilisation des cellules hôtes transformées, les ligands obtenus selon ce procédé ainsi que les préparations diagnostiques et pharmaceutiques les contenant.
PCT/EP1996/004765 1995-11-08 1996-11-02 Ligands de recombinaison pour l'antigene cd30 de la membrane cellulaire humaine Ceased WO1997017374A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU74971/96A AU7497196A (en) 1995-11-08 1996-11-02 Recombinant ligands for the human cell membrane antigen cd30

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19543039.5 1995-11-08
DE1995143039 DE19543039C1 (de) 1995-11-08 1995-11-08 Rekombinante Liganden für das menschliche Zellmembran-Antigen CD30

Publications (1)

Publication Number Publication Date
WO1997017374A1 true WO1997017374A1 (fr) 1997-05-15

Family

ID=7777801

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1996/004765 Ceased WO1997017374A1 (fr) 1995-11-08 1996-11-02 Ligands de recombinaison pour l'antigene cd30 de la membrane cellulaire humaine

Country Status (3)

Country Link
AU (1) AU7497196A (fr)
DE (1) DE19543039C1 (fr)
WO (1) WO1997017374A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7090843B1 (en) 2000-11-28 2006-08-15 Seattle Genetics, Inc. Recombinant anti-CD30 antibodies and uses thereof
US7387776B2 (en) 2002-01-09 2008-06-17 Medarex, Inc. Human monoclonal antibodies against CD30
US7790160B2 (en) 2004-10-01 2010-09-07 Medarex, Inc. Method of treating CD30 positive lymphomas
US8207303B2 (en) 2005-02-18 2012-06-26 Medarex, Inc. Monoclonal antibodies against CD30 lacking in fucosyl residues

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002363939A1 (en) * 2001-11-20 2003-06-10 Seattle Genetics, Inc. Treatment of immunological disorders using anti-cd30 antibodies

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0256654A2 (fr) * 1986-07-07 1988-02-24 Centocor, Inc. Immunoglobuline chimère murine-humaine, spécifique pour l' antigène 17-1A associés aux tumeurs
WO1989009622A1 (fr) * 1988-04-15 1989-10-19 Protein Design Labs, Inc. Anticorps chimeriques specifiques au recepteur il-2
WO1991007437A2 (fr) * 1989-11-20 1991-05-30 Parker, David, L. Anticorps cd-30 ameliores et fragments de ces derniers
WO1991009966A1 (fr) * 1989-12-21 1991-07-11 Ortho Pharmaceutical Corporation Anticorps de recombinaison specifique du cd4
DE4205938A1 (de) * 1992-02-27 1993-09-02 Medac Klinische Spezialpraep Immunotoxine
WO1994004189A1 (fr) * 1992-08-25 1994-03-03 Medac Gesellschaft Fur Klinische Spezialpräparate Mbh Anticorps/radio-isotope conjugues de diagnostic et/ou therapie de tumeurs

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0256654A2 (fr) * 1986-07-07 1988-02-24 Centocor, Inc. Immunoglobuline chimère murine-humaine, spécifique pour l' antigène 17-1A associés aux tumeurs
WO1989009622A1 (fr) * 1988-04-15 1989-10-19 Protein Design Labs, Inc. Anticorps chimeriques specifiques au recepteur il-2
WO1991007437A2 (fr) * 1989-11-20 1991-05-30 Parker, David, L. Anticorps cd-30 ameliores et fragments de ces derniers
WO1991009966A1 (fr) * 1989-12-21 1991-07-11 Ortho Pharmaceutical Corporation Anticorps de recombinaison specifique du cd4
DE4205938A1 (de) * 1992-02-27 1993-09-02 Medac Klinische Spezialpraep Immunotoxine
WO1994004189A1 (fr) * 1992-08-25 1994-03-03 Medac Gesellschaft Fur Klinische Spezialpräparate Mbh Anticorps/radio-isotope conjugues de diagnostic et/ou therapie de tumeurs

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
J.D. RODWELL: "ENGINEERING MONOCLONAL ANTIBODES", NATURE, vol. 342, no. 6245, 2 November 1989 (1989-11-02), LONDON GB, pages 99 - 100, XP000069444 *
Y. L. CHIANG ET AL.: "DIRECT CDNA CLONING OF THE REARRANGED IMMUNOGLOBULIN VARIABLE REGION", BIOTECHNIQUES, vol. 7, no. 4, 1 January 1989 (1989-01-01), NATICK US, pages 360 - 366, XP000350904 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7090843B1 (en) 2000-11-28 2006-08-15 Seattle Genetics, Inc. Recombinant anti-CD30 antibodies and uses thereof
US7387776B2 (en) 2002-01-09 2008-06-17 Medarex, Inc. Human monoclonal antibodies against CD30
US8088377B2 (en) 2002-01-09 2012-01-03 Medarex, Inc. Human monoclonal antibodies against CD30
US7790160B2 (en) 2004-10-01 2010-09-07 Medarex, Inc. Method of treating CD30 positive lymphomas
US8207303B2 (en) 2005-02-18 2012-06-26 Medarex, Inc. Monoclonal antibodies against CD30 lacking in fucosyl residues
US8491898B2 (en) 2005-02-18 2013-07-23 Medarex, L.L.C. Monoclonal antibodies against CD30 lacking in fucosyl residues

Also Published As

Publication number Publication date
DE19543039C1 (de) 1996-11-21
AU7497196A (en) 1997-05-29

Similar Documents

Publication Publication Date Title
DE69433422T2 (de) Monoklonaler anti-hiv antikörper
DE69624436T2 (de) Humaner 4-1bb spezifischer humaner antikörper und diesen produzierende zellinie
DE69233435T2 (de) Vorläufer von für tumorabstossung verantwortlichen antigenen, die antigene und deren verwendungen
DE69233153T2 (de) Humanisierte monoklonale antikörper
DE69434578T2 (de) Expressionsvektoren die für bispezifische Proteine kodieren, und Verfahren zur Herstellung von biologisch-aktiven bispezifischen Fusionsproteinen in Zellen von Säugetieren
DE69233163T2 (de) Muriner monoklonaler Antikörper (5c8) erkennt ein humanes Glykoprotein auf der Oberfläche von T-Lymphozyten.
DE69530763T2 (de) Antikörper gegen e-selektin
DE69031591T2 (de) Cd4-spezifischer rekombinanter antikörper
DE69308573T2 (de) Bispezifische immunoadhesine
DE69233482T2 (de) Verfahren zur Verminderung der Immunogenität der variablen Antikörperdomänen
DE3751004T2 (de) Chimärer Antikörper mit Spezifität für menschliches Tumor-Antigen.
DE69333807T2 (de) Marker für krebs und biosynthetisches bindeprotein dafür
DE69230545T2 (de) Antikörperderivate
DE69429095T2 (de) Humanisierte antikoerper
DE69031410T2 (de) Monoklonale Antikörper gegen den humanen alpha/beta-T-Zellenrezeptor, ihre Herstellung und Verwendung
DE68909441T2 (de) Modifizierte Antikörper.
DE69531679T2 (de) Für e-selectin und p-selectin spezifische kreuzreaktive monoklonale antikörper
DE69527975T2 (de) Humanisierte antikörper gegen cd38
DE69605181T3 (de) Antikörper gegen cd30, die proteolytische spaltung und abgabe des membrangebundenen cd30 antigens verhindern
DE69635480T2 (de) Apoptosis induzierendes cytokin
DE69936927T2 (de) Polyspezifische bindemoleküle und deren verwendung
DE69909459T2 (de) Cd19xcd3 spezifische polypeptide und deren verwendung
DE68925536T2 (de) Humanisierte immunglobuline, deren herstellung und verwendung
DE69133326T2 (de) Verbesserte humanähnlich gemachte immunglobuline
DE69838454T2 (de) Natürlicher menschlicher antikörper

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE HU IL IS JP KE KG KP KR KZ LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG US UZ VN AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: JP

Ref document number: 97517821

Format of ref document f/p: F

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: CA

122 Ep: pct application non-entry in european phase