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WO1991007437A2 - Anticorps cd-30 ameliores et fragments de ces derniers - Google Patents

Anticorps cd-30 ameliores et fragments de ces derniers Download PDF

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WO1991007437A2
WO1991007437A2 PCT/US1990/006802 US9006802W WO9107437A2 WO 1991007437 A2 WO1991007437 A2 WO 1991007437A2 US 9006802 W US9006802 W US 9006802W WO 9107437 A2 WO9107437 A2 WO 9107437A2
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cells
hodgkin
hrs
immunotoxins
disease
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PCT/US1990/006802
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WO1991007437A3 (fr
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Michael Pfreundschuh
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Parker, David, L.
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    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
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    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
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    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6867—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from a cell of a blood cancer
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70578—NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
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    • C07—ORGANIC CHEMISTRY
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    • 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
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    • C07—ORGANIC CHEMISTRY
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    • 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
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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    • 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
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3061—Blood cells
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Definitions

  • Chemotherapy of Hodgkin's disease is undoubtedly one of the major breakthroughs in clinical oncology over the last 25 years.
  • the introduction of the multi-agent chemotherapy regimens such as MOPP (1) and ABVD (2) and the optimized use of radiation in early stages of the disease has improved the probability of curing these patients from less than 5% in 1963 to about 70% at the present time (3-5) .
  • the present invention addresses one or more defi ⁇ ciencies in the prior art by providing improved methods and compositions for tl ⁇ e treatment of Hodgkin's disease, as well as other diseases such as those involving large cell anaplastic lymphoma or graft-versus-host disease.
  • linking constructs Numerous types of linking constructs are known, including simply direct disulfide bond formation between sulfhydryl groups contained on amino acids such as cysteine, or otherwise introduced into respective protein structures.
  • disulfide linkage in also meant to include the use of a linker moiety which includes a disulfide bond, as discussed further herein below.
  • binding ligand exhibits a Kd of less than about 200 nM for, for example, L540 Hodgkin cells
  • the binding ligand will exhibit Kds that are significantly less than 200 nM.
  • binding affinity, in terms of Kd of less than about 40 nM and even those less than about 20 nM will be particularly preferred for uses in accordance herewith.
  • the present inventors have discovered that these high binding affinities may be achieved against certain particular antigens, including the 70 Kd antigen recognized by the IRac antibody or the CD-30 antigen, as discussed in more detail hereinbelow.
  • a second antigen which the inventors have found to be particularly useful for the targeting of Hodgkin's disease-directed immunotoxins is the 70 kDa antigen which has been characterized by Hsu et al. (47, 48) through the use of the IRac antibody.
  • the IRac antibody was developed through the use of Hodgkin's disease cells from tumor samples which were purified and stimulated with phorbol acetate (TPA) .
  • TPA phorbol acetate
  • the inventors have found that the IRac antibody is particularly useful both in the preparation of immunotoxins and in the identification of cross-blocking immunotoxins which might be similarly useful.
  • binding an antibody or antibody fragment, which, when applied to the particular tissue under conditions suitable for immunohistochemistry, will elicit either no staining or a mixed staining pattern with only a few positive cells of large lymphoid or monocytoid morphology scattered among a field of mostly negative cells.
  • Disulfide coupling may be achieved directly between cysteine residues of the respective proteins, e.g., by means of disulfide exchange reactions wherein the protein is reduced and derivatized with Ellman's reagent.
  • direct disulfide bond formation between many binding ligands and toxin will generally not be preferred, since a cysteine in the ligand is not accessible for coupling.
  • Reduction of cysteine bridges in the ligand, to provide reactive SH groups, may damage the functional integrity of the ligand.
  • hindered disulfide bond is intended to refer to a disulfide bond having groups near or adjacent to the disulfide bond that reduce its susceptibility to reduction, e.g., by thiols, by 3-fold or more, preferably greater than 5-fold, relative to the disulfide bonds generated by SPDP or 2-iminothiolane hydrochloride reagents.
  • the cells were incubated for 48 hours with (a) HRS-l.dgA (Purchase Order MRA ( ⁇ ) , HRS-3.dgA (•), HRS-4.dgA (0), Ber-H2.dgA (A), Ki-1.dgA (D) or (b) HRS-3 Fab'.dgA (•) and HRS-4 Fab'.dgA (0) .
  • the use and nature of the disulfide linker is thought to be important to the pharmacologic properties of the immunotoxin in that, preferably, the conjugate should remain intact while circulating through the blood stream, but, once the conjugate attaches itself to a target cell, the toxin moiety should be able to dissociate from the ligand and enter the cell to work its toxic effect upon the target.
  • CD30 immunotoxins directed against the Ki-1 antigen on Hodgkin cells may be identified which have high potency and specificity of cytotoxic effect and sufficiently restricted binding to normal human tissues that they are candidates for the treatment of Hodgkin's disease in man.
  • the Ki-1 antigen (CD30) was first described by Schwab et al., 1982 (23). It is composed of two nonreducible subunits of 105 and 120 kDa molecular weight (24) .
  • the antibody which was raised against the Hodgkin cell line L428 (25) , was originally thought to be specific for Hodgkin and Reed-Sternberg cells.
  • Ki-1 antigen is not expressed on resting mature or precursor B or T cells, but it can be induced on these cells by PHA, HTLV1 and IL-l or Epstein-Barr virus (EBV) .
  • Ki-1 identifies both activated normal T- and B- lymphocytes and lymphomas derived from such cells (26) . Because the Ki-1 antigen is expressed on all cases of
  • Kd ability to form highly toxic immunotoxins (IC 50 ) , as well as tumor cell selectivity.
  • useful monoclonal antibodies will be characterized by Kd of at least about 200 nM for L540 or L428 cells, and even more preferably less than about 40 or even 20 nM.
  • the most preferred antibodies will have a binding affinity of between about 7 and about 27 nM for L540 cells, or even lower.
  • Such other antibodies may then be further screened to identify those having additional useful and desirable attributes such as high binding capability and selectivity for Hodgkin cells, ability to form highly toxic immunotoxins, hybridoma stability, ability to secrete large amounts of antibody, stability of the antibody and resultant immunotoxin, ability to give Fab' fragments in good yield, and the like.
  • RPMI 1640 medium Gibco
  • 10% fetal calf serum 2 mM glutamine, 50 uM 2-mercaptoethanol, and 50 ug/ml gentamycin at 37"C in a humidified, 5% C02 atmosphere.
  • the developers of IRac have indicated that these cultures could be maintained for up to 7 days, with cell viability ranging from 70 to 80%.
  • TPA for antigen induction, TPA was dissolved in DMSO at about 14 ug/ml and added to the above cell cultures at a final concentration of about 2 ng/ml, with fresh TPA containing medium being added about every second day.
  • the induction was carried out for 3 days, and its effect monitored by immunocytochemical staining with anti-CD30 and anti-2H9 on cytospin smears.
  • Successful induction was judged by the loss of CD30 and 2H9 from cell membranes, as well as cytologic changes, as evidenced by a decrease in the nuclear/cytoplasmic rations, increased size and number of cytoplasmic projections, as well as decreased cell proliferation.
  • ricin A chain may be "truncated" by the removal of 30 N- terminal amino acids by Nagarase (Sigma) , and still retain an adequate toxin activity. It is proposed that where desired, this truncated A chain may be employed in conjugates in accordance with the invention.
  • the cross-linker may react with the lysine residue(s) of one protein (e.g., the selected antibody or fragment) and through the thiol reactive group, the cross-linker, already tied up to the first protein, reacts with the cysteine residue (free sulfhydryl group) of the other protein (e.g., dgA).
  • a thiol group e.g., pyridyl disulfide, malei ides, halogens, etc.
  • the cross-linker may react with the lysine residue(s) of one protein (e.g., the selected antibody or fragment) and through the thiol reactive group, the cross-linker, already tied up to the first protein, reacts with the cysteine residue (free sulfhydryl group) of the other protein (e.g., dgA).
  • the spacer arm between these two reactive groups of any cross-linkers may have various length and chemical composition.
  • a longer spacer arm allows a better flexi ⁇ bility of the conjugate components while some particular components in the bridge (e.g., benzene group) may lend extra stability to the reactive group or an increased resistance of the chemical link to the action of various aspects (e.g., disulfide bond resistant to reducing agents) .
  • the most preferred cross-linking reagent is SMPT, which is a bifunctional cross-linker containing a disulfide bond that is "sterically hindered" by an adjacent benzene ring and methyl groups. It is believed that steric hindrance of the disulfide bond serves a function of protecting the bond from attack by thiolate anions such as glutathione which can be present in tissues and blood, and thereby help in preventing decoupling of the conjugate prior to its delivery to the site of action by the binding ligand.
  • thiolate anions such as glutathione which can be present in tissues and blood
  • the SMPT cross- linking reagent lends the ability to cross-link functional groups such as the SH of cysteine or primary amines (e.g., the epsilon amino group of lysine) .
  • Another possible type of cross-linker includes the hetero- bifunctional photoreactive phenylazides containing a cleavable disulfide bond such as sulfosuccinimidyl-2-(p- azido salicylamido) ethyl-1,3'-dithiopropionate.
  • the N- hydroxy-succinimidyl group reacts with primary amino groups and the phenylazide (upon photolysis) reacts non- selectively with any amino acid residue.
  • conjugate Once conjugated, it will be important to purify the conjugate so as to remove contaminants such as unconjugated A chain or binding ligand. It is important to remove unconjugated A chain because of the possibility of increased toxicity. Moreover, it is important to remove unconjugated binding ligand to avoid the possibility of competition for the antigen between conjugated and unconjugated species.
  • a number of purification techniques are disclosed in the Examples below which have been found to provide conjugates to a sufficient degree of purity to render them clinically useful. In general, the most preferred technique will incorporate the use of Blue-Sepharose with a gel filtration or gel permeation step.
  • the A-chain component of all the immunotoxins fully retained its ability to inhibit protein synthesis in rabbit reticulocyte lysates (36) after the A-chain had been released from the immunotoxins by reduction with DTT.
  • 125 I-labeled antibody 50 ul was mixed for one hour at 4"C with L540 cells (2 x 10 6 cells/ml, 50 ul) in PBS/BSA/N 3 " .
  • the cells were separated from the supernatant by centrifugation (12,000 x g, 1 min) through 75 ul of a mixture of 8.8% (v/v) Dow Corning silicone fluid 200/1CS, 7.2% 200/5CS and 84% Dow Corning 550.
  • the Eppendorf tubes were then snap-frozen and the tips containing the cell pellets were cut off. The radioactivity in the cell pellet and in the supernatant were measured.
  • the cells were then again washed three times with PBS/BSA/N 3 " and analyzed on a FACS IV (Becton- Dickinson, Oxnard, USA) .
  • the molar concentrations of antibody and immunotoxin which gave 50% of the maximal fluorescence (i.e., under saturating conditions) were determined.
  • the pattern of reactivity of the five CD30 antibodies was very similar with the exception of HRS-4 which unexpectedly stained normal pancreatic tissue. They all strongly stained Hodgkin's disease tissue although there was a tendency in the lymphocyte dominant subtype to give weaker staining.
  • the Fab' fragments of HRS-3 and HRS-4 yielded immunotoxins that were only 7.8- and 3-fold less potent respectively than their IgG.dgA counterparts. Their lower activity can be explained by the fact that they can bind to only a single antigen on the cell surface and so bound 1.8-2.4 fold more weakly than their divalent counterparts.
  • Fab' immunotoxins and IgG immunotoxins have different advantages that recommend their use for therapy. The stronger affinity, greater cytotoxic activity and longer half life in vivo are the major advantages of IgG immunotoxins over Fab' immunotoxins (43) .
  • the Fab' immunotoxins may penetrate better into solid tumors (43) and have lower immunogenicity in man because they lack the relatively immunogenic Fc portion of the antibody (45) .
  • Staphylococcal protein-A Sepharose, DEAE Sepharose and Sephacryl S-200 HR were obtained from Pharmacia Ltd.
  • Tissue culture medium RPMI 1640 and fetal calf serum were from Gibco-Biocult Ltd. (Paisley, Scotland) .
  • Falcon tissue flasks were purchased from Becton Dickinson (Lincoln Park, USA) .
  • 3 H-Leucine was obtained from Amersham International (Aylesbury, UK) .
  • the human Hodgkin's disease-derived cell line L540 (46) and the sublines which were obtained by reestab ⁇ lishing L540 tumors in culture were maintained in RPMI 1640 supplemented with 20% (v/v) fetal calf serum, 4 mM
  • the mouse monoclonal antibodies used in this study were HRS-3, Ber-H2 (32), and IRac (47,48). All are of the IgGl subclass.
  • HRS-3 and Ber-H2 recognize the CD30 antigen which has been shown to be composed of two nonreducible subunits of 105 and 120 kDa antigen on Hodgkin and Reed-Sternberg cells (47) .
  • Cryostat sections of normal human tissues were treated with antibodies and stained using indirect immunofluorescence and immunoperoxidase techniques as described elsewhere (65) .
  • Deglycosylated ricin A-chain immunotoxins were prepared essentially as described in Example I.
  • Immunotoxins or antibodies were injected intravenously (i.v.) under sterile conditions into the tail vein in a volume of 200 ul PBS containing 2 mg/ml
  • IRac binds to a different antigen from HRS-3 and Ber-H2 indicates that IRac.dg and either HRS-3.dgA or Ber-H2.dgA may be useful as a 'cocktail' m vivo to maximize tumor cell kill.
  • the most potent immunotoxin was that prepared from intact IRac antibody (Table VII) . It had an IC 50 of 1 x 10 "11 M which is similar to ricin itself under the same experimental conditions.
  • the next most potent immuno- toxins were HRS-3.dgA and Ber-H2.dgA which were 9 times and 20 times less effective than IRac.dgA, with IC 50 values of 9 x 10 "11 and 2 x 10 "10 M respectively.
  • the Fab' immunotoxins were administered to the mice in doses that represented the same proportion of the LD 50 (i.e., 40%) as for the intact antibody immunotoxins.
  • the HRS-3 Fab' immunotoxin was only slightly less effective at inhibiting the growth of 60-
  • the IRac Fab' immunotoxin was substantially (P ⁇ 0.002) less effective than its intact antibody counterpart (growth index: 8.0 versus 0.8; permanent CR: 2/8 versus 12/24) .
  • IRac.dgA and which after a period of complete remission regrew into solid tumors at the original tumor site.
  • the IRac.dgA-resistant sublines were approximately as sensitive to HRS-3.dgA as the original L540 line indicating that treatment of the mice with a cocktail of IRac.dgA and HRS-3.dgA would reduce the likelihood of mutant tumor cell escape.
  • the immunotoxins used in this example exhibited surprisingly good antitumor effects in a solid Hodgkin's disease xenograft model.
  • the growth index (ratio of tumor volume per group on day 30:day 1) was 0.8 for IRac.dgA, 1.4 for HRS-3.dgA and 4.6 for Ber-
  • H2.dgA as compared with 9.7 for untreated control animals.
  • IRac. gA recipients tumors of approximately 1 cm diameter were smaller on average 30 days after treatment than on the day of treatment.
  • 100% of small (10-20 mm 3 ) tumors were destroyed by a single IRac.dgA injection, indicating the importance of tumor size on complete remission rates.
  • Possible explanations for the high in vivo efficacy of the present immunotoxins are that degly ⁇ cosylated ricin A-chain, the SMPT linker, and a final purification step on Blue Sepharose were employed when manufacturing the immunotoxin. These procedures enable the preparation of 'second generation' immunotoxins that have higher purity, higher in vivo stability, and which avoid liver entrapment better than immunotoxins of the first generation, resulting in substantially improved antitumor activity in mouse tumor models.
  • HRS-3.dgA treatment resulted in lasting complete remissions in 7/16 mice and a tumor growth index of 1.4 as compared with 2/8 mice and a tumor growth index of 2.7 in the recipients of HRS-3 Fab'.dgA.
  • IRac immunotoxins treatment with IRac.dgA produced lasting complete remissions in 12/24 mice and a growth index of 0.8 as compared with 2/8 mice and a growth index of 8.0 in the recipients of IRac Fab'.dgA.
  • the difference in the degree of superiority of the two intact antibody immunotoxins over their Fab' counterparts correlated with their relative cytotoxic potency m vitro.
  • the HRS-3 Fab'.dgA was only 7.8 fold less potent at killing L540 cells in vitro than the intact antibody immunotoxin, whereas the IRac Fab'.dgA was 60-fold less potent.
  • the higher cytotoxicity of IgG over Fab' immunotoxins in vitro is well established and due to the superior affinity of the bivalent intact immunotoxin.
  • compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the composition, methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.
  • Guinea pig line 10 hepato- carcinoma model characterization of monoclonal antibody and in vivo effect of unconjugated antibody and antibody conjugated to diphtheria toxin A-chain. Cancer Res.. 43:4420-4428.

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Abstract

Sont décrits des procédés et des compositions relatifs au traitement de la maladie de Hodgkin ainsi que des procédés impliquant des cellules porteuses de la maladie de Hodgkin ou porteuses de la maladie de Reed-Sternberg, comprenant l'élimination spécifique des cellules atteintes par la maladie de Steinberg au moyen d'une technique aux immunotoxines. Les compositions de l'invention comprennent des conjugués de toxines composés d'un ligand de liaison des cellules infectées par la maladie de Hodgkin conjugué à une fraction de chaîne de toxine A comme la chaîne de ricine A ou la chaîne de ricine A déglycosylée, à l'aide d'un agent de réticulation ou d'une autre liaison conjuguée comprenant une liaison bisulfure. Dans des formes d'exécution préférées de l'invention, des doses thérapeutiques de conjugués sont administrées à un patient atteint par la maladie de Hodgkin afin d'éliminer de manière spécifique les cellules infectées par la maladie, sans être particulièrement toxiques pour les cellules non tumorales. Ces conjugués sont composés d'un anticorps CD-30 ou IRac ou d'un fragment de celui-ci conjugué à la chaîne A déglycosylée, à l'aide d'une liaison SMPT. Sont également décrits des hybrides et des anticorps monoclonaux spécifiques, ainsi qu'une méthodologie associée, que l'on peut employer, par exemple, pour préparer ces immunotoxines. D'autres utilisations sont également possibles comme des applications au niveau du diagnostic.
PCT/US1990/006802 1989-11-20 1990-11-20 Anticorps cd-30 ameliores et fragments de ces derniers WO1991007437A2 (fr)

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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
EP0657533A1 (fr) * 1993-10-30 1995-06-14 Biotest Pharma Gmbh Anticorps monoclonaux avec une cytotoxicité élévée contre l'antigène CD16 humain, et des anticorps monclonaux bispécifiques utilisant tels anticorps monoclonaux et des anticorps CD30-HRS-3
US5480981A (en) * 1992-05-26 1996-01-02 Immunex Corporation CD30 ligand
WO1996022384A1 (fr) * 1995-01-18 1996-07-25 Boehringer Mannheim Gmbh Anticorps anti-cd30 prevenant le clivage proteolytique et la liberation de l'antigene cd30 membranaire
WO1996040260A3 (fr) * 1995-06-07 1997-02-20 Innogenetics Nv Immunotoxines specifiques aux cellules exprimant cd80 et cd86
WO1997017374A1 (fr) * 1995-11-08 1997-05-15 Medac Gesellschaft Für Klinische Spezialpräparate Gmbh Ligands de recombinaison pour l'antigene cd30 de la membrane cellulaire humaine
WO1999040187A1 (fr) * 1998-02-06 1999-08-12 Hinrich Abken Acides nucleiques pour la modulation de l'activation cellulaire
WO2002017970A3 (fr) * 2000-08-28 2003-01-09 Ludwig Inst Cancer Res Anticorps de cd-30 etiquetes par radionucleides metalliques et leur utilisation
EP1482972A2 (fr) * 2001-11-20 2004-12-08 Seattle Genetics, Inc. Traitement des troubles immunologiques au moyen des anticorps anti-cd30
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

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* Cited by examiner, † Cited by third party
Title
Anticancer Research, volume 8, 1988, (Athens, GR), M. Pfreundschuh et al.: "Hodgkin and reed-sternberg cell associated monoclonal antibodies HRS-1 and HRS-2 react with activated cells of lymphoid and monocytoid origin", pages 217-224 see page 217, abstract; page 219, table 1 cited in the application *
Cancer Research, volume 48, 1988, (Philadelphia, US), M.A. Chetie et al.: "Evalution of ricin A chain-containing immunotoxins directed against CD19 and CD22 antigens on normal and malignan human B-cells as potential reagents for in vivo therapy1", pages 2610-2617, see page 2610, abstract cited in the application *
Cancer Research, volume 50, 1 January 1990, (Philadelphia, US), A. Engert et al.: "Evaluation of ricin A chain-containing immunotoxins directed against the CD30 antigen as potential reagents for the treatment of Hodgkin's disease1", pages 84-88 see page 84, abstract *
Cancer Research, volume 50, 15 May 1990, (Philadelphia, US), A. Engert et al.: "Antitumor effects of ricin A chain immunotoxins prepared from intact antibodies and fab fragments on solid human Hodgkin's disease tumors in mice1", pages 2929-2935 see page 2929, abstract *
Cancer Surveys, volume 4, no. 2, 1985 (Oxford, GB), V. Diehl et al.: "Phenotypic and genotypic analysis of Hodgkin's disease derived cell lines: histopatholigical and clinical implications", pages 399-419 see pages 399-400, summary; page 403, table 2; page 411-412, especially page 411, line 116 *
Leucocyte Typing, volume 3, 1987, A.J. Michel (ed.), Oxford, University Press, (Oxford, GB), R. Schwarting et al.: "BER-H2: a new monoclonal antidody of the Ki-1 family for the detection of Hodgkin's disease in formaldehyde-fixed tissue sections", pages 574-575 see the whole article cited in the application *

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6667039B1 (en) 1992-05-26 2003-12-23 Immunex Corporation CD30 ligand
US5480981A (en) * 1992-05-26 1996-01-02 Immunex Corporation CD30 ligand
US5677430A (en) * 1992-05-26 1997-10-14 Immunex Corporation Antibodies directed against CD30 ligand
US7232660B2 (en) 1992-05-26 2007-06-19 Immunex Corporation CD30 ligand
US6143869A (en) * 1992-05-26 2000-11-07 Immunex Corporation CD30 ligand oligomers and polypeptides
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
EP0657533A1 (fr) * 1993-10-30 1995-06-14 Biotest Pharma Gmbh Anticorps monoclonaux avec une cytotoxicité élévée contre l'antigène CD16 humain, et des anticorps monclonaux bispécifiques utilisant tels anticorps monoclonaux et des anticorps CD30-HRS-3
US5643759A (en) * 1993-10-30 1997-07-01 Biotest Pharma Gmbh Method for preparing bispecific monoclonal antibodies
WO1996022384A1 (fr) * 1995-01-18 1996-07-25 Boehringer Mannheim Gmbh Anticorps anti-cd30 prevenant le clivage proteolytique et la liberation de l'antigene cd30 membranaire
WO1996040260A3 (fr) * 1995-06-07 1997-02-20 Innogenetics Nv Immunotoxines specifiques aux cellules exprimant cd80 et cd86
AU709988B2 (en) * 1995-06-07 1999-09-09 Innogenetics N.V. Immunotoxins specific for CD80 and CD86 expressing cells
US6071519A (en) * 1995-06-07 2000-06-06 Innogenetics N.V. Immunotoxins specific for CD86 expressing cells
WO1997017374A1 (fr) * 1995-11-08 1997-05-15 Medac Gesellschaft Für Klinische Spezialpräparate Gmbh Ligands de recombinaison pour l'antigene cd30 de la membrane cellulaire humaine
WO1999040187A1 (fr) * 1998-02-06 1999-08-12 Hinrich Abken Acides nucleiques pour la modulation de l'activation cellulaire
WO2002017970A3 (fr) * 2000-08-28 2003-01-09 Ludwig Inst Cancer Res Anticorps de cd-30 etiquetes par radionucleides metalliques et leur utilisation
US7090843B1 (en) 2000-11-28 2006-08-15 Seattle Genetics, Inc. Recombinant anti-CD30 antibodies and uses thereof
EP1482972A2 (fr) * 2001-11-20 2004-12-08 Seattle Genetics, Inc. Traitement des troubles immunologiques au moyen des anticorps anti-cd30
EP1482972A4 (fr) * 2001-11-20 2005-11-23 Seattle Genetics Inc Traitement des troubles immunologiques au moyen des anticorps anti-cd30
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

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