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WO1994004189A1 - Anticorps/radio-isotope conjugues de diagnostic et/ou therapie de tumeurs - Google Patents

Anticorps/radio-isotope conjugues de diagnostic et/ou therapie de tumeurs Download PDF

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Publication number
WO1994004189A1
WO1994004189A1 PCT/EP1993/002293 EP9302293W WO9404189A1 WO 1994004189 A1 WO1994004189 A1 WO 1994004189A1 EP 9302293 W EP9302293 W EP 9302293W WO 9404189 A1 WO9404189 A1 WO 9404189A1
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Prior art keywords
antibody
ber
cells
mab
vivo
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Ceased
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PCT/EP1993/002293
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English (en)
Inventor
Harald Stein
Brunangelo Falini
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Medac Gesellschaft fuer Klinische Spezialpraeparate mbH
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Medac Gesellschaft fuer Klinische Spezialpraeparate mbH
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Priority to AU49536/93A priority Critical patent/AU4953693A/en
Publication of WO1994004189A1 publication Critical patent/WO1994004189A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1045—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1093—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • the invention relates to pharmaceutical compositions for thera ⁇ Chamberic and/or diagnostic use comprising an antibody conjugate consisting of a monoclonal antibody with binding affinity to the CD30 cell surface antigen and a radioactive isotope linked to the antibody either directly or through a linker molecule or by means of a chelating agent.
  • immunoscintigraphy is regarded as an important adjunct to conventional imaging procedures such as CAT scan (CT), NMR or ultrasound (US). Immunoscintigraphy can also be applied as "im- munoscintimetry" , i.e. for the quantification of tumor vitality expressed as tumor uptake or in evaluating therapy response. The diagnosis of primary tumors is not yet a main indication for immunoscintigraphy, and immunoscintigraphy is also not suitable for tumor screening.
  • HAJA Human anti-mouse antibodies
  • radioimmunotherapy has shown significant therapeutic effects in non-solid cancers, especially in the treatment of hematological neoplasias, e.g. lymphomas and leukemias (35, 36).
  • Imaging modalities comprise X-ray CT scan, sono- graphy, magnetic resonance imaging (all morphologically orienta ⁇ ted) and nuclear medicine methods like gallium-67 scintigraphy and skeletal and bone marrow scintigraphy as well as positron- emission tomography (PET using F-18-FDG) .
  • CT and sono- graphy are very sensitive but show a low specificity especially after treatment.
  • Gallium scintigraphy has a low sensitivity in some areas and cannot differentiate between inflammatory changes and tumor involvement.
  • the problem which is underlying the present invention is to provide a pharmaceutical composition, which is used for detec ⁇ ting tumor cells and/or for tumor therapy in cases that are resistant to conventional therapy.
  • the pharmaceutical composi ⁇ tions should have a high binding activity as well as a high - A
  • a pharmaceutical composition comprising an antibody conjugate consisting of a monoclonal antibody with binding affinity to the CD30 cell surface antigen and a radioactive isotope linked to the antibody either directly or through a linker molecule or by means of a chelating agent.
  • compositions of the present invention are prepared for use as a diagnostic agent for the detection of tumor cells by radioi aging and/or for use as a therapeutic agent for the treatment of human malignances characterized by the expression of CD30 surface antigen.
  • compositions of the present inven ⁇ tion are characterized by the high binding affinity and the high specifity of the antibodies contained therein. Since signifi ⁇ cantly less or no cross-reactivity with other tissues is obser ⁇ ved, no side-reactions occur with the compositions of the pre ⁇ sent invention.
  • the radioisotopes are linked to the antibodies by way of direct or indirect methods.
  • chelating agents which are bound to the antibody are used to form strong complexes with the respective radioi ⁇ sotopes (40).
  • the well known N 2 S 2 technique (41) is another ex ⁇ ample for an indirect method which can be applied according to the present invention.
  • thiol (SH) groups of the antibodies are photoactivated (42) or chemically activated (43) .
  • the antibo ⁇ dies of the pharmaceutical compositions are the murine antibody Ber-H2 or any other antibody that recognizes the Ber-H2 epitope.
  • the monoclonal antibody (mAb) Ber-H2 (CD30) antibody was briefly described in 1987 and in more detail in 1989 by R. Schwarting et al.
  • the antibody is produced by the equally named Hybridoma, which has been deposited at the European Collection of Animal Cell Culture (ECACC), Public Health Laboratory Service, Porton Down, Salisbury, Wiltshire, U.K., under the conditions of the Budapest Treaty under the preliminary number Ber-H2 92012823 on January 28, 1992.
  • the Ber-H2 murine monoclonol antibody (mAb) (1) recognizes a fixative-resistant epitope of the activation antigen CD30 (Ki-1) (2), a glycoprotein of 120 kD which is strongly expressed on the surface of Hodgkin's (H) and Reed-Sternberg (R-S) cells of Hodg- kin's disease (HD) (3,5), and all cells of the newly recognized category of high-grade non-Hodgkin's lymphoma, the anaplastic large cell (ALC) lymphoma (6,8).
  • the Ber-H2 mAb only reacts with a small population of large cells preferentially localized around B cell follicles.
  • Ber-H2 As a diagnostic agent, it is crucial that the in vivo distribution of the monoclonal antibody after intrave ⁇ nous application is the same as the CD30 antigen, i.e. that the Ber-H2 will bind in vivo similarly specific to the CD30 antigen as in vitro. It is in fact well known that a number of important factors, including the stability, isotype and molecular size of the mAb, the presence of the target antigen in the serum, the size, sclerosis and vascularization of the tumors, the permeabi ⁇ lity of the vessels to the antibody, and the ability of the antibody to reach its target without being cleared by the liver or spleen may affect the in vivo distribution of a given mAb (9,10).
  • the Ber-H2 mAb fulfilled all essential prerequisites for its use as a diagnostic agent and consequently for its therapeu ⁇ tic application as a radiopharmaceutical. It is able to reach the tumor cells (Hodgkin and - Reed-Sternberg cells) in a suffi ⁇ ciently high concentration when given intravenously and it is unreactive with normal human tissues in vivo.
  • tumor cells Hodgkin and - Reed-Sternberg cells
  • the present invention is based on clear evidence that: a) immunoscintigraphy with radiolabeled Ber-H2 mAb (CD30) allow the sites involved by Hodgkin's disease to be detected; b) when injected in vivo, the Ber-H2 mAb binds exclusively to H and RS, which is entirely consistent with the Ber-H2 staining pat ⁇ tern previously described in vitro using frozen sections; c) complete saturation of CD30 binding sites on H and RS cells in all sites involved by HD can be achieved; d) there are no side effects associated with the administration of unmodified Ber-H2 in the dosage used in this study; e) strong in vivo binding of the unmodified Ber-H2 to H and RS cells does not produce any anti-tumor effect.
  • CD30 radiolabeled Ber-H2 mAb
  • the disadvantage of 131 I is its high amount of ⁇ -emission. For imaging ⁇ emission is required. The relatively long half-life of I leads to a lower imaging quality.
  • the radioisotope can be linked to the antibody by chelating agents or other spacer molecules. It is the advantage of In that the half-life of the radioisotope corresponds to the biological half-life of antibodies, which leads to an efficient use of the respective antibody conjugates. go—
  • T.c is another radionuclide which can be used for radioimmuno- imaging. It has a very short half-life and its costs are low, because it is a generator product. As the radiation dose is low, this radioisotope allows a relatively harmless handling or ap ⁇ plication in radioimmunoimaging, for the physician as well as for the patient.
  • the difficult linker chemistry i.e. the strong binding of the radioisotope to the antibody, is the only dis ⁇ advantage when using 99m Tc.
  • Ber-H2 differs from the prototype CD30 mAb Ki-1 (IgG3 subclass) that has been reported to react with activated macrophages (30).
  • Ki-1 IgG3 subclass
  • the invention provides immunohistological evidence for the sur ⁇ prisingly high avidity in vivo binding of Ber-H2 mAb to H and RS cells, as demonstrated by the fact that a complete saturation could be reached at all in vivo CD30 binding sites on H and RS cells in all body sites involved in the disease (lymph nodes, spleen and bone marrow) .
  • the dose necessary was much lower than that reported to be necessary for good in vivo targeting of solid tumors (31) and other human lymphomas (32).
  • the in vivo targeting of H and RS cells in the patients occurred under con ⁇ ditions considered to have a negative influence on the bio-dis ⁇ tribution of mAbs within neoplastic tissues, e.g. lymph node or splenic or extranodal and extrasplenic "bulky disease" (cases 1 and 2) areas of necrosis in the spleen (case 2) and nodular sclerosing histology (case 3).
  • neoplastic tissues e.g. lymph node or splenic or extranodal and extrasplenic "bulky disease" (cases 1 and 2) areas of necrosis in the spleen (case 2) and nodular sclerosing histology (case 3).
  • the immunohistological results obtained according to the inven ⁇ tion provide the rational basis for using the Ber-H2 mAb as a therapeutic agent for CD30-expressing neoplasms (e.g. HD and ALC lymphomas) in conjunction with other therapeutic regimens and especially for those cases that are resistant to conventional therapy.
  • Hodgkin's disease is an ideal model for this purpose since: a) the percentage of neoplastic cells is relatively low; b) the Ber-H2 mAb does not significantly cross-react with normal human tissues and c) most cases of HD are highly radiosensitive.
  • the fin ⁇ dings according to the present invention demonstrate that such a therapeutic effect can be obtained by administering low doses of Ber-H2 immunoconjugates.
  • 90Y As ⁇ radiation is required for radioimaging, 90Y, which is a pure ⁇ emitter can only be applied for therapeutic uses. Because of its high energy, lower doses of antibody conjugates are necessa ⁇ ry and the depth of penetration in tissue (6 mm) can be of use in some applications. Since yttrium is osteophilic, the problem associated with the use of 90Y is its toxicity for bone marrow.
  • rhenium isotopes are utilized. Wheras 188Re as a generator product is very cheap, 186Re is much more expensive. Because of their relatively low specific activity comparatively higher doses of rhenium isotopes are required for therapy as compared to yttrium.
  • rhenium isotopes can advantageously be utilized in the form of an antibody conjugate both for therapeutic and imaging (i.e. diagnosis or quantification) applications without the need of subjecting the patient to separate injections of antibody conjugates for diagnosis and therapy.
  • compositions according to the pre ⁇ sent invention may be applied as pure antibody preparations
  • the conjugates can be formulated together with suitable pharmaceu ⁇ tically acceptable carriers and aiding substances, respectively.
  • the pharmaceutical compositions are in a suitable form for in ⁇ jection.
  • Preferably 1 to 2 mg of antibody cojugate are utilized for ima ⁇ ging and 10 to 50 mg per single injection are used for therapy depending on the specific activity.
  • the invention is further described below by way of examples, wherein the in vivo targeting of H and RS cells was assessed in four patients by two different methods: a) radioimaging of the tumor following injection of a diagnostic dose of 131I-labeled Ber-H2 mAb; and b) immunohistological analysis of tissue sec ⁇ tions, for direct evidence of antibody localization on the tumor cell membrane.
  • Figure 1 is an abdominal CT scan of Patient 1 which shows large lymph node masses between the two kidneys.
  • Figure 2 is a SPECT (single photon emission computerized tomo ⁇ graphy) taken at the same abdominal level as Fig. 1. Lymph node masses (T) are imaged by 131 I Ber-H2 (72 hours after the infu ⁇ sion) .
  • Figure 3 is an anterior view of the head 48 hours following Ber-H2 infusion (Patient 3). A left neck lymphoma mass (T) is clearly imaged (* indicates thyroid uptake).
  • Figure 4 is a left neck lymph node biopsy from the same patient as Fig. 5, taken 72 hours following Ber-H2 infusion, a) Frozen section incubated only with rabbit anti-mouse antiserum and developed by the APAAP technique. Clusters of H and RS cells encased by fibrous tissue are strongly labeled in red. Notice the thickened node capsule (C) (hematoxylin counterstain; x 125); b and c) Higher power views of the same field as Fig. 6a showing strong surface in vivo targeting of tumor cells surroun ⁇ ded by fibrous tissue (6c) (hematoxylin counterstain; x 500).
  • Figure 5 The spleen removed at staging laparotomy shows massive involvement by HD (Patient 2).
  • Figure 6 Frozen section from the spleen nodules shown in Fig. 5 following incubation with rabbit anti-mouse antiserum and developed by the APAAP technique ( * Indicates a central arteriole. Hematoxylin counterstain; x 400).
  • the Ber-H2 mAb (mouse IgGl) was purified from conventional hy- bridoma culture supernatant by affinity chromotography on pro ⁇ tein A-sepharose CL-4B, as previously described (12).
  • the anti ⁇ body was eluted with 0.5 M citrate buffer pH 5.0, and dialysed against 0.01 M PBS, pH 7.2.
  • the antibody preparation was more than 98% pure as determined by cross immunoelectrophoresis and SDS-PAGE analysis. After ultracentrifugation to remove microag- gregates, the preparation was passed through a 0.2 ⁇ filter (Millipore) to ensure sterility, and stored at -70 °C prior to use.
  • the purified antibody passed the safety control tests as established by the document entitled " dirten fur die Her- wolf und Prufung in vivo applizierbarer monoklonaler Antik ⁇ rper” (13).
  • the antibody preparation was shown to be free from bacteria, fungi and adventitious viruses.
  • the absence of murine viral contaminants was demonstrated by the mouse antibody production (MAP) test, in which contamination with 16 murine viruses was evaluated by injection of the test article into mice and determination of antibody production to the viruses of interest.
  • MAP mouse antibody production
  • the Limulus A ebocyte Lysate assay for endotoxin was negative.
  • the total content of DNA per dose was less than 10 picograms.
  • Patient 1 received 0.5 mg I-Ber-H2.
  • Studies of scaled-up doses were performed by co-injection of the other patients with 14 mg, 29 mg, or 39 mg unlabeled Ber-H2 mAb and 1 mg 131 I-Ber-H2 for a total dose of approximately 15 mg, 30 mg and 40 mg respectively (Table 1) . - 15 -
  • Cs Clinical staging
  • PS Pathological stating
  • BMT Autologous bone marrow transplantation
  • IL-2 high dose interleukin-2 the ⁇ rapy
  • HD Hodgkin's desease
  • NS Nodular sclerosing
  • LD lympho ⁇ cyte depletion
  • MC Mixed cellular!ty.
  • I-Ber-H2 using regions of interest analysis (thyroid, lungs, heart, liver, spleen, kydney and lymph nodes) was determined by the geometrical mean method of count rates corrected for decay and background and expressed as a percentage of whole body reac ⁇ tivity (17-19) .
  • Plasmatic, urinary and fae ⁇ cal radioactivity were measured by counting an aliquot of each in a Na ⁇ (Tl) well detector interphased to a multichannel analy ⁇ zer. Nonlinear regression calculations were then performed by Marquardt's method to determine standard pharmacokinetic parame ⁇ ters. - 17 -
  • Patient 2 underwent a re-staging exploratory laparoto y 72 hours following infusion of the radiolabeled antibody. Intraoperatively, the spleen and several abdominal lymph nodes were removed; wedge liver biopsies and a Jamshidy bone marrow biopsy were also per ⁇ formed. Patients 3 and 4 had a lymph node biopsy performed 48 and 24 hours respectively following injection of mAb.
  • Pre-infusion serum levels of soluble CD30 molecule in the serum were determined in all patients by an ELISA technique, as pre ⁇ viously described (26).
  • BM Bone marrow
  • CE clinical examination
  • CT Computed tomo ⁇ graph
  • med./hil. mediastinal and hiler
  • H & RS Hodgkin and Reed-Sternberg cell
  • HD Hodgkin disease
  • NS Nodular sclero- sing
  • MC Mixed cellularity
  • n not available
  • E equivocal image due to the high blook background.
  • Pre-infusion bone marrow biopsies Pre-infusion bone marrow biopsies; post-infusion bone marrow biopsy.
  • Patient 1 had a large (10 cm) mass and multiple pulmonary nodu ⁇ les.
  • the mass in the abdomen was visualiz.'-d by 131 I-Ber-H2 and was clearer with SPECT than with planar scintigram (Figs. 1 and 2).
  • lung lesions were not detected by immunoscintigra ⁇ phy.
  • Patient 2 had pathologically changed abdominal lymph nodes that were regarded as normal at CT, suspicious at lymphangiography, and were not positively imaged by I-Ber-H2. Enlarged media ⁇ stinal and hilar lymph nodes at CT scan were also documented by immunoscintigraphy.
  • Patient 3 had several enlarged lymph nodes (2.5 cm) in the left supraclavear region. Optimal imaging of nodes in the neck was obtained 48 hours following 131 I-Ber-H2 injection (Fig. 3). As a control, no targeting of the neck nodes was observed following
  • Patient 4 had a small lymph node (1.5 cm) in the left laterocer- vical region and several enlarged lymph nodes (3 cm) in paracor- tic and iliac regions. At the time when the node in the neck was removed for immunohistological studies (24 hours following in ⁇ jection of 131 I-Ber-H2) , there was no positive imaging. Abdomi ⁇ nal lymph nodes were well visualized by I-Ber-H2 at 72 hours.
  • Non-specific liver and spleen uptake was seen in all patients. Thyroid and urinary bladder uptake of I-Ber-H2 in all injec ⁇ ted patients indicates in vivo dehalogenation. Thyroid uptake occurred in spite of the administration of Lugol solution, but did not cause hypothyroidism in any of our patients. A similar degree of liver, spleen and thyroid uptake has been reported in other studies that used 131I-labeled mAbs for the imaging of cutaneous T cell lymphomas (16) and non-Hodgkin lymphomas of B cell type (19) .
  • Table 3 summarizes the intercept (Ao) and the half time (Tl/2) obtained from both sing ⁇ le organs and tumor by a monoexponential model non-linear re ⁇ gression analysis.
  • Biexponentially calculated pharmacokinetic parameters are given in Table 4. - 22 -
  • the liver was not histologically involved by HD and no Ber-H2 binding was detected in the organ at immunohistological level. In consequence, the exact localization of 131 I-Ber-H2 in the liver could not be established.
  • Patient 3 had a clinically involved left latero-cervical lymph node, that was also positive on scanning, removed 48 hours fol ⁇ lowing Ber-H2 infusion.
  • the histological pattern was that of a nodular sclerosis HD rich in H and RS cells.
  • Direct incubation of frozen lymph node sections with secondary rabbit anti-mouse immunoglobulin antibody followed by APAAP complexes gave strong surface staining of H and RS cells (Fig. 4 a,b). All neoplastic cells in the different areas of the frozen sections, including those encased by bundles of fibrous tissue (Fig. 4c), were labe ⁇ led, indicating in vivo bound Ber-H2.
  • Pretreatment CD30 serum levels were as follows: patient 1 (400 U/l), patients 2 and 3 (not detectable), patient 4 (100 U/l). - 26 -
  • Fraker PJ, Speck JC Protein and cell membrane iodination with a sparingly soluble chloramide l,3,4,6,-tetrachloro-3o. Biochem Biophys Res Commun 80:849, 1978 - 28 -

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Abstract

Des compositions pharmaceutiques utiles en thérapie et/ou en diagnostic comprennent un anticorps conjugué constitué d'un anticorps monoclonal à affinité de liaison avec l'antigène CD30 de la surface cellulaire et un isotope radio-actif lié à l'anticorps directement ou par l'intermédiaire d'une molécule de liaison ou d'un agent chélateur. Dans un mode de réalisation préféré de l'invention, ces anticorps sont l'anticorps murin Ber-H2 ou un autre anticorps qui reconnaît l'épitope Ber-H2. Des isotopes appropriés pour cette invention sont par exemple ?99mTc, 111In, 123I, 131I, 186Re, 188Re et 90¿Y.
PCT/EP1993/002293 1992-08-25 1993-08-25 Anticorps/radio-isotope conjugues de diagnostic et/ou therapie de tumeurs Ceased WO1994004189A1 (fr)

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AU49536/93A AU4953693A (en) 1992-08-25 1993-08-25 Antibody/radioisotope conjugate for tumor diagnosis and/or therapy

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EP92250225.7 1992-08-25
EP92250225 1992-08-25

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996009075A1 (fr) * 1994-09-21 1996-03-28 Keshelava Viktor V Procede de traitement d'affections malignes
DE19543039C1 (de) * 1995-11-08 1996-11-21 Medac Klinische Spezialpraep Rekombinante Liganden für das menschliche Zellmembran-Antigen CD30
WO2002017970A3 (fr) * 2000-08-28 2003-01-09 Ludwig Inst Cancer Res Anticorps de cd-30 etiquetes par radionucleides metalliques et leur utilisation
EP1378523A1 (fr) * 2002-07-01 2004-01-07 STEIN, Harald, Prof. Dr. Anticorps anti-cd30 et utilisations de ceux-ci
US7387776B2 (en) 2002-01-09 2008-06-17 Medarex, Inc. Human monoclonal antibodies against CD30
CZ300074B6 (cs) * 2006-12-20 2009-01-21 Azacycles S. R. O. Inteligentní trífunkcní makrokonjugáty a farmaceutický nebo diagnostický prostredek s jejich obsahem
US7790160B2 (en) 2004-10-01 2010-09-07 Medarex, Inc. Method of treating CD30 positive lymphomas
US8138313B2 (en) 2007-06-15 2012-03-20 Deutsches Krebsforschungszentrum Stiftung Des Offentlichen Rechts Treatment of tumors using specific anti-L1 antibody
US8207303B2 (en) 2005-02-18 2012-06-26 Medarex, Inc. Monoclonal antibodies against CD30 lacking in fucosyl residues
WO2018115485A1 (fr) 2016-12-22 2018-06-28 Pierfrancesco Tassone Anticorps monoclonal ciblant un épitope de cd43 unique associé au cancer sialoglycosilé
US10400037B2 (en) 2014-09-30 2019-09-03 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Binding molecules, especially antibodies, binding to L1CAM (CD171)

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WO1991007437A2 (fr) * 1989-11-20 1991-05-30 Parker, David, L. Anticorps cd-30 ameliores et fragments de ces derniers
WO1993017715A1 (fr) * 1992-03-05 1993-09-16 Board Of Regents, The University Of Texas System Agents diagnostiques et/ou therapeutiques cibles sur des cellules endotheliales neovasculaires

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WO1991007437A2 (fr) * 1989-11-20 1991-05-30 Parker, David, L. Anticorps cd-30 ameliores et fragments de ces derniers
WO1993017715A1 (fr) * 1992-03-05 1993-09-16 Board Of Regents, The University Of Texas System Agents diagnostiques et/ou therapeutiques cibles sur des cellules endotheliales neovasculaires

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996009075A1 (fr) * 1994-09-21 1996-03-28 Keshelava Viktor V Procede de traitement d'affections malignes
DE19543039C1 (de) * 1995-11-08 1996-11-21 Medac Klinische Spezialpraep Rekombinante Liganden für das menschliche Zellmembran-Antigen CD30
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
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US8088377B2 (en) 2002-01-09 2012-01-03 Medarex, Inc. Human monoclonal antibodies against CD30
EP1378523A1 (fr) * 2002-07-01 2004-01-07 STEIN, Harald, Prof. Dr. Anticorps anti-cd30 et utilisations de ceux-ci
US7335741B2 (en) 2002-07-01 2008-02-26 Harald Stein Means for use in diagnostics and/or therapy
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
CZ300074B6 (cs) * 2006-12-20 2009-01-21 Azacycles S. R. O. Inteligentní trífunkcní makrokonjugáty a farmaceutický nebo diagnostický prostredek s jejich obsahem
US8138313B2 (en) 2007-06-15 2012-03-20 Deutsches Krebsforschungszentrum Stiftung Des Offentlichen Rechts Treatment of tumors using specific anti-L1 antibody
US9260521B2 (en) 2007-06-15 2016-02-16 Medigene Ag Treatment of tumors using specific anti-L1 antibody
US10400037B2 (en) 2014-09-30 2019-09-03 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Binding molecules, especially antibodies, binding to L1CAM (CD171)
WO2018115485A1 (fr) 2016-12-22 2018-06-28 Pierfrancesco Tassone Anticorps monoclonal ciblant un épitope de cd43 unique associé au cancer sialoglycosilé
US11174318B2 (en) 2016-12-22 2021-11-16 Università Degli Studi Magna Graecia Catanzaro Monoclonal antibody targeting a unique sialoglycosylated cancer-associated epitope of CD43
US11965033B2 (en) 2016-12-22 2024-04-23 Università Degli Studi Magna Graecia Catanzaro Monoclonal antibody targeting a unique sialoglycosylated cancer-associated epitope of CD43

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