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WO1997035614A1 - Utilisation d'anticorps contre la glycoproteine cd48 pour le traitement des lymphomes et des leucemies des cellules t et b - Google Patents

Utilisation d'anticorps contre la glycoproteine cd48 pour le traitement des lymphomes et des leucemies des cellules t et b Download PDF

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WO1997035614A1
WO1997035614A1 PCT/AU1997/000195 AU9700195W WO9735614A1 WO 1997035614 A1 WO1997035614 A1 WO 1997035614A1 AU 9700195 W AU9700195 W AU 9700195W WO 9735614 A1 WO9735614 A1 WO 9735614A1
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antibody
cells
human
cell
antibodies
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PCT/AU1997/000195
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English (en)
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Glenn Martin Smith
Haiping Sun
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Crc For Biopharmaceutical Research Pty. Ltd.
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Priority claimed from AUPN8962A external-priority patent/AUPN896296A0/en
Priority claimed from AUPN9035A external-priority patent/AUPN903596A0/en
Application filed by Crc For Biopharmaceutical Research Pty. Ltd. filed Critical Crc For Biopharmaceutical Research Pty. Ltd.
Priority to JP9532935A priority Critical patent/JP2000509015A/ja
Priority to AU21435/97A priority patent/AU2143597A/en
Publication of WO1997035614A1 publication Critical patent/WO1997035614A1/fr

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    • 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
    • C07K16/2803—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 immunoglobulin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • the present invention relates to a method of treating T and B cell lymphomas and leukemias.
  • the method involves the use of antibodies targetted against CD48. BACKGOUND OF INVENTION
  • MoAbs monoclonal antibodies
  • hybridomas Because MoAbs can bind to antigens expressed on the surface of malignant hematopoietic cells, optimistic projections proclaimed that these agents could be used in serotherapy to specifically target and destroy those cells. Moreover, by offering distinct cytotoxic mechanisms, MoAb therapy could potentially circumvent tumour cell resistance.
  • a number of major obstacles have limited the potential of this approach, including the problems of immunogenicity of rodent immunoglobulins, modulation of antigen by tumour cells, non-specific uptake of antibody by phagocytes, low binding affinity of some antibodies, and circulating antigen in the plasma in certain situations.
  • CD48 a 47kd glycophosphatidylinositol-linked glycoprotein, has a number of characteristics which suggest it may be a good target for immunotherapy.
  • CD48 is expressed on a wide range of lymphoid malignancies but not other tissues (2,3,4). Although both normal and malignant T and B cells express CD48, most CD34 positive cells do not express CD48. CD48 is also present at high levels on the surface of T and B cells. The biological function of CD48 in humans is still not clear. In mice CD48 is a high affinity ligand of CD2 (5) but is a low affinity ligand of human CD2 (6,7).
  • Anti-CD48 antibodies have been described (3), and one such antibody has been trialed for use in anti-tumour therapy (13). This trial involved the injection of up to 50mg of an IgM anti-CD48 antibody into four patients with Chronic Lymphatic Leukemia. However, only transient drops in circulating lymphocytes were observed. No impact on the progression of the underlying disease was observed in any patient. These results suggest that anti-CD48 antibodies do not provide strong anti-tumour effects.
  • the present invention consists in a method of treating T or B cell lymphomas or leukemias which method includes administering to a subject in need thereof an antibody of class IgG directed against CD48.
  • the IgG isotype may be an isotype selected from mouse IgG2a, human IgGl, human IgG2 and rat IgG2b.
  • the preferred isotype is human IgGl or IgG2.
  • the preferred isotype is mouse IgG2a.
  • the preferred isotype is rat IgG2b.
  • the term 'antibody' refers to any specific binding substance having a binding domain with the required specificity.
  • the term covers antibody fragments, derivatives, functional equivalents and homologues of antibodies, including any polypeptide including an immunoglobulin binding domain, whether natural or synthetic. Chimeric molecules including an immunoglobulin domain, or equivalent, fused to another polypeptide are therefore included.
  • the antibody is directed against the HuLym-3 antigen which has recently been cloned and sequenced (9).
  • Chimeric anti-CD48 antibodies in which the Fc portion is replaced with a human Fc region, exhibit improved characteristics over murine anti-CD48 antibodies. These characteristics may include higher effector function, longer serum half-life and lower immunogenicity.
  • the antibody directed against CD48 is a chimeric (or humanised) antibody.
  • the chimeric antibody may be a murine antibody in which at least part of the Fc portion is replaced with a human Fc portion.
  • the efficacy of the anti-CD48 antibody may be enhanced by conjugation to, for example, a radioisotope, cytokine, protein toxin or anti-cancer agent.
  • the anti-cancer agent may be selected from doxorubicin, cisplatin, taxol, interferon, Pseudomonas exotoxin A, fumagillin, AGM-1470, tamoxifen, nitrosureas including ACNU, BCNU, CCNU and PCNU, diaziquone, decarbazine, hydrea, semustine, matulone, teniposide and terazante.
  • the method of the first aspect of the present invention may be used to treat non-Hodgkin's lymphoma or lymphoid leukemias.
  • CD48 is expressed on less than 5% of CD34 positive progenitor cells.
  • anti-CD48 antibodies should target lymphocytic leukemia and lymphoma cells whilst leaving the majority of CD34+ progenitor cells to expand and repopulate depleted cell types.
  • the HuLym3 hybridoma cell line was a gift from Dr. Mauro S Sandrin, The Austin Research Institute, Melbourne (17) and was cultured in RPMI1640 with either 10% foetal bovine serum (FBS) or 10% bovine IgG free serum (Starrate), 2 mM glutamine at 37°C in a 37° incubator.
  • the cell lines COS1, CHO-K1, Raji, Daudi, MOLT-4, U-937 and CCRF-CEM where obtained from ATCC.
  • COS and CHO cells where cultured in 1:1 DMEM/F12 (CSL) with 10% FBS at 37°C, 5% CO2.
  • Raji, Daudi, MOLT-4, U-937 and CCRF-CEM where cultured in RPMI 1640, 2mM glutamine, 10% FCS at 37°C and 5% CO2.
  • Antibody (IgG2a) was purified from HuLy-M3 hybridoma conditioned media or from ascites fluid produced in either nude mice or BalbC/CBA crosses using protein A affinity chromatography (Pharmacia). The purity of the antibody was confirmed by 10% SDS-PAGE and the activity confirmed by flow cytometry using human leukemic cell lines. For animal experiments the antibody was further purified by ion exchange chromatography and gel filtration. An IgG2a isotype control antibody (anti-human TSH) was obtained from Bioquest and repurified as above. Protein concentration was estimated by absorbance at 280nm (18). Rat Ca ⁇ path-1 antibody was a gift from Bob Hale, MRC, Cambridge, UK. The IgM anti-CD48 antibody WM63 was obtained from Ken Bradstock, Department of Haematology, Westmead Hospital.
  • Human peripheral blood (10 ml from patients and 50ml from normals) was obtained from normal individuals or CLL and NHL patients of St Vincent's Hospital, Sydney, Australia and was collected into EDTA tubes to prevent clotting and lymphocytes and monocytes (PBMC) prepared on a Ficoll gradient. Viable cells were counted by Trypan-Blue exclusion and resuspended to a final concentration, in PBS, of 1 x IO 6 cells/ml.
  • anti-CD34-FITC, anti-CD45-PerCP and biotinylated anti-CD48 or isotype control antibodies were incubated with 5.0 x IO 6 cells for 30 minutes at 4°C washed once with 2 ml of wash media (PBS/1% BSA), streptavidin-PE was then added for 30 minutes at 4°C.
  • Cells were washed twice, fixed in 500 ⁇ l of fixing buffer containing 1% sucrose and 0.5% paraformaldehyde in PBS and if not profiling immediately, stored at 4°C with the addition of 1 ml of PBS/1% BSA. Fluorescence was estimated within 24 h of sample preparation on a Coulter Epics flow cytometer.
  • FITC conjugated anti-mouse or anti-human IgGl antibody was added for 30 minutes at 4°C. After washing with cold PBS/1% BSA twice, the cells were fixed with 0.5% paraformadehyde, 1% sucrose in PBS for 15 minutes at room temperature and resuspended in PBS/1% BSA before analysis by flow cytometry.
  • human PBMC were prepared and incubated with test monoclonal antibody at 4°C and/or 37°C as described above. After washing, the cells suspensions were duplicated and fixed either with 4% paraformadehyde in PBS (cell surface stain) or 4% paraformadehyde/0.1% Triton X-100 in PBS (intracellular and surface stain) for 30 minutes at room temperature. After washing with PBS/1% BSA, the cells were incubated with FITC conjugated anti-mouse or anti-human IgGl antibody for 30 minutes at 4°C.
  • confocal laser scanning microscopy was performed using a Sarastro 2000 CLSM (Molecular Dynamics, Sunnyvale, CA, USA), with a plan apochromat 60x/1.40 NA oil immersion lens and an argon-ion class II laser.
  • Optical sections (usually 0.3 mm intervals) through FITC-labelled cells were captured using a 50mm fixed pinhole, with excitation at 488 nm, a 510 nm beam splitter and a 510nm barrier filter. Image processing was performed using a Silicon Graphics Personal Iris 4D 35 workstation. The cell viability was examined by Trypan blue exclusion. Therapy of SCID mice with Raji lymphoma by HLM3
  • mice Six to eight-week old female SCID mice (CB17) were commercially obtained from Animal Resources Centre, Western Australia. Mice were housed in a Cl Lab maintained as a specific pathogen-free (SPF) facility. Groups of five mice were injected intravenously with Raji cells in RPMI 1640
  • cDNA was subjected to 35 cycles of PCR in separate tubes with various 5'- primers (Ig - Prime Kit, Novagen).
  • the VH and VL PCR products were cloned into T-vector (20) by electroporation and transformed into E coli (DH5a). All of the VH and VL PCR products were DNA sequenced using T7 Sequencing kit (Pharmacia Biotech) in both forward and reverse directions.
  • amino acid sequence of the heavy and light chains was determined by N - Terminal amino acid sequencing of the alkylated seperated chains in a 477A Protein Sequencer & 120A Analyser ( Applied Biosystems ).
  • VH and VL were re-PCR amplified to introduce a 5' Apa LI site to both variable regions and 3' Bam HI site and Bgl II site to VH and VL respectively.
  • the Hind III - Apa LI leader sequence and Apa LI - Bam HI VH sequence or Apa LI - Bgl II VL sequence where ligated in a three component ligation into the Hind III - Bam HI digested HCMV vectors.
  • the ligation products were transformed into E coli , DH5a by electroporation (2.2 kv, 250 uF capacitance using a Gene Pulser (BioRad).
  • Protein A Sepharose CL-4B (Pharmacia) or POROS 50A affinity chromatography (Perfusion Chromatography) eluted with 100 mM glycine (pH 3.0), and dialysed against PBS (pH 7.4) for buffer exchange.
  • concentration of stock solution is higher than lmg/ml.
  • a Sandwich ELISA was used for determining the concentration of assembled human antibody.
  • Goat anti-human IgG Fc specific antibody Jackson ImmunoResearch Laboratories, Inc., USA
  • Nunc Maxisorb plates at 2ug/ml at 4oC overnight.
  • ADCC Assay ADCC was determined using a Cytotoxicity Detection Kit (LDH)
  • PBMC Peripheral blood mononuclear cells
  • the human Raji cell line was used as a source of target cells
  • Campathl (CDw52) monoclonal antibody rat IgG2b
  • Mouse IgG2a (anti-TNP, Pharmagen) and human IgGl (The Binding Site) antibodies were used as isotype controls for HuLym3 and chimeric HuLym3, respectively.
  • PBMC where resuspended at 1 x 10 7 /ml in assay medium (RPMI1640 with 1%BSA).
  • Raji cells were adjusted to a final concentration of 1 x 10 5 /ml in assay medium and incubated with different concentrations of each antibody ( 0.01- lOug/ml) for 30 minutes at RT.
  • the effectors and Ab labelled target cells (1 x
  • CD34+ cells expressing CD48 was determined by triple label flow cytometry using antibodies against CD34, CD45 and CD48.
  • CD34+ cells were initially selected then CD48+/CD45+ cells were examined.
  • Two healthy donor's and two CLL and NHL patient's PBMC were examined.
  • Less than 5% of CD34 positive cells in healthy individuals and patients with CLL and NHL were found to express CD48. All samples examined had a level of around 4% ( ⁇ . 1%) of CD34+ cells being CD48+ .
  • the number of anti-CD48 binding sites per cell was estimated using Quantum Simply Cellular Microbeads and flow cytometry. Healthy individuals (two) and CLL patients (two) had similar numbers of binding sites with approximately 40000 _+ 10000 binding sites present per cell.
  • the B-lymphoma cell line Raji expressed higher levels of CD48 than patient or normal individuals with approximately 200000 binding sites/cell.
  • mice injected with Raji cells on day 0 were treated with 200ug murine anti-CD48 antibody or an isotype control antibody on days 0, 2 and 4.
  • the results are shown in Figures 2(a) and (b).
  • Treatment of mice injected with 1 x 10 B Raji cells with anti-CD48 antibody resulted in a 40% increase in the time to hind leg paralysis.
  • Those treated with an isotype control antibody developed hind leg paralysis after approximately 32 days.
  • the effect of anti-CD48 antibody dose on mouse survival was also investigated.
  • Figure 2c indicates that an antibody dose of 20 Tg can prolong the time to hind leg paralysis in 60% of mice
  • Figure 2d shows the anti-tumour effect of anti-CD48 antibodies of different isotypes.
  • An IgM antibody shows no increased survival of mice over the control antibody while the IgG2a antibody shows a marked survival benefit.
  • variable regions of this anti-CD48 antibody for the construction of a mouse/human chimeric antibody.
  • the variable regions where amplified by PCR using degenerate primers (Ig-Primer Kit, Novagen, USA). Use of these primers resulted in the generation of multiple PCR products.
  • the Vh product was identified by Kabat data base searching which indicated that one product contained a 50bp deletion. Amino acid sequence could not be obtained from the heavy chain presumably due to the N-terminus being blocked.
  • the anti-CD48 Vh and VI gene segments were used to construct chimeric antibody expression vectors, HCMV.Vh and HCMV. VI. Plasmid DNA was cotransfected into COS cells for transient expression and CHOK1 cells for stable expression. CHOKl clones expressing the highest levels of chimeric antibody were picked after G418 selection using a sandwich ELISA The structure of the chimeric antibody was confirmed by SDS-PAGE and western blots (23). The chimeric antibody was shown to have near identical binding properties to the murine version when tested on various cell lines and PBMC samples (23) and to have the same relative affinity as the murine version as determined by a competitive ELISA (23).
  • the chimeric antibody was able to mediate significant lysis in ADCC assays using human PMBCs as effector cells. Concentrations of the antibody ranging from 0.01-10 ug/ml were tested at effector to target cell ratios of 6:1,
  • the rat Campath-1 antibody (IgG2b) was also included in some assays. Chimeric HuLym3 mediated specific lysis 2-6 times more efficiently than did the murine HuLym3 and 2-3 times higher than rat Campathl. The level of specific lysis with chimeric HuLym3 was similar for antibody concentrations between 0.1 and 5ug/ml and effector to target ratios of 12:1 to 50:1 with chimeric HuLym3 typically giving over 60% specific lysis. Results of a typical ADCC assay are shown in Table 1 and Figure 3. The observed maximal specific cell lysis was dependent on the source of the effector cells as previously described (24).
  • CD48 is expressed on the surface lymphocytes, monocytes and the vast majority of lymphocytic leukemia and lymphoma cells (2,3).
  • CD34 represents an early marker in haemopoietic cell development (25). It would be beneficial for a therapeutic to target leukemia or lymphoma cells but not the CD34+ cells.
  • Crosslinking by a bivalent antibody can result in patching, capping, and finially internalisation of surface antigen,
  • the rates at which this process can occur vary from antigen to antigen.
  • Some lymphoid differentiation antigens such as CD3 and CD7 can be internalised in minutes, whereas for others such as CD45 and CAMPATH-1 the process may take hours.
  • Anti-CD48 antibodies remain present on the surface of cells for at least 24 hours without modulation. The stability of anti-CD48 antibodies on the surface of cells is likely to play an important role in the observed cytotoxic effects mediated by this antibody.
  • CD48 is induced to high levels of expression on EBV-infected B cells (26) This was confirmed by analysis of the human Raji cell line which is EBV+ and expresses approximatly 200000 sites/cell.
  • IgM anti-CD48 antibody has been used in a pilot phase I clinical trial (13), Four CLL patients were treated with up to 64mg of antibody over 6 days. A significant but transient reduction in the number of circulating leucocytes was observed.
  • the IgM anti-CD48 antibody was capable of strong complement activation in-vitro but similar to the IgM Campath antibody which was capable of massive complement activation only caused transient reductions in circulating tumour cells. Further clinical trials with different isotypes of the Campath-1 antibody suggested that mediation of ADCC was important for a strong anti-tumour effect in-vivo (14, 15).
  • Murine IgG2a and human IgGl antibodies have been shown to mediate ADCC and anti-tumour activity (27).
  • an anti-CD48 antibody can medite a potent in- vivo anti-tumour effect and can give long term survival to SCID mice injected with Raji cells, which if treated with an isotype control antibody develop hind leg paralysis after approximately 34 days.
  • the disease presentation in this model is similar to other SCID mouse models using human B-cell lines (28), such as the Daudi cell line (29).
  • the time course to hind leg paralys is much more rapid with the Raji cell line in comparision with the other models.
  • lxlO 6 Daudi cells injected IV into SCID mice results in hind leg paralysis after about 34 days while the injection 1 x IO 6 Raji cells resulted in hind leg paralysis after about 20 days.
  • the Raji cell line causes a more rapid form of disease.
  • cell dosing with Raji cells at 1 x 10 ⁇ , a similar cell dose as reported in other models, and the results of a lower cell dose which allows survival of the mice for approximately one month, a similar survival period for untreated animals as reported the Daudi SCID model.
  • treatment with anti- CD48 antibody prolonged the time to hind leg paralysis by 40%.
  • anti-CD48 antibodies produced long term survival in the majority of mice with mice surviving at least ten times longer than untreated animals. We have also shown that the antibody is active at much lower doses.
  • the therapeutic effect of the anti-CD48 antibody in SCID mice appears to be antigen specific as an isotype control antibody which does not bind to Raji cells has no therapeutic effect.
  • the cytotoxic effect of the anti- CD48 antibody is likely to depend on a number of features including inability of the antibody to modulate the antigen and the effective interaction of murine IgG2a with murine effector functions. Because SCID mice lack significant T and B cell responses any effector response would either a direct toxicity of the monoclonal antibody on the tumour cells or the recruitment of other cells with cytotoxic activity such as neutrophils, macrophages or natural killer cells. As the anti-CD48 antibody has no direct cytotoxicity on Raji cells (unpublished results) the recruitment of effector cells seems the most likely explanation of the observed anti-tumour effect.
  • a chimeric antibody is predicted to have a number of improved characteristics for clinical use over the original murine antibody including higher effector function, longer serum half-life and lower immunogenicity (14, 15, 16).
  • Chimeric antibodies consisting of a human IgGl constant region have, in numerous cases exhibited a higher in-vitro cell killing activity in ADCC assays with human effector cells (14, 15).
  • Chimeric antibodies usually have a half-life at least 5 fold longer than murine antibodies in humans (16) and being 75% human the immune response to chimeric antibodies is often much less than the murine equivalent (16).
  • an antibody against CD48 is capable of mediating a strong anti-tumour effect in SCID mice and a chimeric version of this antibody is capable of mediating strong ADCC activity with human
  • anti-CD48 antibodies may be useful in the treatment of a number of diseases including lymopoid leukemias and lymphoma.
  • Huang S and Terstappen LWMM Formation of harmatopoietic microenvironment and haematopietic stem cells from single human bone stem cells. Nature (1992) 360, 745-749.

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Abstract

Technique de traitement des lymphomes et des leucémies des cellules T et B. Dans le cadre de cette technique, on administre à un sujet un anticorps d'isotype IgG dirigé contre la glycoprotéine CD48.
PCT/AU1997/000195 1996-03-27 1997-03-27 Utilisation d'anticorps contre la glycoproteine cd48 pour le traitement des lymphomes et des leucemies des cellules t et b WO1997035614A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP9532935A JP2000509015A (ja) 1996-03-27 1997-03-27 Ｔ細胞及びｂ細胞リンパ腫及び白血病の治療のためのｃｄ４８に対する抗体の使用
AU21435/97A AU2143597A (en) 1996-03-27 1997-03-27 The use of antibodies against cd48 for the treatment of t and b cell lymphomas and leukemias

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AUPN8962 1996-03-27
AUPN8962A AUPN896296A0 (en) 1996-03-27 1996-03-27 The use of antibodies against cd48 for the treatment t and b cell lymphomas and leukemias
AUPN9035 1996-03-29
AUPN9035A AUPN903596A0 (en) 1996-03-29 1996-03-29 The use of antibodies against CD48 for the treatment T and B cell lymphomas and leukemias

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WO2012047567A1 (fr) 2010-09-27 2012-04-12 Regeneron Pharmaceuticals, Inc Anticorps anti-cd48 et leurs utilisations
WO2016100712A1 (fr) * 2014-12-18 2016-06-23 Rhode Island Hospital Visualisation d'une colonisation bactérienne et de la formation d'un biofilm sur des explants pour des traumatismes orthopédiques
US9533039B2 (en) 2010-09-27 2017-01-03 Regeneron Pharmaceuticals, Inc. Methods of treating systemic lupus erythematosus (SLE) using anti-CD48 antibodies
EP3270965A4 (fr) * 2015-03-18 2018-09-05 Seattle Genetics, Inc. Anticorps cd48 et conjugués de ceux-ci
US10280221B2 (en) 2013-03-15 2019-05-07 Glaxosmithkline Intellectual Property Development Limited Anti-LAG-3 binding proteins
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EP1987839A1 (fr) * 2007-04-30 2008-11-05 I.N.S.E.R.M. Institut National de la Sante et de la Recherche Medicale Anticorps monoclonal cytotoxique anti-LAG-3 et son utilisation pour le traitement ou la prévention d'un rejet de greffe d'organe et de maladies auto-immunes

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BLOOD, (1995), Volume 86(4), HERTESTEIN et al., "Emergence of CD52-, Phosphatidylinositolglycan-Anchor-Deficient T Lymphocytes After in Vivo Application of Campath - 1H for Refractory B-cell Non Hodgkin Lymphoma", pages 1487-92. *
DERWENT WPAT ONLINE ABSTRACT, Accession No. 94-269293; & JP,A,06 269 293 (SUMITOMO ELECTRIC IND LTD), 27 September 1994. *

Cited By (24)

* Cited by examiner, † Cited by third party
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US7427400B2 (en) 1997-09-18 2008-09-23 Ivan Bergstein Methods of cancer diagnosis and therapy targeted against a cancer stem line
US7504103B2 (en) 1997-09-18 2009-03-17 Ivan Bergstein Methods of cancer diagnosis and therapy targeted against a cancer stem line
US7608259B2 (en) 1997-09-18 2009-10-27 Ivan Bergstein Methods of cancer diagnosis and therapy targeted against a cancer stem line
US7361336B1 (en) * 1997-09-18 2008-04-22 Ivan Bergstein Methods of cancer therapy targeted against a cancer stem line
US8715945B2 (en) 1997-09-18 2014-05-06 Ivan Bergstein Methods of cancer diagnosis and therapy targeted against a cancer stem line
US8846325B2 (en) 1997-09-18 2014-09-30 Ivan Bergstein Methods of cancer diagnosis and therapy targeted against a cancer stem line
US7534417B2 (en) * 2000-02-24 2009-05-19 Agensys, Inc. 103P2D6: tissue specific protein highly expressed in various cancers
US7405061B2 (en) * 2002-11-13 2008-07-29 Raven Biotechnologies, Inc. Antigen PIPA and antibodies that bind thereto
US9097717B2 (en) 2009-04-10 2015-08-04 Osaka University Methods of killing myeloma stem and precursor cells by administering anti-CD48 antibodies
EP2418222A1 (fr) * 2009-04-10 2012-02-15 Osaka University Agent thérapeutique pour des maladies dans lesquelles se produit une prolifération néoplasique de plasmocytes
EP2418222A4 (fr) * 2009-04-10 2013-11-06 Univ Osaka Agent thérapeutique pour des maladies dans lesquelles se produit une prolifération néoplasique de plasmocytes
TWI507416B (zh) * 2010-09-27 2015-11-11 Regeneron Pharma 抗ｃｄ４８抗體及其用途
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