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
  • C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
  • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
• • 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

Definitions

• the present invention relates to a method of reducing the number of cancerous B cells in the bone marrow of a patient having a B cell lymphoma prior to radioimmunotherapy comprising administration of an anti- CD20 antibody.
• Combined therapeutic methods of treating a patient having lymphoma with associated bone marrow involvement are also encompassed.
• Radioimmunotherapy of B cell lymphoma is limited by marrow involvement, i.e., infiltration of the bone marrow by cancerous B lymphocytes. This complicates radioimmunotherapy in two regards: (1) antibody binding ,to diseased cells in the marrow will deliver a dose of radiation to the marrow thereby causing unwanted myelosuppression; and (2) marrow crowding of normal cells and progenitors will weaken healthy marrow reserves so that patients may actually be closer to grade 3 or 4 cytopenias than would be the case in patients without marrow involvement.
• the patient may be less tolerant to radioimmunotherapy, e.g., with B cell depleting antibody conjugated to a radioisotope such as 90 Y or 131 I .
• radioimmunotherapy e.g., with B cell depleting antibody conjugated to a radioisotope such as 90 Y or 131 I .
• a radioisotope such as 90 Y or 131 I .
• patients with greater than 25% bone marrow involvement are generally excluded from treatment with radioimmunotherapy.
• IDEC-Y2B8 radioimmunotherapy baseline bone marrow involvement and platelet count are better predictors of hematologic toxicity than dosimetry. Blood 1998 Supplement November, 92(10): 417a (1721) Poster Board #/ Session: 393-III) .
• the present invention relates to methods of treating patients having B cell lymphoma accompanied by bone marrow involvement comprising administering a monoclonal antibody or fragment thereof such that said bone marrow involvement is reduced or alleviated.
• the invention encompasses methods of reducing the number of cancerous B cells in the bone marrow of a patient having non-Hodgkin' s lymphoma prior to radioimmunotherapy comprising administering to said patient an effective amount of a therapeutic antibody.
• the methods are also useful for reducing bone marrow involvement prior to administration of antibodies labeled with cytotoxic moieties such as toxins, or any immunotherapeutic which could damage healthy bone marrow progenitors by virtue of their location in the vicinity of targeted cells which have infiltrated the bone marrow.
• cytotoxic moieties such as toxins, or any immunotherapeutic which could damage healthy bone marrow progenitors by virtue of their location in the vicinity of targeted cells which have infiltrated the bone marrow.
• anti-CD20 antibodies are used, although antibodies to other B cell surface markers may also be used, e.g., anti-CD19 antibodies.
• the cell surface protein which is targeted should have the .characteristics of being expressed mainly on cancerous B cells and not generally on normal cells or B cell precursors, and preferably does not shed, internalize or modulate upon being bound by antibody.
• antibody fragment includes any therapeutically effective portion or derivative of a therapeutic antibody, which is effective to bind to the intended target and produce the intended result . Included are Fab 2 fragments, Fab fragments, Fv fragments, domain-deleted antibodies, etc.
• the antibodies used in the present invention are human, chimeric or humanized antibodies, such that the antibodies contain human constant region domains capable of stimulating human effector functions.
• a preferred antibody is the chimeric anti-CD20 antibody, Rituximab ® (marketed as Rituxan ® in the U.S. and Mabthera ® in Britain) .
• the patients who will most benefit from the present invention will be patients who have greater than 25% bone marrow involvement before being treated with the disclosed immunotherapy. Such patients may be identified by prior diagnostic imaging using antibodies radiolabeled with gamma-emitting isotopes such as X11 ln. Such patients may also be identified following bone marrow biopsy. According to a study by Wiseman et al . , such patients have a very high chance of developing thrombocytopenia due to radioimmunotherapy.
• any patient with any level of bone marrow involvement will benefit from the present invention in that they will benefit from a decreased risk of radioimmunotherapy-induced thrombocytopenia following the disclosed treatment.
• the dosages to be used in the present invention may vary depending on the patient, the extent of bone marrow involvement, and the antibody used.
• Chimeric anti-CD20 antibody such as Rituximab ® may be administered at a dosage of at least about 50 mg/m 2 weekly for at least 4 weeks.
• a preferred dosage regimen is about 375 mg/m 2 weekly for four weeks .
• the treatment methods of the present invention naturally encompass treatment with a radiolabeled antibody subsequent to purging of the marrow.
• the radiolabeled antibody may also be directed to any B cell surface marker which is found generally on cancerous cells and not normal cells.
• the radiolabeled antibody is an anti-CD20 antibody.
• Preferred radiolabels are beta emitting isotopes such as 90 Y or 131 I, but any radioisotope may be used so long as it may be effectively conjugated to the antibody, it has a relatively short decay range, and it succeeds in killing nearby cells, i.e., the cells to which it is targeted.
• a preferred radiolabeled anti- ,CD20 antibody is Y2B8.
• a patient should generally be treated within one week after administration of the depleting antibody, so long as they are not severely cytopenic, e.g., platelets ⁇ 150,000. If the patient is cytopenic following treatment with the depleting antibody, recovery should be allowed to occur, e.g.
• more depleting antibody may be administered directly before immunotherapy.
• Such a secondary dosage may be administered, for example, at about 250 mg/m 2 for about two weeks directly before or overlapping with radioimmunotherapy.
• Radiolabeled anti-CD20 antibodies like Y2B8 are administered at a dosage of about 0.1 to 0.5 mCi/kg. It, should be clear that the treatment methods disclosed herein may be combined with other known treatment methods such as chemotherapy or radiotherapy. Bone marrow or peripheral blood stem cells may be harvested from said patient subsequent to treatment with anti-CD20 antibody and prior to treatment with said radiolabeled antibody in order to effect autologous bone marrow or stem cell transplantation after radiotherapy.
• cytokines useful for this purpose are IL-4, GM-CSF and TNF-alpha. Cytokines may also be administered simultaneously with or prior to or subsequent to administration of the depleting antibody or radiolabeled antibody in order to stimulate immune effector functions. Cytokines useful for this purpose include interferon alpha, GM-CSF and G-CSF. Chemotherapeutic regimens may be used to supplement the therapies disclosed herein, and may be administered simultaneously with or sequentially in any order with administration of said radiolabeled antibody.
• the chemotherapy regimen may be selected from the group consisting of CHOP, ICE, Mitozantrone, Cytarabine, DVP, ATRA, Idarubicin, hoelzer chemotherapy regime, La La chemotherapy regime, ABVD, CEOP, 2-CdA, FLAG & IDA (with or without subsequent G-CSF treatment) , VAD, M & P, C- Weekly, ABCM, MOPP and DHAP .
• a preferred chemotherapeutic regimen is CHOP.
• the methods of the present invention may be used to treat a variety of B cell lymphomas but are particularly useful wherein said B cell lymphoma is non-Hodgkin' s lymphoma (NHL) .
• B cell lymphoma is non-Hodgkin' s lymphoma (NHL) .
• Rituximab ® has already been approved for the treatment of low-grade- follicular NHL, but the present inventors have surprisingly found that Rituximab ® is also beneficial for the treatment of intermediate- and high-grade NHL, including bulky disease.
• the lymphomas which are treatable by the methods of the present invention include low grade/ follicular non-Hodgkin' s lymphoma (NHL), small lymphocytic (SL) NHL, intermediate grade/ follicular NHL, intermediate grade diffuse NHL, chronic lymphocytic leukemia (CLL) , high grade immunoblastic NHL, high grade lymphoblastic NHL, high grade small noneleaved cell NHL, bulky disease NHL, mantle cell lymphoma, AIDS-related lymphoma and Waldenstrom' s Macroglobulinemia, so long as such lymphomas are accompanied by bone marrow involvement which complicates the availability of radioimmunotherapy.
• NHL low grade/ follicular non-Hodgkin' s lymphoma
• SL small lymphocytic
• NHL intermediate grade/ follicular NHL
• intermediate grade diffuse NHL intermediate grade diffuse NHL
• CLL chronic lymphocytic leukemia
• high grade immunoblastic NHL high grade lymphoblastic NHL
• the MTD was 0.4 mCi/kg (0.3 mCi/kg for patients with mild thrombocytopenia) .
• Adverse events were mainly hematologic, transient and reversible.

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• 2000
  • 2000-07-25 CA CA002378646A patent/CA2378646A1/en not_active Abandoned
  • 2000-07-25 MX MXPA02001398A patent/MXPA02001398A/es active IP Right Grant
  • 2000-07-25 CN CNA2008100921383A patent/CN101259270A/zh active Pending
  • 2000-07-25 JP JP2001514978A patent/JP2003513012A/ja active Pending
  • 2000-07-25 CN CNB008116644A patent/CN100389825C/zh not_active Expired - Lifetime
  • 2000-07-25 EP EP00965561A patent/EP1207906A4/de not_active Withdrawn
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• 2002
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