CN100389825C - Treatment of patients having non-hodgkins lymphoma with bone marrow involvement with anti-CD20 antibodies - Google Patents
Treatment of patients having non-hodgkins lymphoma with bone marrow involvement with anti-CD20 antibodies Download PDFInfo
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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
- C07K16/2887—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
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- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- 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
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Abstract
This invention relates to methods of reducing bone marrow involvement in B cell lymphoma patients prior to radioimmunotherapy by administering monoclonal antibodies which target cancerous B cells.
Description
Invention field
The present invention relates to reduce before radioimmunotherapy the method for the carcinous B cell number in the B cell lymphoma patient bone marrow, this method comprises uses anti-CD 20 antibodies.Also provide treatment to involve the lymphoma patient's of relevant bone marrow combinational therapeutic methods.
Background of invention
The radioimmunotherapy of B cell lymphoma (radioimmunotherapy) is owing to involve bone marrow (marrow involvement), and promptly carcinous bone-marrow-derived lymphocyte is to the infiltration of bone marrow, and is restricted.This makes radioimmunotherapy complicated aspect two: (1) can send being radiated in the bone marrow of doses with the bonded antibody of diseased cells in the bone marrow, thereby causes unnecessary bone marrow depression; (2) normal cell and ancester cell crowded (the marrow crowding) in bone marrow will weaken healthy bone marrow deposit, thus the patient in fact than the patient who does not have bone marrow to involve more near the 3rd or 4 grade of cytopenia.Under any situation, when for example adopt the coupling isotope as
90Y or
131During the B cell depletion antibody of I, the patient may have relatively poor toleration to radioimmunotherapy.Therefore, bone marrow involves degree and surpasses 25% patient and generally be excluded outside radioimmunotherapy.
Wiseman and colleague find that clinical parameter baseline platelet count and bone marrow involve degree, be accept Y2B8 (a kind of with
90The link coupled anti-CD 20 antibodies of Y) Zhi Liao the toxic accurate prediction index of rudimentary folliculus type non-Hodgkin lymphoma patient body inner blood.For example, the 4th grade of thrombocytopenic patient in the patient who does not involve bone marrow, occur and account for 8% (2/25), and this accounts for 25% (1/4) in the patient who has 0.1-5% bone marrow to involve, in the patient who has 5-20% bone marrow to involve, account for 45% (5/11), in the patient who has 20-25% bone marrow to involve, account for 100% (6/6) (Wiseman etc., the IDEC-Y2B8 radioimmunotherapy: the bone marrow of baseline involve with platelet count be better hematotoxicity prognosticator than dosimetry.Blood (Blood) 1998, November supplementary issue, 92 (10): 417a (1721) Poster Board#/Session:393-III).
Usefully, exploitation reduces the degree methods of involving of bone marrow among the non-Hodgkin lymphoma patient, so that these patients can be benefited from new radioimmunotherapy, and takes this to provide the therapy of another approach and reduces the probability that recurs.The invention provides these methods.
Summary of the invention
The present invention relates to treat the method that is attended by the B cell lymphoma patient that bone marrow involves, this method comprises uses monoclonal antibody or its fragment, involves so that reduce or alleviate described bone marrow.Particularly, present invention resides in the preceding method that reduces the carcinous B cell number in the non-Hodgkin lymphoma patient bone marrow of radioimmunotherapy, it comprises the therapeutic antibodies of using effective dose to described patient.These methods also can be used for use by the antibody of cytotoxicity part (as toxin) labelling or any may damage the immunotherapeutic agent that is positioned near the healthy bone marrow ancester cell the target cell of soaking into bone marrow before, reduction bone marrow involves.
Although also can adopt antibody such as anti-CD 19 antibodies, preferably adopt anti-CD 20 antibodies at other B cell surface marker.Should have the main characteristic of on carcinous B cell, expressing and generally on normal cell or B cell precursor, not expressing as the cell cortex protein of target, and when with antibodies, preferably do not come off, internalization or modulation (modulate).
Term antibody " fragment " comprises therapeutic antibodies any in treatment effectively part or derivant, it is binding purpose target and produce expected results effectively.This comprises Fab
2Fragment, Fab fragment, Fv fragment, territory disappearance antibody etc.Preferably, the used antibody of the present invention is people's antibody, chimeric antibody or humanized antibody, so that this antibody contains the human constant region domain that can stimulate people's effector function (effectorfunctions).Preferred antibody is that chimeric anti-CD 20 antibodies Rituximab (is on the American market
, on the English market be
).
Greatest benefit patient of the present invention will be that bone marrow involves degree above 25% patient before adopting immunization therapy of the present disclosure to handle.These patients can by adopt to discharge gamma-ray isotope (as
111In) diagnostic imaging that carries out in advance of radiolabeled antibody is determined.These patients also can determine by bone marrow biopsy.
According to the research of Wiseman etc., these patients can be owing to radioimmunotherapy has very high probability generation thrombocytopenia.Yet, because the probability of this untoward reaction takes place after radioimmunotherapy will be increased according to the degree that bone marrow involves, they all will benefit from the present invention so have any patient that any bone marrow involves degree, because will bring out thrombocytopenic dangerous the reduction and benefit owing to disclosure treatment back radioimmunotherapy.
The used dosage of the present invention can change with degree and the used antibody that patient, bone marrow involve.Chimeric anti-CD 20 antibodies such as Rituximab can be by weekly at least about 50mg/m
2Dosage continue at least 4 all administrations.The preferred dosage dosage regimen is weekly about 375mg/m
2, continued for 4 weeks.
Because reducing the bone marrow for preparing among the lymphoma patient who accepts radioimmunotherapy, the purpose of the method for the present invention is that involves, so Therapeutic Method of the present invention adopts radiolabelled antibody to treat after being included in bone marrow purging naturally.This radiolabelled antibody also can point to and appear at cancerous cell usually but not any B cell surface marker on the normal cell.Preferably, this radiolabelled antibody is an anti-CD 20 antibodies.
Preferred radioactive label be discharge Beta-ray isotope as
90Y or
131I, but also can adopt any radiosiotope, if it can be effectively with this antibody coupling, have relative short decay range (decay range), and can successfully kill and wound near cell (being the cell of its institute's targeting).Preferred radioactive label anti-CD 20 antibodies is Y2B8.
The patient generally should receive treatment in loss antibody is used one week of back, as long as they do not have serious cytopenia (as platelet＜150,000) to get final product.If this patient cytopenia occurs behind the loss Antybody therapy, then should allow before radioimmunotherapy, to recover for example minimum AGC＞1000 or platelet＞150,000.In allowing peripheral blood and/or bone marrow, under the situation of cellular-restoring, can directly before immunization therapy, use loss antibody once more.For example, can be directly before immunization therapy or eclipsed with it period by about 250mg/m
2Amount continue about 2 weeks to use this second dosage.
The dosage of radiolabelled antibody also will be with the specificity of patient, antibody, half-life, stability etc., also have the degree of disease to change certainly.Radioactive label anti-CD 20 antibodies such as YAB8 use by the dosage of about 0.1-0.5mCi/kg.
Should understand, Therapeutic Method disclosed herein can with other known Therapeutic Method such as chemotherapy or radiotherapy associating.In order behind radiotherapy, to realize autologous bone marrow or stem cell transplantation, can before adopting anti-CD 20 antibodies treatment back, adopting described radiolabelled antibody treatment, collect bone marrow or peripheral hematopoietic stem cells from described patient.
In order to raise CD20 or the expression of other target protein on carcinous B cell surface before loss antibody or radiolabelled antibody are used, adopting the cytokine therapy patient may also be useful.For the rise of CD20, the cytokine that can be used for this purpose has IL-4, GM-CSF and TNF-α.Cytokine also can be when loss antibody or radioactive antibody be used, before or after use so that the immune stimulatory effector function.The cytokine that is used for this purpose comprises interferon-alpha, GM-CSF and G-CSF.
Can adopt the chemotherapy scheme to replenish Therapeutic Method disclosed herein, and the chemotherapy scheme can with the using side by side or one after the other undertaken of described radioactive antibody by any order.This chemotherapy scheme can be selected from CHOP, ICE, mitoxantrone (Mitozantrone), cytosine arabinoside, DVP, ATRA, idarubicin, hoelzer chemotherapy scheme, La La chemotherapy scheme, ABVD, CEOP, 2-CdA, FLAG﹠amp; IDA (associating or the G-CSF that does not unite subsequently treat), VAD, M﹠amp; P, C-Weekly, ABCM, MOPP and DHAP.Preferred chemotherapy scheme is CHOP.
The inventive method can be used for the treatment of various B cell lymphomas, but is particularly useful when described B cell lymphoma is non-Hodgkin lymphoma (NHL).Rituximab has been approved for the low classification folliculus NHL of treatment, also is useful but the inventor is surprised to find Rituximab for middle classification and high fractionated NHL (comprising large volume disease (bulky disease)).Therefore, can comprise low classification/folliculus non-Hodgkin lymphoma (NHL) (low grade/follicular non-Hodgkin ' s lymphoma) by the lymphoma of the inventive method treatment, small lymphocyte (SL) NHL, middle classification/folliculus NHL (intermediate grade/follicular NHL), middle classification diffusivity NHL (intermediate grade diffuse NHL), chronic lymphocytic leukemia (CLL), high classification immunoblast NHL (high grade immunoblastic NHL), high classification lymphoblast NHL (high grade lymphoblastic NHL), the little no schistocyte NHL of high classification (high grade small noncleaved cell NHL), large volume disease NHL (bulky disease NHL), lymphoma mantle cell, relevant lymphoma of AIDS and macroglobulinemia Waldenstron involve and get final product so long as these lymphoma are attended by the complicated bone marrow of availability that makes radioimmunotherapy.
We illustrate the exemplary treatment condition by following data now.
The I/II phase of the radioimmunotherapy of recurrent or intractable non-Hodgkin lymphoma (NHL): Y2B8
90
The Y test
This I/II phase tests and comprises 58 recurrents or intractable NHL patient, and 60 years old mean age, 43% bone marrow involve, (White etc., the placard in the 7th international malignant lymphoma meeting is showed Lugano, Switzerland to 60% large volume damage＞5cm.Oncology's annual (Annals ofOncology), supplementary issue 3 (1999) 10: 64 (215)).All patients are accepting 5mCi
111All carried out dosimetry behind the antibody I n2B8 of In labelling by γ videographic measurment and series urine and blood sampling.Before video picture and treatment, employing Rituximab cleans periphery B cell and optimizes the distribution of radiolabelled antibody.After one week, use Y2B8 (0.2,0.3 or 0.4mCi/kg) for the 2nd and 3 group patient.Do not carry out the collection of bone marrow or stem cell.
The result:
MTD is 0.4mCi/kg (the slight patient who reduces is 0.3mCi/kg for platelet).Untoward reaction is a blood, temporary transient with reversible substantially.Generally speaking, lowest platelet counts＜10,000/mm appear in 5 patients (10%)
3, and minimum AGC＜500 appear in 14 patients (28%).3 patients (6%) occurred carrying out the infection of hospitalization in the observation period in 1 year.Only HAMA/HACA appears in 2% patient.It is normal that the average serum immunoglobulin kept in the observation period in 1 year.ORR is 67% (26%CR and 41%PR) in all Histological research, and is 82% for the patient who suffers from rudimentary NHL.Pressing the methodology of Kaplan Meier, is 12.9+ month for responder average T TP, and reaction duration is 11.7+ month.In the patient who suffers from the baseline splenomegaly, 4/8 (50%) patient responds, and relatively, is 74% (29/39) (p=0.1761) in the patient of no splenomegaly.Two clinical parameters, i.e. baseline platelet count and bone marrow in the baseline biopsy involve degree, have predicted the seriousness of hematotoxicity better than dosimetry parameter.
Claims (21)
1. anti-CD 20 antibodies or its fragment are used for having in preparation and surpass B cell lymphoma patient that 25% bone marrow involves and reduce or alleviate purposes in the medicine that bone marrow involves, described medicine be used for and radioimmunotherapy simultaneously, separately or in succession use.
2. the purposes of claim 1, wherein said medicine can be involved described bone marrow and be reduced to less than 25%.
3. the anti-CD 20 antibodies of effective dose or its fragment were used for before radioimmunotherapy reducing in preparation the purposes that surpasses the medicine of carcinous B cell number in the non-Hodgkin lymphoma patient bone marrow that 25% bone marrow involves.
4. anti-CD 20 antibodies or its fragment are used for having in preparation and surpass B cell lymphoma patient that 25% bone marrow involves and reduce or alleviate purposes in the medicine that bone marrow involves, described medicine be used for and radioimmunotherapy and at least a cytokine simultaneously, separately or in succession use.
5. the purposes of claim 4, wherein said at least a cytokine is selected from interferon-alpha, GM-CSF and G-CSF.
6. the purposes of claim 4 was wherein used the up-regulated that described cytokine makes CD20 on the carcinous B cell surface before using described anti-CD 20 antibodies or its fragment.
7. the purposes of claim 6, wherein said cytokine is selected from IL-4, GM-CSF.
8. each purposes of claim 1-2, wherein said patient is when using described radioimmunotherapy or adopts the patient of chemotherapy scheme treatment afterwards.
9. the purposes of claim 8, wherein said chemotherapy scheme is CHOP, ICE, mitoxantrone, cytosine arabinoside, DVP, ATRA, idarubicin, hoelzer chemotherapy scheme, La La chemotherapy scheme, ABVD, CEOP, 2-CdA, FLAG﹠amp; IDA (associating or the G-CSF that does not unite subsequently treat), VAD or M﹠amp; P, C-Weekly, ABCM, MOPP or DHAP.
10. anti-CD-20 antibody or its fragment are used for having in preparation and surpass B cell lymphoma patient that 25% bone marrow involves and reduce or alleviate purposes in the medicine that bone marrow involves, described medicine be used for and radiolabelled antibody simultaneously, separately or in succession use.
11. the purposes of claim 10, wherein said radiolabelled antibody are anti-CD 20 antibodies or its fragment in conjunction with CD20.
12. the purposes of claim 11, wherein said radioactive label anti-CD 20 antibodies is Y2B8.
13. the purposes of claim 12, wherein said radioactive label anti-CD 20 antibodies is used by the dosage of about 0.1-0.5mCi/kg.
14. each purposes of aforementioned claim, wherein said B cell lymphoma is non-Hodgkin lymphoma (NHL).
15. the purposes of claim 14, wherein said NHL is low classification/folliculus non-Hodgkin lymphoma (NHL), small lymphocyte (SL) NHL, middle classification/folliculus NHL, middle classification diffusivity NHL, chronic lymphocytic leukemia (CLL), high classification immunoblast NHL, high classification lymphoblast NHL, the little no schistocyte NHL of high classification, large volume disease NHL, lymphoma mantle cell, the relevant lymphoma of AIDS or macroglobulinemia Waldenstron.
16. each purposes of aforementioned claim, wherein said cold anti-CD 20 antibodies is people's antibody, chimeric antibody or humanized antibody.
17. the purposes of claim 16, wherein said chimeric anti-CD 20 antibodies is Rituximab.
18. the purposes of claim 17, wherein said chimeric anti-CD 20 antibodies is pressed weekly at least about 50mg/m
2Dosage used at least 4 weeks.
19. the purposes of claim 18, wherein said chimeric anti-CD 20 antibodies is pressed weekly at least about 375mg/m
2Dosage used for 4 weeks.
20. each purposes of claim 10-19, the anti-CD 20 antibodies that wherein is not labeled is by about 250mg/m
2Dosage use.
21. each purposes of claim 10-19 is wherein after adopting the anti-CD 20 antibodies treatment, collect bone marrow or peripheral hematopoietic stem cells from described patient before adopting described radiolabelled antibody treatment.
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| EP1740946B1 (en) | 2004-04-20 | 2013-11-06 | Genmab A/S | Human monoclonal antibodies against cd20 |
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| WO2017053469A2 (en) | 2015-09-21 | 2017-03-30 | Aptevo Research And Development Llc | Cd3 binding polypeptides |
| PE20181004A1 (en) | 2015-10-02 | 2018-06-26 | Hoffmann La Roche | BISPECIFIC ANTIBODIES AGAINST HUMAN CD20 AND THE HUMAN TRANSFERRIN RECEPTOR AND METHODS OF USE |
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| RU2019110955A (en) * | 2016-09-16 | 2020-10-20 | Нордик Нановектор Аса | TREATMENT OF NECHODGKIN'S LYMPHOMA WITH LILOTOMAB AND 177Lu-LILOTOMAB WITH SATETHRAXETAN |
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- 2000-07-25 AU AU76260/00A patent/AU784971B2/en not_active Expired
- 2000-07-25 CN CNA2008100921383A patent/CN101259270A/en active Pending
- 2000-07-25 CA CA002378646A patent/CA2378646A1/en not_active Abandoned
- 2000-07-25 WO PCT/US2000/040459 patent/WO2001010462A1/en active Application Filing
- 2000-07-25 MX MXPA02001398A patent/MXPA02001398A/en active IP Right Grant
- 2000-07-25 EP EP00965561A patent/EP1207906A4/en not_active Withdrawn
- 2000-07-25 CN CNB008116644A patent/CN100389825C/en not_active Expired - Lifetime
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| US5595721A (en) * | 1993-09-16 | 1997-01-21 | Coulter Pharmaceutical, Inc. | Radioimmunotherapy of lymphoma using anti-CD20 |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2003513012A (en) | 2003-04-08 |
| CN101259270A (en) | 2008-09-10 |
| EP1207906A4 (en) | 2005-07-06 |
| HK1048945A1 (en) | 2003-04-25 |
| AU7626000A (en) | 2001-03-05 |
| MXPA02001398A (en) | 2002-08-12 |
| WO2001010462A1 (en) | 2001-02-15 |
| CN1373671A (en) | 2002-10-09 |
| EP1207906A1 (en) | 2002-05-29 |
| AU784971B2 (en) | 2006-08-10 |
| CA2378646A1 (en) | 2001-02-15 |
| TWI279233B (en) | 2007-04-21 |
| NO20020639L (en) | 2002-04-11 |
| MY136635A (en) | 2008-11-28 |
| NO20020639D0 (en) | 2002-02-08 |
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