JP2003513012A - Treatment of patients with non-Hodgkin's lymphoma with bone marrow lesions by anti-CD20 antibodies - Google Patents
Treatment of patients with non-Hodgkin's lymphoma with bone marrow lesions by anti-CD20 antibodiesInfo
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- JP2003513012A JP2003513012A JP2001514978A JP2001514978A JP2003513012A JP 2003513012 A JP2003513012 A JP 2003513012A JP 2001514978 A JP2001514978 A JP 2001514978A JP 2001514978 A JP2001514978 A JP 2001514978A JP 2003513012 A JP2003513012 A JP 2003513012A
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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
-
- 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
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- 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
Abstract
(57)【要約】 この発明は、癌性B細胞を標的としたモノクローナル抗体を投与することにより、放射免疫療法前のＢ細胞性リンパ腫患者の骨髄病変を縮小する方法に関する。 (57) [Summary] The present invention relates to a method for reducing bone marrow lesions in B cell lymphoma patients before radioimmunotherapy by administering a monoclonal antibody targeting cancerous B cells.
Description
【０００１】
（発明の分野）
この発明は、抗CD20抗体の投与を特徴とする、Ｂ細胞性リンパ種を有する患者
に対して、放射免疫療法前に骨髄中の癌性Ｂ細胞数を減少させる方法に関する。
骨髄病変（bone marrow involvement）を併発したリンパ腫患者に対する複合的
治療法も包含される。FIELD OF THE INVENTION This invention reduces the number of cancerous B cells in the bone marrow prior to radioimmunotherapy for patients with B-cell lymphoma characterized by administration of anti-CD20 antibody. Regarding the method.
Combined treatment for lymphoma patients with bone marrow involvement is also included.
【０００２】
（発明の背景）
Ｂ細胞性リンパ腫の放射免疫療法は、骨髄病変、すなわち癌性Ｂリンパ球の骨
髄浸潤による制限を受ける。このため、(1)骨髄内で抗体が疾患細胞と結合する
と、1回の骨髄照射治療により望ましくない骨髄抑制が発生する；および(2)正常
な細胞および前駆細胞で満たされた骨髄が、健常な骨髄蓄積を弱めるので、実際
に骨髄病変のない患者よりもグレード（Grade）３または４に近い血球減少が生
じることがある；という２つの点から、放射免疫療法が困難になっている。いず
れの場合でも、放射免疫療法、例えば90Ｙまたは131Ｉ等の放射性同位元素と結
合したＢ細胞除去抗体に対する患者の耐性が低下することがある。その結果、25
％を上回る骨髄病変を有する患者は、通常は放射免疫療法の対象から外される。BACKGROUND OF THE INVENTION Radioimmunotherapy of B-cell lymphoma is limited by bone marrow lesions, ie bone marrow infiltration of cancerous B lymphocytes. Thus, (1) antibody binding to diseased cells in the bone marrow results in unwanted myelosuppression with a single bone marrow irradiation treatment; and (2) bone marrow filled with normal and progenitor cells is healthy. Radioimmunotherapy is difficult because of the fact that it may result in cytopenia closer to Grade 3 or 4 than in patients without bone marrow lesions; In either case, the patient's resistance to radioimmunotherapy, eg, B cell depleting antibodies conjugated to a radioisotope such as 90 Y or 131 I, may be reduced. As a result, 25
Patients with more than% bone marrow lesions are usually excluded from radioimmunotherapy.
【０００３】
Wisemanらが発見したように、臨床パラメータである血小板数初期値（baselin
e platelet counts）および骨髄病変の程度は、90Ｙと結合したマウス抗CD20抗
体であるY2B8での治療を受ける軽度濾胞性非ホジキンリンパ腫（low-grade foll
icular non-Hodgkins lymphoma）患者における、血液毒性の正確な予測因子であ
る。例えば、グレード４の血小板減少を示す患者は、骨髄病変のない患者では８
％（2/25）であるのに対して、骨髄病変が0.1〜5％の患者では25％（1/4）、病
変が5〜20％の患者では45％（5/11）、20〜25％の病変を有する患者の100％（6/
6）であった（Wiseman et al. IDEC-Y2B8 radioimmunotherapy: baseline bone
marrow involvement and platelet count are better predictors of hematolog
ic toxicity than dosimetry(骨髄病変初期値および血小板数は線量計測法より
も良い血液毒性の予測因子である). Blood 1998 Supplement November, 92 (10)
: 417a (1721) Poster Board #/ Session: 393-III）。As discovered by Wiseman et al., An initial value of platelet count (baselin
e platelet counts The) and extent of bone marrow involvement, 90 Y treated with Y2B8 a murine anti-CD20 antibody conjugated with mild follicular non-Hodgkin's lymphoma (low-grade foll
It is an accurate predictor of hematotoxicity in patients with icular non-Hodgkins lymphoma). For example, patients with grade 4 thrombocytopenia are 8 in patients without bone marrow lesions.
% (2/25) compared with 25% (1/4) in patients with 0.1-5% bone marrow lesions, 45% (5/11) in patients with 5-20% lesions, 20- 100% of patients with 25% lesions (6 /
6) (Wiseman et al. IDEC-Y2B8 radioimmunotherapy: baseline bone
marrow involvement and platelet count are better predictors of hematolog
ic toxicity than dosimetry (Bone marrow lesion initial value and platelet count are better predictors of hematotoxicity than dosimetry). Blood 1998 Supplement November, 92 (10).
: 417a (1721) Poster Board # / Session: 393-III).
【０００４】
非ホジキンリンパ腫患者の骨髄病変を縮小させる方法を開発して、これらの患
者が新しい放射免疫療法の利益を施すことで、もう１つの治療手段を提供して再
発の可能性を低下させることは有用であろう。本発明はこのような方法を提供す
る。Develop methods to reduce bone marrow lesions in non-Hodgkin's lymphoma patients, benefiting them with new radioimmunotherapy, thus providing another therapeutic modality and reducing the likelihood of recurrence That would be useful. The present invention provides such a method.
【０００５】
（発明の要約）
本発明は、骨髄病変を併発しているＢ細胞性リンパ腫患者の治療法であって、
モノクローナル抗体またはその断片の投与により、前記骨髄病変を縮小または緩
和することを特徴とする治療法に関する。本発明は、具体的には非ホジキンリン
パ腫患者に有効量の治療抗体を投与することを特徴とする、放射免疫療法実施前
の前記患者の骨髄内癌性Ｂ細胞数を減少させる方法を包含する。また該方法は、
トキシン類などの細胞毒性部分で標識した抗体、または骨髄に浸潤した標的細胞
と近いために健常骨髄前駆細胞を障害する可能性のある何らかの免疫治療の適用
の前に、骨髄病変を縮小する上でも有用である。SUMMARY OF THE INVENTION The present invention is a method of treating a patient with B-cell lymphoma complicated with bone marrow lesions, comprising:
The present invention relates to a therapeutic method characterized by reducing or alleviating the bone marrow lesions by administering a monoclonal antibody or a fragment thereof. The invention specifically encompasses a method of reducing the number of intramedullary cancerous B cells in a patient prior to radioimmunotherapy, which comprises administering to the patient a non-Hodgkin's lymphoma an effective amount of a therapeutic antibody. . In addition, the method is
Also in reducing bone marrow lesions prior to the application of antibodies labeled with cytotoxic moieties such as toxins, or any immunotherapy that could damage healthy bone marrow progenitor cells due to their proximity to target cells infiltrating the bone marrow. It is useful.
【０００６】
抗CD20抗体の使用が好ましいが、他のＢ細胞表面マーカーに対する抗体、例え
ば抗CD19抗体を使用してもよい。標的とする細胞表面タンパク質は、主として癌
性Ｂ細胞に発現し、通常は正常細胞あるいはB細胞前駆体に発現しない性質を持
たなければならず、また抗体と結合することにより放出（shed）、細胞内取込み
（internalize）、あるいは調節が起こらないものであることが好ましい。Although the use of anti-CD20 antibodies is preferred, antibodies to other B cell surface markers may be used, for example anti-CD19 antibodies. The target cell surface protein must be expressed mainly in cancerous B cells and normally not expressed in normal cells or B cell precursors, and can also be bound to antibodies to shed, Preferably, no internalize or regulation occurs.
【０００７】
抗体「断片」という用語は、意図する標的と結合し、意図する結果をもたらす
上で効果のある、治療抗体の治療効果を示すいずれかの部分または誘導体を含む
。Fab2断片、Fab断片、Fv断片、ドメイン欠失抗体などが含まれる。本発明にお
いて使用する抗体は、ヒトエフェクター機能刺激能のあるヒトの一定領域ドメイ
ンを含む抗体であるような、ヒト抗体、キメラ抗体、またはヒト化抗体であるこ
とが好ましい。好ましい抗体は、抗CD20キメラ抗体Rituximab（登録商標）であ
る（米国での商品名はRituxan（登録商標）、英国での商品名はMabthera（登録
商標））。The term antibody “fragment” includes any moiety or derivative that exhibits a therapeutic effect on a therapeutic antibody that is effective in binding its intended target and producing its intended result. Fab 2 fragments, Fab fragments, Fv fragments, domain deleted antibodies and the like are included. The antibody used in the present invention is preferably a human antibody, a chimeric antibody, or a humanized antibody such as an antibody containing a human constant region domain capable of stimulating human effector functions. A preferred antibody is the anti-CD20 chimeric antibody Rituximab® (trade name in the United States Rituxan®, Mabthera® in the UK).
【０００８】
本発明により最も利益を受けるのは、本開示の免疫療法で治療を受ける前に25
％の骨髄病変を有している患者であろう。このような患者は、111In等のγ線放
出同位元素で放射性標識した抗体を用いた画像診断により、事前に同定すること
ができる。またこのような患者は骨髄生検（bone marrow biopsy）で同定するこ
ともできる。The greatest benefit of the present invention is 25 prior to treatment with the immunotherapy of the present disclosure.
% Patients with bone marrow lesions. Such patients can be identified in advance by diagnostic imaging using an antibody radioactively labeled with a γ-ray emitting isotope such as 111 In. Such patients can also be identified by bone marrow biopsy.
【０００９】
Wisemanらの研究によると、このような患者が放射免疫療法により血小板減少
症を発症する可能性は極めて高い。しかし、放射免疫療法後にこのような副作用
を発現する可能性は、骨髄病変の程度に応じて上昇するので、いずれの程度の骨
髄病変を有するいずれの患者でも、公開された治療法の後に放射免疫療法により
誘発される血小板減少の危険性低下という利益をもたらすような、本発明の利益
を受けるであろう。According to a study by Wiseman et al., It is extremely likely that such patients will develop thrombocytopenia by radioimmunotherapy. However, the likelihood of developing such side effects after radioimmunotherapy increases with the extent of bone marrow lesions, so any patient with any degree of bone marrow lesions will be exposed to radioimmunotherapy after published treatment. It would benefit from the present invention, with the benefit of a reduced risk of therapy-induced thrombocytopenia.
【００１０】
本発明で用いる用量は、患者、骨髄病変の程度、および使用する抗体によって
変えても良い。Rituximab（登録商標）などの抗CD20キメラ抗体は、少なくとも
用量約50mg/m2/週で少なくとも４週間投与して良い。好ましい投与法は、約375m
g/m2/週で４週間である。The dose used in the present invention may vary depending on the patient, the degree of bone marrow lesions, and the antibody used. The anti-CD20 chimeric antibody, such as Rituximab®, may be administered at a dose of at least about 50 mg / m 2 / week for at least 4 weeks. A preferred administration method is about 375 m
g / m 2 / week for 4 weeks.
【００１１】
本発明の方法の目的は、放射免疫療法実施に備えて、リンパ腫患者の骨髄病変
を縮小させることであるので、当然ながら本発明の方法は骨髄浄化（purging）
後の放射性標識抗体による治療を含む。また放射性標識抗体は、通常は癌性細胞
上にあって健常細胞にはないＢ細胞表面マーカーのいずれかを標的としてもよい
。好ましい放射性標識抗体は、抗CD20抗体である。Since the purpose of the method of the present invention is to reduce the bone marrow lesions of patients with lymphoma in preparation for radioimmunotherapy, the method of the present invention is naturally purifying.
Includes subsequent radiolabeled antibody treatment. The radiolabeled antibody may also target any of the B cell surface markers that are normally on cancerous cells but not on healthy cells. A preferred radiolabeled antibody is anti-CD20 antibody.
【００１２】
好ましい放射性標識は、90Ｙまたは131Ｉ等のβ線放出同位元素であるが、抗
体と有効に結合し、崩壊範囲が比較的短く、隣接する細胞、すなわち標的細胞を
殺傷できるのであれば、いずれの放射性同位元素を用いてもよい。好ましい放射
性標識CD20抗体はY2B8である。A preferred radiolabel is a β-emitting isotope such as 90 Y or 131 I, as long as it binds effectively to the antibody and has a relatively short decay range and is capable of killing adjacent cells, the target cell. For example, any radioisotope may be used. A preferred radiolabeled CD20 antibody is Y2B8.
【００１３】
患者は、重篤な血球減少症、例えば血小板数が150,000未満でない限り、通常
は除去抗体投与後１週間以内に治療を受けるべきである。除去抗体での治療後に
患者が血球減少症となった場合は、回復、例えば最下点（nadir）AGCが1000を上
回るか、または血小板数が150,000を上回るまで待った後で、放射免疫療法を実
施しなければならない。抹消血および/または骨髄細胞の回復が可能な場合は、
免疫療法前にさらに多くの除去抗体を直接投与してもよい。このような二次投与
は、例えば放射免疫療法の前またはこれと同時に約250mg/m2で約２週間直接実施
しても良い。Patients should be treated for severe cytopenias, eg, within 1 week after administration of depleted antibody, unless the platelet count is less than 150,000. If the patient becomes cytopenic after treatment with the ablation antibody, radioimmunotherapy may be given after recovery, eg, waiting for nadir AGC> 1000 or platelet count> 150,000. Must. If peripheral blood and / or bone marrow cell recovery is possible,
More depleted antibodies may be administered directly before immunotherapy. Such secondary administration may be performed directly, for example prior to or concurrently with radioimmunotherapy at about 250 mg / m 2 for about 2 weeks.
【００１４】
放射性標識抗体の用量も、患者、抗体の特異性、半減期、安定性など、また当
然ながら疾患の程度により変えて良い。Y2B8のような放射性標識抗CD20抗体は、
用量約0.1〜0.5mCi/kgで投与する。The dose of radiolabeled antibody may also be varied according to the patient, the specificity of the antibody, the half-life, the stability, etc. and of course the extent of the disease. Radiolabeled anti-CD20 antibody, such as Y2B8,
The dose is about 0.1 to 0.5 mCi / kg.
【００１５】
本明細書で開示した治療法は、化学療法または放射線療法などの他の既知の治
療法と組合せても良いことが明らかなはずである。抗CD20抗体での治療の終了後
、かつ前記放射性標識抗体投与の前に、放射線治療後に自己由来骨髄または幹細
胞の移植を行う目的で、前記患者より骨髄または末梢血幹細胞を収集（harvest
）してもよい。It should be clear that the therapeutic methods disclosed herein may be combined with other known therapeutic methods such as chemotherapy or radiation therapy. Harvesting bone marrow or peripheral blood stem cells from the patient for the purpose of transplanting autologous bone marrow or stem cells after radiotherapy after completion of treatment with anti-CD20 antibody and before administration of the radiolabeled antibody (harvest).
) May be.
【００１６】
除去抗体または放射性標識抗体の投与の前に、CD20、または癌性Ｂ細胞表面に
ある他の標的タンパク質の発現のアップレギュレーションすることを目的として
、サイトカインによる治療を患者に施すことも有用と思われる。CD20のアップレ
ギュレーション（upregulation）に有用なサイトカインは、IL-4、GM-CSFおよび
TNF-αである。サイトカインは、免疫エフェクターの機能の刺激を目的として、
除去抗体あるいは放射性標識抗体投与と同時、またはその前あるいは後に投与し
てもよい。この目的に有用なサイトカインには、インターフェロンα、GM-CSFお
よびG-CSFがある。It is also useful to subject the patient to treatment with cytokines for the purpose of up-regulating the expression of CD20, or other target proteins on the surface of cancerous B cells, prior to administration of ablated or radiolabeled antibodies. I think that the. Cytokines useful for CD20 upregulation include IL-4, GM-CSF and
It is TNF-α. Cytokines are used to stimulate the function of immune effectors,
It may be administered simultaneously with, before, or after the administration of the cleared antibody or the radiolabeled antibody. Cytokines useful for this purpose include interferon alpha, GM-CSF and G-CSF.
【００１７】
本明細書に開示の治療法の補完を目的として化学療法を用いても良く、また前
記放射性標識抗体の投与と同時に、あるいはいずれかの順番で連続的に投与して
も良い。化学療法は、CHOP療法、ICE療法、ミトザントロン（Mitozantrone）、
シタラビン（Cytarabine）、DVP療法、ATRA療法、イダルビシン（Idarubicin）
、ヘルツァー（hoelzer）化学療法、La La化学療法、ABVD療法、CEOP療法、2-Cd
A療法、FLAG & IDA療法（G-CSF投与併用または併用なし）、VAD療法、M & P療法
、C-Weekly療法、ABCM療法、MOPP療法およびDHAP療法から選択して良い。好まし
い化学療法薬はCHOPである。Chemotherapy may be used for the purpose of complementing the therapeutic methods disclosed herein, and may be administered simultaneously with the administration of the radiolabeled antibody or sequentially in any order. Chemotherapy includes CHOP therapy, ICE therapy, Mitozantrone,
Cytarabine, DVP therapy, ATRA therapy, idarubicin
, Hoelzer chemotherapy, La La chemotherapy, ABVD therapy, CEOP therapy, 2-Cd
A therapy, FLAG & IDA therapy (with or without G-CSF administration), VAD therapy, M & P therapy, C-Weekly therapy, ABCM therapy, MOPP therapy and DHAP therapy may be selected. The preferred chemotherapeutic agent is CHOP.
【００１８】
本発明の方法は、様々なＢ細胞性リンパ腫に使用できるが、前記Ｂ細胞性リン
パ腫が非ホジキンリンパ腫（NHL）である場合は特に有用である。Rituximab（登
録商標）はすでに軽度濾胞性NHLの治療について認可されているが、本発明者ら
は、Rituximab（登録商標）が大きな（bulky）疾患を含む中等度および高度NHL
の治療にも驚くほど有益であることを認めている。従って、軽度/濾胞性非ホジ
キンリンパ腫（NHL）、小リンパ球性（SL）NHL、中等度/濾胞性NHL、中等度びま
ん性NHL、慢性リンパ球性リンパ腫（CLL）、高度免疫芽球性NHL、高度リンパ芽
球性NHL、高度小非分割細胞性NHL、bulky疾患NHL、マントル細胞リンパ腫、エイ
ズ関連リンパ腫、およびワルデンシュトローム（Waldenstrom's）マクログロブ
リン血症（Macroglobulinemia）が放射免疫治療の適用を困難にする骨髄病変を
併発している限り、本発明の方法により治療可能なリンパ腫にはこのようなリン
パ腫が含まれる。The method of the present invention can be used for various B-cell lymphomas, but is particularly useful when the B-cell lymphoma is non-Hodgkin's lymphoma (NHL). Although Rituximab® has already been approved for the treatment of mild follicular NHL, the present inventors have found that Rituximab® has moderate and advanced NHL including bulky disease.
It is admitted that it is also surprisingly beneficial for the treatment of. Therefore, mild / follicular non-Hodgkin lymphoma (NHL), small lymphocytic (SL) NHL, moderate / follicular NHL, moderate diffuse NHL, chronic lymphocytic lymphoma (CLL), hyperimmune blast NHL , Highly lymphoblastic NHL, highly small non-dividing cell NHL, bulky disease NHL, mantle cell lymphoma, AIDS-related lymphoma, and Waldenstrom's macroglobulinemia are difficult to apply radioimmunotherapy Lymphomas treatable by the methods of the present invention include such lymphomas, as long as they are associated with bone marrow lesions.
【００１９】 以下のデータは現在の治療条件例を示す。[0019] The following data show examples of current treatment conditions.
【００２０】
（再発性（relapsed）または難治性（refractory）非ホジキンリンパ腫（NH
L）の放射免疫療法：Y2B8第I/II相90Ｙ治験）
この第I/II相治験の対象は、58例の再発性または難治性のNHL患者であり、年
齢の中央値は60歳で、骨髄病変患者が43％、５cmを上回る大きな病変を有する患
者が60％であった（White et al. Poster Presentation at VII International
Conference on Malingnant Lymphoma, Lugano, Switzerland. Annals of Oncolo
gy Supple. 3 (1999) 10:64 (215)）。全患者に対し、111In標識抗体In2B8，５m
Ciを投与した後に、ガンマカメラによる測定、および尿および血液試料の連続採
取による線量測定を実施した。画像診断と治療の後、Rituximab（登録商標）を
用いて末梢Ｂ細胞を除去し、放射性標識抗体の分布を最適化した。１週間後、Y2
B8（0.2、0.3または0.4mCi/kg）を第２群および３群の患者に投与した。骨髄ま
たは幹細胞の収集は実施しなかった。(Relapsed or refractory non-Hodgkin's lymphoma (NH
L) radioimmunotherapy: Y2B8 Phase I / II 90 Y trial) This Phase I / II trial included 58 patients with relapsed or refractory NHL with a median age of 60 years. , 43% of patients with bone marrow lesions and 60% with large lesions larger than 5 cm (White et al. Poster Presentation at VII International).
Conference on Malingnant Lymphoma, Lugano, Switzerland. Annals of Oncolo
gy Supple. 3 (1999) 10:64 (215)). 111 In-labeled antibody In2B8, 5m for all patients
After administration of Ci, gamma camera measurements and dosimetry by continuous collection of urine and blood samples were performed. After diagnostic imaging and treatment, peripheral B cells were removed using Rituximab® to optimize radiolabeled antibody distribution. One week later, Y2
B8 (0.2, 0.3 or 0.4 mCi / kg) was administered to patients in groups 2 and 3. No bone marrow or stem cell collection was performed.
【００２１】
（結果）
最大耐用量は0.4mCi/kg（軽度の血小板減少患者では0.3mCi/kg）であった。有
害事象は主として血液学的なもので、一過性かつ可逆性であった。全患者中５例
（10％）は最下点血小板数が10,000/mm3を下回り、14例（28％）は最下点AGCが5
00を下回った。３例の患者（６％）は感染症を獲得し、１年間の観察期間を通じ
て入院を要した。ヒト抗マウス抗体/ヒト抗キメラ抗体の発生は２％に留まった
。平均血清免疫グロブリン値は、１年間の観察期間を通じて正常値を保った。組
織検査全体の総反応率は67％（完全反応26％、部分反応41％）であり、軽度NHL
患者では82％であった。カプラン・マイヤー（Kaplan Meier）法で算出した所、
反応した患者のTTPの中央値は12.9+ヶ月であり、反応の持続時間は11.7+ヶ月で
あった。初期段階で巨脾症（baseline splenomegaly）を有していた患者では、
８例中４例（50％）が反応したのに対して、巨脾症のない患者では74％（29/39
）が反応した（p＝0.1761）。血小板数初期値および治験前生検（baseline biop
sy）による骨髄病変度の２種類の臨床パラメータは、血液毒性の重篤度を予測す
る上で総線量パラメータよりも優れていた。(Results) The maximum tolerated dose was 0.4 mCi / kg (0.3 mCi / kg in patients with mild thrombocytopenia). Adverse events were primarily hematological, transient and reversible. 5 out of all patients (10%) had a nadir platelet count below 10,000 / mm 3 , 14 (28%) had a nadir AGC of 5
It fell below 00. Three patients (6%) acquired infection and were required to be hospitalized throughout the 1-year observation period. Occurrence of human anti-mouse antibody / human anti-chimeric antibody was limited to 2%. Mean serum immunoglobulin levels remained normal throughout the one year observation period. The overall reaction rate of the entire histological examination was 67% (complete reaction 26%, partial reaction 41%), and mild NHL
82% of patients. When calculated by the Kaplan Meier method,
The median TTP of responding patients was 12.9+ months and the duration of response was 11.7+ months. In patients who had baseline splenomegaly at an early stage,
4 out of 8 (50%) responded, compared with 74% (29/39 in patients without splenomegaly)
) Reacted (p = 0.1761). Initial platelet count and pre-trial biopsy (baseline biop
The two clinical parameters of bone marrow lesion degree by sy) were superior to the total dose parameter in predicting the severity of hematotoxicity.
───────────────────────────────────────────────────── フロントページの続き (81)指定国 ＥＰ(ＡＴ，ＢＥ，ＣＨ，ＣＹ， ＤＥ，ＤＫ，ＥＳ，ＦＩ，ＦＲ，ＧＢ，ＧＲ，ＩＥ，Ｉ Ｔ，ＬＵ，ＭＣ，ＮＬ，ＰＴ，ＳＥ)，ＯＡ(ＢＦ，ＢＪ ，ＣＦ，ＣＧ，ＣＩ，ＣＭ，ＧＡ，ＧＮ，ＧＷ，ＭＬ， ＭＲ，ＮＥ，ＳＮ，ＴＤ，ＴＧ)，ＡＰ(ＧＨ，ＧＭ，Ｋ Ｅ，ＬＳ，ＭＷ，ＭＺ，ＳＤ，ＳＬ，ＳＺ，ＴＺ，ＵＧ ，ＺＷ)，ＥＡ(ＡＭ，ＡＺ，ＢＹ，ＫＧ，ＫＺ，ＭＤ， ＲＵ，ＴＪ，ＴＭ)，ＡＥ，ＡＧ，ＡＬ，ＡＭ，ＡＴ， ＡＵ，ＡＺ，ＢＡ，ＢＢ，ＢＧ，ＢＲ，ＢＹ，ＢＺ，Ｃ Ａ，ＣＨ，ＣＮ，ＣＲ，ＣＵ，ＣＺ，ＤＥ，ＤＫ，ＤＭ ，ＤＺ，ＥＥ，ＥＳ，ＦＩ，ＧＢ，ＧＤ，ＧＥ，ＧＨ， ＧＭ，ＨＲ，ＨＵ，ＩＤ，ＩＬ，ＩＮ，ＩＳ，ＪＰ，Ｋ Ｅ，ＫＧ，ＫＰ，ＫＲ，ＫＺ，ＬＣ，ＬＫ，ＬＲ，ＬＳ ，ＬＴ，ＬＵ，ＬＶ，ＭＡ，ＭＤ，ＭＧ，ＭＫ，ＭＮ， ＭＷ，ＭＸ，ＭＺ，ＮＯ，ＮＺ，ＰＬ，ＰＴ，ＲＯ，Ｒ Ｕ，ＳＤ，ＳＥ，ＳＧ，ＳＩ，ＳＫ，ＳＬ，ＴＪ，ＴＭ ，ＴＲ，ＴＴ，ＴＺ，ＵＡ，ＵＧ，ＵＳ，ＵＺ，ＶＮ， ＹＵ，ＺＡ，ＺＷ─────────────────────────────────────────────────── ─── Continued front page (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE), OA (BF, BJ , CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K E, LS, MW, MZ, SD, SL, SZ, TZ, UG , ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, C A, CH, CN, CR, CU, CZ, DE, DK, DM , DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, K E, KG, KP, KR, KZ, LC, LK, LR, LS , LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, R U, SD, SE, SG, SI, SK, SL, TJ, TM , TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW
Claims (30)
与することを特徴とする骨髄病変を伴うＢ細胞性リンパ腫を有する患者の治療方
法。1. A method for treating a patient having B-cell lymphoma with bone marrow lesions, which comprises administering a CD20 antibody or a fragment thereof that reduces or alleviates bone marrow lesions.
。3. The method of claim 2, wherein the treatment reduces bone marrow lesions to less than 25%.
記載の方法。4. The anti-CD20 antibody is a human, chimeric or humanized antibody.
The method described.
記載の方法。6. The anti-CD20 chimeric antibody is Rituximab (registered trademark).
The method described.
も４週間投与する請求項６記載の方法。7. The method of claim 6, wherein the anti-CD20 chimeric antibody is administered at a dose of at least about 50 mg / m 2 / week for at least 4 weeks.
求項７記載の方法。8. The method according to claim 7, wherein the anti-CD20 chimeric antibody is administered at a dose of about 375 mg / m 2 / week for 4 weeks.
記載の方法。9. The method further comprising the subsequent administration of radiolabeled antibody.
The method described.
。11. The method according to claim 10, wherein the radiolabeled anti-CD20 antibody is Y2B8.
請求項１１記載の方法。12. The method of claim 11, wherein the radiolabeled anti-CD20 antibody is administered at a dose of about 0.1-0.5 mCi / kg.
の抗CD20抗体を投与する請求項９記載の方法。13. The method of claim 9, wherein the additional anti-CD20 antibody is administered simultaneously with the radiolabeled antibody or sequentially in any order.
する請求項１３に記載の方法。14. The method of claim 13, wherein the additional anti-CD20 antibody is administered at a dose of about 250 mg / m 2 at least once.
に患者より骨髄または抹消血液幹細胞を収集する請求項９記載の方法。15. The method according to claim 9, wherein bone marrow or peripheral blood stem cells are collected from a patient after treatment with an anti-CD20 antibody and before treatment with a radiolabeled antibody.
投与前にCD20の発現が癌性B細胞表面でアップレギュレーションされている請求
項１記載の方法。16. The method according to claim 1, wherein the expression of CD20 is upregulated on the surface of cancerous B cells by the administration of at least one kind of cytokine before the administration of the anti-CD20 antibody.
群より選択される請求項１６記載の方法。17. The method of claim 16, wherein the cytokine is selected from the group consisting of IL-4, GM-CSF and TNF-α.
に化学療法によって治療することをさらに含む請求項９記載の方法。18. The method of claim 9, further comprising treating with chemotherapy concurrently with the administration of the radiolabeled antibody or sequentially in either order.
ビン、DVP療法、ATRA療法、イダルビシン、ヘルツァー化学療法、La La化学療法
、ABVD療法、CEOP療法、2-CdA療法、FLAG & IDA療法（G-CSF投与を併用または併
用なし）、VAD療法、M & P療法、C-Weekly療法、ABCM療法、MOPP療法およびDHAP
療法から構成される群より選択される請求項１９記載の方法。19. The chemotherapy is CHOP therapy, ICE therapy, mitozantrone, cytarabine, DVP therapy, ATRA therapy, idarubicin, Herzer chemotherapy, La La chemotherapy, ABVD therapy, CEOP therapy, 2-CdA therapy, FLAG & IDA therapy. (With or without G-CSF administration), VAD therapy, M & P therapy, C-Weekly therapy, ABCM therapy, MOPP therapy and DHAP
20. The method of claim 19, selected from the group consisting of therapy.
はいずれかの順で連続的に投与することをさらに含む請求項１記載の方法。21. The method of claim 1, further comprising administering at least one cytokine with the anti-CD20 antibody either simultaneously or sequentially in either order.
GM-CSFおよびG-CSFから構成される群より選択される請求項２１に記載の方法。22. At least one cytokine is interferon alpha,
22. The method of claim 21, selected from the group consisting of GM-CSF and G-CSF.
求項１記載の方法。23. The method of claim 1, wherein the B cell lymphoma is non-Hodgkin's lymphoma (NHL).
球性（SL）NHL、中等度/濾胞性NHL、中等度びまん性NHL、慢性リンパ球性リンパ
腫（CLL）、高度免疫芽球性NHL、高度リンパ芽球性NHL、高度小非分割細胞性NHL
、bulky疾患NHL、マントル細胞リンパ腫、エイズ関連リンパ腫およびワルデンシ
ュトロームマクログロブリン血症から構成される群より選択される請求項２３記
載の方法。24. NHL is mild / follicular non-Hodgkin lymphoma (NHL), small lymphocytic (SL) NHL, moderate / follicular NHL, moderate diffuse NHL, chronic lymphocytic lymphoma (CLL), advanced Immunoblastic NHL, highly lymphoblastic NHL, highly small non-dividing cell NHL
24. The method of claim 23, wherein the method is selected from the group consisting of :, a bulky disease NHL, mantle cell lymphoma, AIDS-related lymphoma, and Waldenstrom macroglobulinemia.
投与することを特徴とする、放射免疫治療前の患者の骨髄内癌性Ｂ細胞数を減少
する方法。25. A method for reducing the number of intramedullary cancerous B cells in a patient before radioimmunotherapy, which comprises administering an effective amount of anti-CD20 antibody to a patient having non-Hodgkin's lymphoma.
ある請求項２５記載の方法。26. The method according to claim 25, wherein the anti-CD20 antibody is a human antibody, a chimeric antibody, or a humanized antibody.
載の方法。28. The method of claim 27, wherein the chimeric antibody is Rituximab®.
とも４週間投与する請求項２５記載の方法。29. The method of claim 25, wherein the anti-CD20 chimeric antibody is administered at a dose of at least about 50 mg / m 2 / week for at least 4 weeks.
請求項２９記載の方法。30. The method of claim 29, wherein the anti-CD20 chimeric antibody is administered at a dose of about 375 mg / m 2 / week for 4 weeks.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US14828799P | 1999-08-11 | 1999-08-11 | |
| US60/148,287 | 1999-08-11 | ||
| PCT/US2000/040459 WO2001010462A1 (en) | 1999-08-11 | 2000-07-25 | Treatment of patients having non-hodgkins lymphoma with bone marrow involvement with anti-cd20 antibodies |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2003513012A true JP2003513012A (en) | 2003-04-08 |
| JP2003513012A5 JP2003513012A5 (en) | 2007-06-28 |
Family
ID=22525101
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2001514978A Pending JP2003513012A (en) | 1999-08-11 | 2000-07-25 | Treatment of patients with non-Hodgkin's lymphoma with bone marrow lesions by anti-CD20 antibodies |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP1207906A4 (en) |
| JP (1) | JP2003513012A (en) |
| CN (2) | CN100389825C (en) |
| AU (1) | AU784971B2 (en) |
| CA (1) | CA2378646A1 (en) |
| HK (1) | HK1048945A1 (en) |
| MX (1) | MXPA02001398A (en) |
| MY (1) | MY136635A (en) |
| NO (1) | NO20020639L (en) |
| TW (1) | TWI279233B (en) |
| WO (1) | WO2001010462A1 (en) |
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| JPN6010024381, Ｄ．Ｔ． ＮＧＵＹＥＮ ｅｔ ａｌ, Ｅｕｒ Ｊ Ｈａｅｍａｔｏｌ, 1999, Ｖ６２, Ｐ７６−８２ * |
| JPN6010024383, Ｓｕｓａｎ Ｊ． ＫＮＯＸ ｅｔ ａｌ, Ｃｌｉｎｉｃａｌ Ｃａｎｃｅｒ Ｒｅｓｅａｒｃｈ, 1996, Ｖ２, ｐ４５７−４７０ * |
| JPN7010001364, Ｗｈｉｔｅ ｅｔ ａｌ．, Ａｎｎａｌｓ ｏｆ Ｏｎｃｏｌｏｇｙ, 199903, Ｖｏｌ．１０， Ｓｕｐｐｌｅ．３, ｐ．６４ * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2012513390A (en) * | 2008-12-22 | 2012-06-14 | ミレニアム ファーマシューティカルズ， インコーポレイテッド | Combination of Aurora kinase inhibitor and anti-CD20 antibody |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2378646A1 (en) | 2001-02-15 |
| AU784971B2 (en) | 2006-08-10 |
| CN101259270A (en) | 2008-09-10 |
| CN1373671A (en) | 2002-10-09 |
| TWI279233B (en) | 2007-04-21 |
| EP1207906A1 (en) | 2002-05-29 |
| CN100389825C (en) | 2008-05-28 |
| NO20020639D0 (en) | 2002-02-08 |
| MY136635A (en) | 2008-11-28 |
| NO20020639L (en) | 2002-04-11 |
| HK1048945A1 (en) | 2003-04-25 |
| AU7626000A (en) | 2001-03-05 |
| EP1207906A4 (en) | 2005-07-06 |
| MXPA02001398A (en) | 2002-08-12 |
| WO2001010462A1 (en) | 2001-02-15 |
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