JP2020529416A - 血液悪性腫瘍の治療 - Google Patents
血液悪性腫瘍の治療 Download PDFInfo
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- JP2020529416A JP2020529416A JP2020505341A JP2020505341A JP2020529416A JP 2020529416 A JP2020529416 A JP 2020529416A JP 2020505341 A JP2020505341 A JP 2020505341A JP 2020505341 A JP2020505341 A JP 2020505341A JP 2020529416 A JP2020529416 A JP 2020529416A
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- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
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Abstract
Description
本出願は、米国特許法第119条(e)の下、2017年7月31日に出願された米国仮特許出願第62/539,114号、表題「Treatments for a Hematological Malignancy」の利益を主張するものであり、その内容は参照により本明細書に組み込まれる。
本発明は、CD38抗原に特異的な放射標識モノクローナル抗体の組成物に関し、より具体的には、血液悪性腫瘍の治療に有用なα線放出核種で標識された抗CD38モノクローナル抗体を含む組成物に関する。
単数形「a」、「an」、「the」等は、文脈上別途明確に指示されない限り、複数の指示対象を含む。したがって、例えば、「a」希釈剤は、単一の希釈剤及び複数の異なる希釈剤の両方を含む。
本発明は、CD38に対する放射標識モノクローナル抗体を含む組成物と、該組成物の投与によって、血液悪性腫瘍を有する哺乳動物を治療するための方法、CD38を発現する細胞の成長及び/又は増殖を阻害するための方法、ならびにCD38を発現する細胞に関与する疾患又は障害を治療する方法とに関する。
2)J.Biol.Chem.2011,(286):22170−22177
3)米国特許第8,153,765号及びClin Cancer Res 2014,20(17):4574−83
4)J Immunol 2011,(186):1840−1848
5)米国特許第8,877,899号
Janssen Biotech(USA)社製のダラツムマブ(DARA)を、Montefiore Medical Center、New York,USAの薬局から購入した。アイソタイプ対照ヒトIgG1は、Creative Diagnotics(New York,USA))から購入した。乾燥硝酸塩の形態の225ACは、Oak Ridge National Laboratory,USAから入手した。塩化インジウム111の形態のインジウム−111(111In)は、MDS Nordion(Vancouver,BC,Canada)から購入した。CD38陽性リンパ腫細胞株Daudiは、ATCC(Manassas,USA)から調達し、CD38陽性多発性骨髄腫細胞株KMS−28BM及びKMS−28PEはXenoTech(Japan)から調達した。Daudi細胞株は、RPMI、10%FBS及び抗菌薬カクテルで成長させ、KMS−28BM及びKMS−28PE細胞株は、10%FBSを補充したRPMIで成長させた。二官能性キレート剤p−SCN−Bn−DOTA(これらの実施例ではDOTAと称される)をMacrocyclics(Texas,USA)から購入した。
図4Aに示されるように、たとえ、37oC又は室温で、DARAに対して様々なモル過剰のDOTAで行われたDOTAとDARAとのコンジュゲーション反応由来の225Ac−DARAコンジュゲートであっても、様々な濃度のCD38に対する225Ac−DARAコンジュゲートの結合は、非標識抗CD38と比較して本質的に変化しない。
裸のDARA、225Ac−DARA、及び無関係なIgG−225Acが、ある範囲のCD38抗原発現レベルを有する多発性骨髄腫細胞株において細胞溶解を誘導する能力を、様々な時点及び濃度で評価した。
Daudi腫瘍担持マウスにおいて111In−DARAのmicroSPECT/CTによる画像化を行い、腫瘍におけるその特異的取り込みを確認した(図9)。腫瘍の誘発のために、雌SCIDマウス(Charles River Laboratoriesから調達したCB17/Icr−Prkdcscid/IcrIcoCrl)の右側腹部に、50μL生理食塩水中の5×106Daudi細胞を皮下注射した。腫瘍の成長を3日ごとに電子キャリパーで測定し、式V=0.5(L×W2)を用いて腫瘍体積を算出し、幅を腫瘍短径とした。腫瘍細胞接種後14日目に、腫瘍が約200mm3の平均体積に達したとき、マウスをmicroSPECT/CTにより撮像したか、又は111In−DARAで処理した。画像化のために、3匹のマウスに400μCiの111In−DARAを腹腔内(IP)注射し、注射後1、4、24時間、続いて2、3、7及び10日目にmicroSPECT/CT(MI Labs,Netherlands)で撮像した。
本発明のまた別の態様は、以下のとおりであってもよい。
〔1〕CD38を発現する細胞に関与する疾患又は障害を治療する方法であって、
CD38に対するモノクローナル抗体を含む有効量の医薬組成物を対象に投与することを含み、前記モノクローナル抗体が、アクチニウム( 225 Ac)で標識されていることを特徴とする方法。
〔2〕前記モノクローナル抗体が、CD38に対するヒト又はヒト化免疫グロブリン(IgG1)を含む、前記〔1〕に記載の方法。
〔3〕前記モノクローナル抗体が、ダラツムマブ、MOR202、SAR650984を含む、前記〔1〕に記載の方法。
〔4〕前記モノクローナル抗体が、ダラツムマブを含む、前記〔1〕に記載の方法。
〔5〕CD38を発現する前記細胞が、CD38発現癌細胞又はCD38発現T細胞、B細胞、NK細胞、もしくは形質細胞である、前記〔1〕に記載の方法。
〔6〕CD38を発現する前記細胞が、固形腫瘍細胞又は血液悪性腫瘍細胞を含む、前記〔1〕に記載の方法。
〔7〕前記血液悪性腫瘍細胞が、多発性骨髄腫細胞、急性リンパ性白血病細胞、急性骨髄性白血病細胞、慢性リンパ性白血病細胞、慢性骨髄性白血病細胞、ホジキンリンパ腫細胞、非ホジキンリンパ腫細胞、T−LGL白血病細胞、NK細胞白血病細胞、又はヘアリーセル白血病細胞を含む、前記〔6〕に記載の方法。
〔8〕前記医薬組成物が、CD38のエピトープに対する非放射標識モノクローナル抗体を更に含む、前記〔1〕に記載の方法。
〔9〕前記医薬組成物が、前記アクチニウムで標識されたモノクローナル抗体と同じCD38のエピトープに対する非放射標識モノクローナル抗体を更に含む、前記〔1〕に記載の方法。
〔10〕前記有効量が、0.1uCi/kg〜5uCi/kgを含む0.1ug/kg〜1mg/kg抗体の用量を含む、前記〔9〕に記載の方法。
〔11〕前記有効量が、0.1uCi/kg〜1uCi/kgを含む0.1ug/kg〜50ug/kg抗体の用量を含む、前記〔9〕に記載の方法。
〔12〕前記有効量が、単回用量として投与される、前記〔10〕又は〔11〕に記載の方法。
〔13〕前記有効量が、2回の等しい分割用量として投与され、第2の用量が第1の用量の3〜8日後に投与される、前記〔10〕又は〔11〕に記載の方法。
〔14〕1つ以上のさらなる治療薬を投与することを更に含む、前記〔1〕に記載の方法。
〔15〕前記1つ以上のさらなる治療薬の投与が、前記医薬組成物の投与の前又は後である、前記〔14〕に記載の方法。
〔16〕前記1つ以上のさらなる治療薬が、化学療法剤、抗炎症剤、免疫抑制剤、免疫調節剤、又はそれらの組み合わせを含む、前記〔14〕に記載の方法。
〔17〕前記1つ以上のさらなる治療薬が、抗骨髄腫剤を含む、前記〔14〕に記載の方法。
〔18〕前記抗骨髄腫剤が、デキサメタゾン、メルファラン、ドキソルビシン、ボルテゾミブ、レナリドミド、プレドニゾン、カルムスチン、エトポシド、シスプラチン、ビンクリスチン、シクロホスファミド、及びサリドマイドから選択される、前記〔14〕に記載の方法。
〔19〕前記医薬組成物が、1つ以上のさらなる治療薬を更に含む、前記〔1〕に記載の方法。
〔20〕前記医薬組成物が、少なくとも1回の用量を含む投与計画において前記対象に投与される、前記〔1〕に記載の方法。
〔21〕前記少なくとも1回の用量が、対照モノクローナル抗体のみを含む投与計画の用量よりも5倍低いCD38に対するモノクローナル抗体の量、又は対照モノクローナル抗体のみを含む投与計画の用量よりも10倍低いCD38に対するモノクローナル抗体の量、又は対照モノクローナル抗体のみを含む投与計画の用量よりも20倍低いCD38に対するモノクローナル抗体の量、又は前記対照モノクローナル抗体のみを含む前記投与計画の前記用量よりも50倍低いCD38に対するモノクローナル抗体の量、又は前記対照モノクローナル抗体のみを含む前記投与計画の前記用量よりも100倍低いCD38に対するモノクローナル抗体の量を含み、前記対照モノクローナル抗体が、前記アクチニウムで標識されたモノクローナル抗体と同じCD38のエピトープに対する非標識モノクローナル抗体を含む、前記〔20〕に記載の方法。
〔22〕前記対照モノクローナル抗体が、約16mg/kg患者体重の用量で投与されるダラツムマブを含む、前記〔21〕に記載の方法。
〔23〕前記投与計画が、対照投与計画よりも少なくとも1回少ない用量、又は対照投与計画よりも少なくとも2回少ない用量、又は対照投与計画よりも少なくとも3回少ない用量、又は対照投与計画よりも少なくとも4回少ない用量、又は対照投与計画よりも少なくとも5回少ない用量を含み、前記対照投与計画は、単独で又は1つ以上の追加の治療薬と組み合わせてのいずれかの、前記アクチニウムで標識されたモノクローナル抗体と同じCD38のエピトープに対する非標識モノクローナル抗体の投与を含む、前記〔20〕に記載の方法。
〔24〕前記対照投与計画が、少なくとも8週間、1週間に1回の用量で投与される8回の用量を含む、前記〔23〕に記載の方法。
〔25〕(a)CD38に対する放射標識モノクローナル抗体と、
(b)CD38を発現する細胞に関与する疾患又は障害を治療するのに有効な量の前記抗体を対象に投与するよう使用者に指示する表示と、
を含むことを特徴とする製造品。
〔26〕前記モノクローナル抗体が、アクチニウム( 225 Ac)で標識されたダラツムマブである、前記〔25〕に記載の製造品。
〔27〕CD38を発現する細胞に関与する前記疾患又は障害を治療するのに有効な前記抗体の量が、10μCi〜200μCiの前記 225 Acで標識されたダラツムマブを含む、前記〔26〕に記載の製造品。
〔28〕CD38を発現する細胞に関与する疾患又は障害の治療に有用な医薬組成物であって、
5〜50重量%のアクチニウム( 225 Ac)で標識されたCD38に対するモノクローナル抗体と、
50〜95重量%の非標識CD38に対する前記モノクローナル抗体と、
薬学的に許容可能な担体と、
を含むことを特徴とする医薬組成物。
〔29〕前記放射標識モノクローナル抗体が、 225 Ac−ダラツムマブであり、前記非標識モノクローナル抗体が、ダラツムマブである、前記〔28〕に記載の医薬組成物。
Claims (29)
- CD38を発現する細胞に関与する疾患又は障害を治療する方法であって、
CD38に対するモノクローナル抗体を含む有効量の医薬組成物を対象に投与することを含み、前記モノクローナル抗体が、アクチニウム(225Ac)で標識されていることを特徴とする方法。 - 前記モノクローナル抗体が、CD38に対するヒト又はヒト化免疫グロブリン(IgG1)を含む、請求項1に記載の方法。
- 前記モノクローナル抗体が、ダラツムマブ、MOR202、SAR650984を含む、請求項1に記載の方法。
- 前記モノクローナル抗体が、ダラツムマブを含む、請求項1に記載の方法。
- CD38を発現する前記細胞が、CD38発現癌細胞又はCD38発現T細胞、B細胞、NK細胞、もしくは形質細胞である、請求項1に記載の方法。
- CD38を発現する前記細胞が、固形腫瘍細胞又は血液悪性腫瘍細胞を含む、請求項1に記載の方法。
- 前記血液悪性腫瘍細胞が、多発性骨髄腫細胞、急性リンパ性白血病細胞、急性骨髄性白血病細胞、慢性リンパ性白血病細胞、慢性骨髄性白血病細胞、ホジキンリンパ腫細胞、非ホジキンリンパ腫細胞、T−LGL白血病細胞、NK細胞白血病細胞、又はヘアリーセル白血病細胞を含む、請求項6に記載の方法。
- 前記医薬組成物が、CD38のエピトープに対する非放射標識モノクローナル抗体を更に含む、請求項1に記載の方法。
- 前記医薬組成物が、前記アクチニウムで標識されたモノクローナル抗体と同じCD38のエピトープに対する非放射標識モノクローナル抗体を更に含む、請求項1に記載の方法。
- 前記有効量が、0.1uCi/kg〜5uCi/kgを含む0.1ug/kg〜1mg/kg抗体の用量を含む、請求項9に記載の方法。
- 前記有効量が、0.1uCi/kg〜1uCi/kgを含む0.1ug/kg〜50ug/kg抗体の用量を含む、請求項9に記載の方法。
- 前記有効量が、単回用量として投与される、請求項10又は11に記載の方法。
- 前記有効量が、2回の等しい分割用量として投与され、第2の用量が第1の用量の3〜8日後に投与される、請求項10又は11に記載の方法。
- 1つ以上のさらなる治療薬を投与することを更に含む、請求項1に記載の方法。
- 前記1つ以上のさらなる治療薬の投与が、前記医薬組成物の投与の前又は後である、請求項14に記載の方法。
- 前記1つ以上のさらなる治療薬が、化学療法剤、抗炎症剤、免疫抑制剤、免疫調節剤、又はそれらの組み合わせを含む、請求項14に記載の方法。
- 前記1つ以上のさらなる治療薬が、抗骨髄腫剤を含む、請求項14に記載の方法。
- 前記抗骨髄腫剤が、デキサメタゾン、メルファラン、ドキソルビシン、ボルテゾミブ、レナリドミド、プレドニゾン、カルムスチン、エトポシド、シスプラチン、ビンクリスチン、シクロホスファミド、及びサリドマイドから選択される、請求項14に記載の方法。
- 前記医薬組成物が、1つ以上のさらなる治療薬を更に含む、請求項1に記載の方法。
- 前記医薬組成物が、少なくとも1回の用量を含む投与計画において前記対象に投与される、請求項1に記載の方法。
- 前記少なくとも1回の用量が、対照モノクローナル抗体のみを含む投与計画の用量よりも5倍低いCD38に対するモノクローナル抗体の量、又は対照モノクローナル抗体のみを含む投与計画の用量よりも10倍低いCD38に対するモノクローナル抗体の量、又は対照モノクローナル抗体のみを含む投与計画の用量よりも20倍低いCD38に対するモノクローナル抗体の量、又は前記対照モノクローナル抗体のみを含む前記投与計画の前記用量よりも50倍低いCD38に対するモノクローナル抗体の量、又は前記対照モノクローナル抗体のみを含む前記投与計画の前記用量よりも100倍低いCD38に対するモノクローナル抗体の量を含み、前記対照モノクローナル抗体が、前記アクチニウムで標識されたモノクローナル抗体と同じCD38のエピトープに対する非標識モノクローナル抗体を含む、請求項20に記載の方法。
- 前記対照モノクローナル抗体が、約16mg/kg患者体重の用量で投与されるダラツムマブを含む、請求項21に記載の方法。
- 前記投与計画が、対照投与計画よりも少なくとも1回少ない用量、又は対照投与計画よりも少なくとも2回少ない用量、又は対照投与計画よりも少なくとも3回少ない用量、又は対照投与計画よりも少なくとも4回少ない用量、又は対照投与計画よりも少なくとも5回少ない用量を含み、前記対照投与計画は、単独で又は1つ以上の追加の治療薬と組み合わせてのいずれかの、前記アクチニウムで標識されたモノクローナル抗体と同じCD38のエピトープに対する非標識モノクローナル抗体の投与を含む、請求項20に記載の方法。
- 前記対照投与計画が、少なくとも8週間、1週間に1回の用量で投与される8回の用量を含む、請求項23に記載の方法。
- (a)CD38に対する放射標識モノクローナル抗体と、
(b)CD38を発現する細胞に関与する疾患又は障害を治療するのに有効な量の前記抗体を対象に投与するよう使用者に指示する表示と、
を含むことを特徴とする製造品。 - 前記モノクローナル抗体が、アクチニウム(225Ac)で標識されたダラツムマブである、請求項25に記載の製造品。
- CD38を発現する細胞に関与する前記疾患又は障害を治療するのに有効な前記抗体の量が、10μCi〜200μCiの前記225Acで標識されたダラツムマブを含む、請求項26に記載の製造品。
- CD38を発現する細胞に関与する疾患又は障害の治療に有用な医薬組成物であって、
5〜50重量%のアクチニウム(225Ac)で標識されたCD38に対するモノクローナル抗体と、
50〜95重量%の非標識CD38に対する前記モノクローナル抗体と、
薬学的に許容可能な担体と、
を含むことを特徴とする医薬組成物。 - 前記放射標識モノクローナル抗体が、225Ac−ダラツムマブであり、前記非標識モノクローナル抗体が、ダラツムマブである、請求項28に記載の医薬組成物。
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