JP6543262B2 - 急性リンパ性白血病の処置のための抗cd38抗体 - Google Patents
急性リンパ性白血病の処置のための抗cd38抗体 Download PDFInfo
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Description
MANCEFSPVSGDKPCCRLSRRAQLCLGVSILVLILVVVLAVVVPRWRQQWSGPGTTKRFPETVLARCVKYTEIHPEMRHVDCQSVWDAFKGAFISKHPCNITEEDYQPLMKLGTQTVPCNKILLWSRIKDLAHQFTQVQRDMFTLEDTLLGYLADDLTWCGEFNTSKINYQSCPDWRKDCSNNPVSVFWKTVSRRFAEAACDVVHVMLNGSRSKIFDKNSTFGSVEVHNLQPEKVQTLEAWVIHGGREDSRDLCQDPTIKELESIISKRNIQFSCKNIYRPDKFLQCVKNPEDSSCTSEI
SKRNIQFSCKNIYR
EKVQTLEAWVIHGG
EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTVSS
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIK
SFAMS
AISGSGGGTYYADSVKG
DKILWFGEPVFDY
RASQSVSSYLA
DASNRAT
QQRSNWPPTF
EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
VQLT
本明細書にて記載する本発明の方法において、また以下に記載する付番した実施形態の各々のいくつかの実施形態において、抗CD38抗体は、抗CD38抗体及び薬学的に許容可能な担体を含む、好適な医薬組成物で提供され得る。担体は、希釈剤、補助剤、賦形剤又はビヒクルであってよく、この担体とともに抗CD38抗体を投与する。そのようなビヒクルは、落花生油、大豆油、鉱物油、ゴマ油などの、石油、動物、植物、又は合成物起源のものを含む、水及び油などの液体であってよい。例えば、0.4%生理食塩水及び0.3%グリシンを用いることができる。これらの溶液は滅菌され、一般には粒子状物質を含まない。これらは、通常の周知の滅菌技術(例えば、濾過)によって滅菌することができる。組成物は、生理学的条件に近づけるために必要なpH調整剤及び緩衝剤、安定剤、増粘剤、潤滑剤並びに着色剤などの薬学的に許容可能な補助物質を含んでよい。このような医薬製剤中の本発明の分子又は抗体の濃度は、大幅に異なってもよく、即ち、重量にして約0.5%未満から、通常は少なくとも約1%まで又は最大で15%若しくは20%まで異なってよく、選択される特定の投与方法に従って、必要とされる用量、流体の体積、粘度などに主に基づいて選択される。好適なビヒクル及び配合物(他のヒトタンパク質、例えば、ヒト血清アルブミンを含む)については、例えば、Remington:The Science and Practice of Pharmacy,21st Edition,Troy,D.B.ed.,Lipincott Williams and Wilkins,Philadelphia,PA 2006,Part 5,Pharmaceutical Manufacturing pp 691〜1092に記載されており、特に、958〜989頁を参照されたい。
本明細書に別途記載される開示に従った本発明の更なる特定の実施形態について、以下に記載する。本明細書にて開示する本発明に関して上記で述べた本発明の実施形態の特徴はまた、これらの更なる付番した実施形態の各々にも関連する。
1.急性リンパ性白血病(ALL)である対象の処置にて使用するための抗CD38抗体。
2.ALLである対象の処置にて、ビンクリスチンと組み合わせて使用するための抗CD38抗体。
3.ALLである対象の処置にて、抗CD38抗体と組み合わせて使用するためのビンクリスチン。
4.3.ALLである対象の処置にて使用するための抗CD38抗体とビンクリスチンの組み合わせ。
5.前記抗CD38抗体が、配列番号4の重鎖可変領域(VH)及び配列番号5の軽鎖可変領域(VL)を含む抗体と、CD38への結合に関して競合する、実施形態1若しくは2に記載の使用のための抗CD38抗体、実施形態3に記載の使用のためのビンクリスチン、又は実施形態4に記載の組み合わせ。
6.前記抗CD38抗体が、抗体依存性細胞介在性細胞傷害(ADCC)、抗体依存性細胞貪食(ADCP)、補体依存性細胞傷害(CDC)、アポトーシス又はCD38酵素活性のインビトロ調節によるALL細胞のインビトロ殺傷を誘発し、好ましくは、前記抗CD38抗体が、ADCC又はCDCによるALL細胞のインビトロ殺傷を誘発する、実施形態1、2若しくは5に記載の使用のための抗CD38抗体、実施形態3若しくは5に記載の使用のためのビンクリスチン、又は実施形態4若しくは5に記載の組み合わせ。
7.前記抗CD38抗体が、ヒトCD38(配列番号1)のSKRNIQFSCKNIYR領域(配列番号2)及びEKVQTLEAWVIHGG領域(配列番号3)に結合する、実施形態1、2、5若しくは6に記載の使用のための抗CD38抗体、実施形態3、5若しくは6に記載の使用のためのビンクリスチン、又は実施形態4〜6に記載の組み合わせ。
8.前記抗CD38抗体が、
a.IgG1、IgG2、IgG3若しくはIgG4のアイソタイプであるか、
b.二分岐グリカン構造を有し、該二分岐グリカン構造のフコース含量が、約50%、40%、45%、40%、35%、30%、25%、20%、15%、14%、13%、12%、11%、10%、9%、8%、7%、6%、5%、4%、3%、2%、1%若しくは0%であるか、又は
c.抗体Fcにおいて、アミノ酸位256、290、298、312、356、330、333、334、360、378若しくは430(ここで、残基の番号付けは、EUインデックスに従う)における置換を含む、実施形態1、2、5〜7に記載の使用のための抗CD38抗体、実施形態3、5〜7に記載の使用のためのビンクリスチン、又は実施形態4〜7に記載の組み合わせ。
9.前記抗CD38抗体が、
a.それぞれ配列番号6、7及び8である重鎖相補性決定領域(HCDR)1(HCDR1)、2(HCDR2)及び3(HCDR3)配列、
b.それぞれ配列番号9、10及び11である軽鎖相補性決定領域(LCDR)1(LCDR1)、2(LCDR2)及び3(LCDR3)配列、
c.配列番号4の重鎖可変領域(VH)及び配列番号5の軽鎖可変領域(VL)、
d.配列番号12のアミノ酸配列と95%、96%、97%、98%若しくは99%同一であるアミノ酸配列を含む重鎖と、配列番号13のアミノ酸配列と95%、96%、97%、98%若しくは99%同一であるアミノ酸配列を含む軽鎖、又は
e.配列番号12の重鎖及び配列番号13の軽鎖を含む、実施形態1、2、5〜8に記載の使用のための抗CD38抗体、実施形態3、5〜8に記載の使用のためのビンクリスチン、又は実施形態4〜8に記載の組み合わせ。
10.ALLが、B細胞系ALL、T細胞系ALL、成人ALL、小児ALL、難治性ALL又は再発性ALLである、実施形態1、2、5〜9に記載の使用のための抗CD38抗体、実施形態3、5〜9に記載の使用のためのビンクリスチン、又は実施形態4〜9に記載の組み合わせ。
11.前記抗CD38抗体が、寛解導入療法又は導入後療法として投与される、実施形態1、2、5〜10に記載の使用のための抗CD38抗体、実施形態3、5〜10に記載の使用のためのビンクリスチン、又は実施形態4〜10に記載の組み合わせ。
12.前記対象が、
a.白血球数が、少なくとも約1×109/Lであるか、又は
b.フィラデルフィア染色体を含むALL細胞を有する、実施形態1、2、5〜11に記載の使用のための抗CD38抗体、実施形態3、5〜11に記載の使用のためのビンクリスチン、又は実施形態4〜11に記載の組み合わせ。
13.前記BCR−ABLキナーゼ阻害薬が、イマチニブ、ダサチニブ、ニロチニブ、ボスチニブ、ポナチニブ、バフェチニブ、サラカチニブ、トザセルチブ、ダヌセルチブ又はイブルチニブである、実施形態1、2、5〜12に記載の使用のための抗CD38抗体、実施形態3、5〜12に記載の使用のためのビンクリスチン、又は実施形態4〜12に記載の組み合わせ。
14.前記抗CD38抗体及びビンクリスチンが、同時に、連続的に又は個別に投与される、実施形態1、2、5〜13に記載の使用のための抗CD38抗体、実施形態3、5〜13に記載の使用のためのビンクリスチン、又は実施形態4〜13に記載の組み合わせ。
15.
a.前記対象が、放射線治療により更に処置されるか、若しくは、既に放射線治療により処置されている(原文(has been treated with radiotherapy))、又は
b.前記対象が、既に造血幹細胞移植を受けている(原文(has received hematopoietic stem cell transplantation))、実施形態1、2、5〜14に記載の使用のための抗CD38抗体、実施形態3、5〜14に記載の使用のためのビンクリスチン、又は実施形態4〜14に記載の組み合わせ。
方法
患者腫瘍モデルALL 7015及びALL 7473を本試験に用いた。
CB17 SCIDマウスに、PBS 100μL中の細胞株NALM−6腫瘍細胞1×105個を腫瘍発生のために尾静脈から静脈内接種した。腫瘍細胞接種の日を0日目と表す。動物を4つの処置群に分け、ダラツムマブ、ビンクリスチン又はビンクリスチンと組み合わせたダラツムマブを、表3に記載する用量で投与した。NALM−6細胞株(ACC128、DZMZ)は、再発性ALLである10歳の男子の末梢血から樹立したものである。細胞株の核型は、46(43〜47)<2n>XY、t(5;12)(q33.2;p13.2)である。
本発明は、以下の態様を包含し得る。
[1]
急性リンパ性白血病(ALL)である対象を処置する方法であって、必要とする患者に、配列番号4の重鎖可変領域(VH)及び配列番号5の軽鎖可変領域(VL)を含む抗体と、CD38への結合に関して競合する抗CD38抗体を投与することを含み、該抗CD38抗体が、抗体依存性細胞介在性細胞傷害(ADCC)、抗体依存性細胞貪食(ADCP)、補体依存性細胞傷害(CDC)、アポトーシス又はCD38酵素活性のインビトロ調節によりALL細胞のインビトロ殺傷を誘発する、方法。
[2]
前記抗CD38抗体が、ヒトCD38(配列番号1)のSKRNIQFSCKNIYR領域(配列番号2)及びEKVQTLEAWVIHGG領域(配列番号3)に結合する、上記[1]に記載の方法。
[3]
前記抗CD38抗体が、CD38を発現するALL細胞の、ADCC又はCDCによるインビトロ殺傷を誘発する、上記[2]に記載の方法。
[4]
前記抗CD38抗体が、IgG1、IgG2、IgG3又はIgG4のアイソタイプである、上記[1]に記載の方法。
[5]
前記抗CD38抗体が、二分岐グリカン構造を有し、該二分岐グリカン構造のフコース含量が、約50%、40%、45%、40%、35%、30%、25%、20%、15%、14%、13%、12%、11%、10%、9%、8%、7%、6%、5%、4%、3%、2%、1%又は0%である、上記[4]に記載の方法。
[6]
前記抗CD38抗体が、抗体Fcにおいて、アミノ酸位256、290、298、312、356、330、333、334、360、378又は430(ここで、残基の番号付けは、EUインデックスに従う)における置換を含む、上記[4]に記載の方法。
[7]
前記抗CD38抗体が、それぞれ配列番号6、7及び8である重鎖相補性決定領域(HCDR)1(HCDR1)、2(HCDR2)及び3(HCDR3)配列を含む、上記[1]に記載の方法。
[8]
前記抗CD38抗体が、それぞれ配列番号9、10及び11である軽鎖相補性決定領域(LCDR)1(LCDR1)、2(LCDR2)及び3(LCDR3)配列を含む、上記[7]に記載の方法。
[9]
前記抗CD38抗体が、配列番号4の重鎖可変領域(VH)及び配列番号5の軽鎖可変領域(VL)を含む、上記[8]に記載の方法。
[10]
前記抗CD38抗体が、配列番号12のアミノ酸配列と95%、96%、97%、98%又は99%同一であるアミノ酸配列を含む重鎖と、配列番号13のアミノ酸配列と95%、96%、97%、98%又は99%同一であるアミノ酸配列を含む軽鎖と、を含む、上記[1]に記載の方法。
[11]
前記抗CD38抗体が、配列番号12の重鎖及び配列番号13の軽鎖を含む、上記[10]に記載の方法。
[12]
前記ALLが、B細胞系ALL、T細胞系ALL、成人ALL又は小児ALLである、上記[1]に記載の方法。
[13]
前記ALLが、難治性又は再発性ALLである、上記[12]に記載の方法。
[14]
前記抗CD38抗体が、寛解導入療法又は導入後療法として投与される、上記[12]に記載の方法。
[15]
前記対象の白血球数が、少なくとも約1×10 9 /Lである、上記[12]に記載の方法。
[16]
前記ALL細胞が、フィラデルフィア染色体を有する、上記[12]に記載の方法。
[17]
前記対象が、BCR−ABLキナーゼ阻害薬による処置に対して、耐性があるか又は耐性を獲得している、上記[12]に記載の方法。
[18]
前記BCR−ABLキナーゼ阻害薬が、イマチニブ、ダサチニブ、ニロチニブ、ボスチニブ、ポナチニブ、バフェチニブ、サラカチニブ、トザセルチブ、ダヌセルチブ又はイブルチニブである、上記[17]に記載の方法。
[19]
前記抗CD38抗体が、ビンクリスチンと組み合わせて投与される、上記[1]又は[12]に記載の方法。
[20]
前記抗CD38抗体及びビンクリスチンが、同時に、連続的に又は個別に投与される、上記[19]に記載の方法。
[21]
前記対象が、放射線治療により更に処置されるか、又は、既に放射線治療により処置されている、上記[1]又は[12]に記載の方法。
[22]
前記対象が、既に造血幹細胞移植を受けている、上記[1]又は[12]に記載の方法。
Claims (18)
- 再発性又は難治性の急性リンパ性白血病(ALL)である対象を処置するための医薬組成物であって、それぞれ配列番号6、7及び8の重鎖相補性決定領域(HCDR)1(HCDR1)、2(HCDR2)及び3(HCDR3)配列、並びに、それぞれ配列番号9、10及び11の軽鎖相補性決定領域(LCDR)1(LCDR1)、2(LCDR2)及び3(LCDR3)配列を含む抗CD38抗体を含み、該医薬組成物は、ビンクリスチンと組み合わせて使用される、医薬組成物。
- 前記抗CD38抗体が、ヒトCD38(配列番号1)のSKRNIQFSCKNIYR領域(配列番号2)及びEKVQTLEAWVIHGG領域(配列番号3)に結合する、請求項1に記載の医薬組成物。
- 前記抗CD38抗体が、CD38を発現するALL細胞の、抗体依存性細胞介在性細胞傷害(ADCC)又は補体依存性細胞傷害(CDC)によるインビトロ殺傷を誘発する、請求項1又は2に記載の医薬組成物。
- 前記抗CD38抗体が、IgG1、IgG2、IgG3又はIgG4のアイソタイプである、請求項1から3のいずれか一項に記載の医薬組成物。
- 前記抗CD38抗体が、二分岐グリカン構造を有し、該二分岐グリカン構造のフコース含量が、約50%、45%、40%、35%、30%、25%、20%、15%、14%、13%、12%、11%、10%、9%、8%、7%、6%、5%、4%、3%、2%、1%又は0%である、請求項4に記載の医薬組成物。
- 前記抗CD38抗体が、抗体Fcにおいて、アミノ酸位256、290、298、312、356、330、333、334、360、378又は430(ここで、残基の番号付けは、EUインデックスに従う)における置換を含む、請求項4に記載の医薬組成物。
- 前記抗CD38抗体が、配列番号4の重鎖可変領域(VH)及び配列番号5の軽鎖可変領域(VL)を含む、請求項1から6のいずれか一項に記載の医薬組成物。
- 前記抗CD38抗体が、配列番号12のアミノ酸配列と95%、96%、97%、98%又は99%同一であるアミノ酸配列を含む重鎖と、配列番号13のアミノ酸配列と95%、96%、97%、98%又は99%同一であるアミノ酸配列を含む軽鎖と、を含む、請求項1から7のいずれか一項に記載の医薬組成物。
- 前記抗CD38抗体が、配列番号12の重鎖及び配列番号13の軽鎖を含む、請求項8に記載の医薬組成物。
- 前記ALLが、B細胞系ALL、T細胞系ALL、成人ALL又は小児ALLである、請求項1から9のいずれか一項に記載の医薬組成物。
- 前記抗CD38抗体が、寛解導入療法又は導入後療法として投与される、請求項10に記載の医薬組成物。
- 前記対象の白血球数が、少なくとも約1×109/Lである、請求項10に記載の医薬組成物。
- 前記ALL細胞が、フィラデルフィア染色体を有する、請求項10に記載の医薬組成物。
- 前記対象が、BCR−ABLキナーゼ阻害薬による処置に対して、耐性があるか又は耐性を獲得している、請求項10に記載の医薬組成物。
- 前記BCR−ABLキナーゼ阻害薬が、イマチニブ、ダサチニブ、ニロチニブ、ボスチニブ、ポナチニブ、バフェチニブ、サラカチニブ、トザセルチブ、ダヌセルチブ又はイブルチニブである、請求項14に記載の医薬組成物。
- 前記抗CD38抗体及びビンクリスチンが、同時に、連続的に又は個別に投与される、請求項1から15のいずれか一項に記載の医薬組成物。
- 前記対象が、放射線治療により更に処置されるか、又は、既に放射線治療により処置されている、請求項1から16のいずれか一項に記載の医薬組成物。
- 前記対象が、既に造血幹細胞移植を受けている、請求項1から16のいずれか一項に記載の医薬組成物。
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