JP2022113883A - 抗bcma car t細胞組成物 - Google Patents
抗bcma car t細胞組成物 Download PDFInfo
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Abstract
Description
本出願は、35U.S.C.§119(e)下で、2017年6月2日出願の米国仮出願第62/514,401号および2016年11月4日出願の米国仮出願第62/417,840号の利益を主張し、それらの各々は、参照によりその全体が本明細書に組み込まれる。
本出願に関連する配列表は、ハードコピーの代わりにテキスト形式で提供され、本明細書に参照により組み込まれる。配列表を含むテキストファイル名は、BLBD_079_02WO_ST25.txtである。テキストファイルは、27KBであり、2017年11月3日に作成され、明細書の出願と同時に、EFS-Webを介して電子的に提出されている。
背景
CAR T細胞である。
CAR T細胞である。
T細胞~約80.0×107の抗BCMA CAR T細胞である。
CAR T細胞当たり約2.0コピーである。
T細胞を含む。
T細胞を含む。
本発明の実施形態において、例えば以下の項目が提供される。
(項目1)
治療上有効な量の抗B細胞成熟抗原(BCMA)キメラ抗原受容体(CAR)T細胞を含む組成物であって、前記治療上有効な量が、約5.0×107を超える抗BCMA CAR T細胞であり、前記抗BCMA CARが、配列番号9に記載されるアミノ酸配列を含む、組成物。
(項目2)
薬学的に許容される担体をさらに含む、項目1に記載の組成物。
(項目3)
50:50のPlasmaLyte A対CryoStor CS10を含む溶液中に配合される、項目1または項目2に記載の組成物。
(項目4)
前記治療上有効な量が、少なくとも約15.0×107の抗BCMA CAR T細胞である、項目1~3のいずれか一項に記載の組成物。
(項目5)
前記治療上有効な量が、少なくとも約45.0×107の抗BCMA CAR T細胞である、項目1~4のいずれか一項に記載の組成物。
(項目6)
前記治療上有効な量が、少なくとも約80.0×107の抗BCMA CAR T細胞である、項目1~5のいずれか一項に記載の組成物。
(項目7)
前記治療上有効な量が、少なくとも約12.0×10の抗BCMA CAR T細胞である、項目1~6のいずれか一項に記載の組成物。
(項目8)
前記治療上有効な量が、約5.0×107の抗BCMA CAR T細胞~約15.0×107の抗BCMA CAR T細胞である、項目1~3のいずれか一項に記載の組成物。
(項目9)
前記治療上有効な量が、約5.0×107の抗BCMA CAR T細胞~約45.0×107の抗BCMA CAR T細胞である、項目1~3のいずれか一項に記載の組成物。
(項目10)
前記治療上有効な量が、約5.0×107の抗BCMA CAR T細胞~約80.0×107の抗BCMA CAR T細胞である、項目1~3のいずれか一項に記載の組成物。
(項目11)
前記治療上有効な量が、約5.0×107の抗BCMA CAR T細胞~約12.0×108の抗BCMA CAR T細胞である、項目1~3のいずれか一項に記載の組成物。
(項目12)
前記治療上有効な量が、約15.0×107の抗BCMA CAR T細胞~約45.0×107の抗BCMA CAR T細胞である、項目1~3のいずれか一項に記載の組成物。
(項目13)
前記治療上有効な量が、約15.0×107の抗BCMA CAR T細胞~約80.0×107の抗BCMA CAR T細胞である、項目1~3のいずれか一項に記載の組成物。
(項目14)
前記治療上有効な量が、約15.0×107の抗BCMA CAR T細胞~約12.0×108の抗BCMA CAR T細胞である、項目1~3のいずれか一項に記載の組成物。
(項目15)
前記抗BCMA CAR T細胞が、前記抗BCMA CARをコードするレンチウイルスベクターで形質導入される、項目1~14のいずれか一項に記載の組成物。
(項目16)
前記レンチウイルスベクターコピー数(VCN)が、1つの抗BCMA CAR T細胞当たり約2.0コピーである、項目15に記載の組成物。
(項目17)
前記レンチウイルスベクターが、ヒト免疫不全ウイルス1(HIV-1)ベクターである、項目15または項目16に記載の組成物。
(項目18)
抗BCMA CARをコードするレンチウイルスで形質導入されたT細胞の集団を含む医薬組成物であって、T細胞の集団が、約5.0×107を超える抗BCMA CAR T細胞を含み、前記抗BCMA CARが、配列番号9に記載されるアミノ酸配列を含む、医薬組成物。
(項目19)
治療上許容される担体をさらに含む、項目18に記載の医薬組成物。
(項目20)
前記組成物が、少なくとも約15.0×107の抗BCMA CAR T細胞を含む、項目18または項目19に記載の医薬組成物。
(項目21)
前記組成物が、少なくとも約45.0×107の抗BCMA CAR T細胞を含む、項目18~20のいずれか一項に記載の医薬組成物。
(項目22)
前記組成物が、少なくとも約80.0×107の抗BCMA CAR T細胞を含む、項目18~21のいずれか一項に記載の医薬組成物。
(項目23)
前記組成物が、少なくとも約12.0×10の抗BCMA CAR T細胞を含む、項目18~22のいずれか一項に記載の医薬組成物。
(項目24)
前記組成物が、約5.0×107の抗BCMA CAR T細胞~約15.0×107の抗BCMA CAR T細胞を含む、項目18または項目19に記載の医薬組成物。
(項目25)
前記組成物が、約5.0×107の抗BCMA CAR T細胞~約45.0×107の抗BCMA CAR T細胞を含む、項目18または項目19に記載の医薬組成物。
(項目26)
前記組成物が、約5.0×107の抗BCMA CAR T細胞~約80.0×107の抗BCMA CAR T細胞を含む、項目18または項目19に記載の医薬組成物。
(項目27)
前記組成物が、約5.0×107の抗BCMA CAR T細胞~約12.0×108の抗BCMA CAR T細胞を含む、項目18または項目19に記載の医薬組成物。
(項目28)
前記組成物が、約15.0×107の抗BCMA CAR T細胞~約45.0×107の抗BCMA CAR T細胞を含む、項目18または項目19に記載の医薬組成物。
(項目29)
前記組成物が、約15.0×107の抗BCMA CAR T細胞~約80.0×107の抗BCMA CAR T細胞を含む、項目18または項目19に記載の医薬組成物。
(項目30)
前記組成物が、約15.0×107の抗BCMA CAR T細胞~約12.0×108の抗BCMA CAR T細胞を含む、項目18または項目19に記載の医薬組成物。
(項目31)
前記T細胞が、CD8+T細胞を含む、項目18~30のいずれか一項に記載の医薬組成物。
(項目32)
再発性/難治性多発性骨髄腫と診断された対象を治療する方法であって、項目1~31のいずれか一項に記載の組成物を前記対象に投与することを含む、方法。
(項目33)
再発性/難治性多発性骨髄腫を有する対象を治療する方法であって、項目1~31のいずれか一項に記載の組成物を前記対象に投与することを含む、方法。
(項目34)
前記組成物が、単一用量で投与される、項目32または項目33に記載の方法。
(項目35)
前記組成物が、静脈内投与される、項目32~34のいずれか一項に記載の方法。
(項目36)
前記多発性骨髄腫が、前記組成物の前記投与前に、プロテアソーム阻害薬および免疫調節剤を含む少なくとも3つの治療計画に対して難治性であった、項目32~35のいずれか一項に記載の方法。
(項目37)
前記多発性骨髄腫が、前記組成物の前記投与前に、1つ以上の治療計画に対して二重難治性であった、項目32~35のいずれか一項に記載の方法。
(項目38)
前記対象が、前記組成物の前記投与前に、ダラツムマブ、レナリドミド、ポマリドミド、ボルテゾミブ、および/またはカルフィルゾミブで治療された、項目32~35のいずれか一項に記載の方法。
(項目39)
前記対象が、前記組成物の前記投与前に、自家造血幹細胞移植を受けた、項目32~38のいずれか一項に記載の方法。
(項目40)
前記対象が、シクロホスファミド300mg/m2およびフルダラビン30mg/m2でリンパ枯渇された、項目32~39のいずれか一項に記載の方法。
配列番号1~3は、本明細書で意図されるBCMA CARに対する例示的な軽鎖CDR配列のアミノ酸配列を示す。
配列番号4~6は、本明細書で意図されるBCMA CARに対する例示的な重鎖CDR配列のアミノ酸配列を示す。
配列番号7は、本明細書で意図されるBCMA CARに対する例示的な軽鎖配列のアミノ酸配列を示す。
配列番号8は、本明細書で意図されるBCMA CARに対する例示的な重鎖配列のアミノ酸配列を示す。
配列番号9は、本明細書で意図される例示的なBCMA CARのアミノ酸配列を示す。
配列番号10は、本明細書で意図される例示的なBCMA CARをコードするポリヌクレオチド配列を示す。
配列番号11は、ヒトBCMAのアミノ酸配列を示す。
配列番号12~22は、様々なリンカーのアミノ酸配列を示す。
配列番号23~35は、プロテアーゼ切断部位および自己切断型ポリペプチド切断部位のアミノ酸配列を示す。
配列番号36は、BCMA CARをコードするベクターのポリヌクレオチド配列を示す。
当技術分野では、特定のCARおよびその標的適応症に関する治療上有効なCAR T細胞用量を予測することに対する重大な課題が存在する。本開示は、概して、改善された抗BCMA CAR T細胞組成物、および再発性/難治性多発性骨髄腫を治療するための方法に関する。
et al.,Annu.Rev.Immunol,21:231-264,2003を参照されたい。BCMAは、B細胞活性化因子(BAFF)および増殖誘導リガンド(APRIL)を結合させる(例えば、Mackay et al.,2003およびKalled et al.,Immunological Reviews,204:43-54,2005を参照されたい)。非悪性細胞の中では、BCMAは、ほとんどが形質細胞および成熟B細胞のサブセットにおいて発現されると報告されている(例えば、Laabi et al.,EMBO J.,77(1):3897-3904,1992;Laabi et al.,Nucleic Acids Res.,22(7):1147-1154,1994;Kalled et al.,2005;O’Connor
et al.,J.Exp.Medicine,199(1):91-97,2004;およびNg et al.,J.Immunol.,73(2):807-817,2004を参照されたい。BCMAが欠損しているマウスは、健康であり、正常な数のB細胞を有するが、長寿の形質細胞の生存は、低い(例えば、O’Connor et al.,2004;Xu et al.,Mol.Cell.Biol,21(12):4067-4074,2001;およびSchiemann et al.,Science,293(5537):2 111-21 14,2001を参照されたい)。BCMA
RNAは、多発性骨髄腫細胞において、および他のリンパ腫において広く検出されており、BCMAタンパク質は、数人の治験責任医師によって多発性骨髄腫患者からの形質細胞の表面で検出されている(例えば、Novak et al.,Blood,103(2):689-694,2004;Neri et al.,Clinical Cancer Research,73(19):5903-5909,2007;Bellucci et al.,Blood,105(10):3945-3950,2005;およびMoreaux et al.,Blood,703(8):3148-3157,2004を参照されたい。
特に定義のない限り、本明細書で使用されるすべての技術的および科学的用語は、本発明が属する当業者によって一般的に理解されるものと同じ意味を有する。本明細書で説明されるものと同様または同等の任意の方法および材料が本発明の実施または試験において使用され得るが、組成物、方法、および材料の好ましい実施形態が本明細書で説明される。本発明の目的で、次の用語が以下に定義される。
様々な実施形態では、概して、T細胞の細胞毒性をBCMA発現細胞へ方向転換する人工受容体が提供される。これらの遺伝し操作された人工受容体は、本明細書において、抗BCMAキメラ抗原受容体(CAR)と称される。
本開示は、特定の実施形態において、抗BCMA CARを含むT細胞、例えば、抗BCMA CAR T細胞を意図する。用語「T細胞」または「Tリンパ球」は、当該技術分野において承認されていて、胸腺細胞、未熟Tリンパ球、成熟Tリンパ球、静止Tリンパ球、または活性化Tリンパ球を含むことを目的とする。T細胞は、Tヘルパー(Th)細胞、例えば、Tヘルパー1(Th1)またはTヘルパー2(Th2)細胞であり得る。T細胞は、ヘルパーT細胞(HTL;CD4+T細胞)CD4+T細胞、細胞毒性T細胞(CTL;CD8+T細胞)、CD4+CD8+T細胞、CD4-CD8-T細胞、またはT細胞の任意の他のサブセットであり得る。特定の実施形態で使用するための適切なT細胞の他の実例のための集団は、未感作T細胞および記憶T細胞を含む。
本明細書で意図される組成物は、治療上有効な量の抗BCMA CAR T細胞を含む。組成物は、これらに限定されないが、医薬組成物を含む。「医薬組成物」は、単独、または1つ以上の他の様式の療法を組み合わせて、細胞または動物への投与のために、薬学的に許容される、または生理学的に許容される溶液中で配合された組成物を指す。必要に応じて、組成物は、他の薬剤、例えば、サイトカイン、成長因子、ホルモン、小分子、化学療法、プロドラッグ、薬物、抗体、または他の様々な薬学的に活性な薬剤などと組み合わせて投与されてもよい。追加の薬剤が、目的とする療法を送達する組成物の能力に悪影響を与えないことを条件として、組成物中に含まれてもよい他の成分に事実上制限はない。
CS10、CryoStor CS5、およびCryoStor CS2が挙げられる。
本明細書で意図される多発性骨髄腫を治療するための方法は、抗BCMA CARを発現する治療上有効な量のT細胞を含む組成物を対象に投与することを含む。
BCMA CARの構造
ネズミ抗BCMA scFv抗体を含有するCARは、抗BMCA scFvに操作可能に連結されたMNDプロモーター、CD8αからのヒンジおよび膜貫通ドメイン、およびCD3ζ鎖の細胞内シグナル伝達が続くCD137同時刺激ドメインを含有するように設計した。例えば、図1を参照されたい。図1に示される抗BMCA CARは、T細胞の表面発現のためのCD8αシグナルペプチド(SP)配列を含む。例示的な抗BMCA
CARのポリヌクレオチド配列は、配列番号10に記載され、抗BMCA CARの例示的なポリペプチド配列は、配列番号9に記載され、例示的なCAR構成概念のベクター地図は、図1に示される。表3は、抗BMCA CARレンチウイルスベクターの様々なヌクレオチド区分に対する同一性、ジェンバンク基準、ソース名、および引用を示す。
抗BCMA CAR T細胞製造プロセス
固有の抗BCMA02CAR T細胞生成物を各患者の治療に製造する。抗BCMA02CAR T細胞生成物の製造プロセスの信頼性を、11個人の正常ドナーPBMCから抗BCMA02CAR T細胞を生成することによって評価した。各ドナーからの抗BCMA02CAR T細胞の増殖は、同時に行われた同等の形質導入されていない培養物と同程度であった(図2A)。
抗BCMA02CAR T細胞は、再発性/難治性多発性骨髄腫のヒト臨床試験において療活性を示す。
序論
キメラ抗原受容体(CAR)T細胞療法は、いくつかの血液学的悪性腫瘍で見られる堅固で持続的な臨床応答を証明した。しかしながら、CD19以外では、CAR T細胞の有望さを支持する臨床データは、制限されている。CAR T細胞安全性および有効性の可能性を、再発性/難治性多発性骨髄腫(MM)、制限された治療選択肢を有する患者集団において試験した。T細胞をMMに向け直すために、細胞成熟抗原(BCMA)、悪性骨髄腫細胞、形質細胞、およびいくつかの成熟B細胞のみによってほぼ均一に発現される腫瘍壊死因子スーパーファミリーの一員を標的にした。抗BCMA活性の初期の裏付けが、最近、CD28同時刺激ドメインで抗BCMACARをコードするガンマ-レトロウイルスベクターで形質導入されたT細胞を用いて証明されたが、有意なサイトカイン放出症候群が、高い病気の負担を有する患者において生じた(Ali et al.,Blood2016)。ヒトにおける治療上有効な用量の抗BCMA02CAR T細胞は、予測不可能であるため、用量漸増試験を実行した。
抗BCMA02CAR T細胞を、プロテアソーム阻害薬および免疫調節剤を含む少なくとも3つの事前レジメンを受けた、再発性および/または難治性BCMA陽性MMを有するか、または二重難治性である患者に投与した。簡潔に言うと、末梢血単核細胞を、白血球除去輸血を介して採取し、形質導入および増殖のために集中製造施設へ移転した。患者は、研究-5日目、-4日目、および-3日目にシクロホスファミド300mg/m2およびフルダラビン30mg/m2でリンパ枯渇し、その後、0日目に抗BCMA02CAR T細胞の単一注入を受けた。
9人の患者は、5.0×107のCAR+T細胞、15.0×107のCAR+T細胞、および45.0×107のCAR+T細胞の3つの用量コホートにおいて抗BCMA02CAR T細胞を注入された。細胞を採取し、すべての患者において製造および放出が成功した。9人の注入された対象の登録時の平均年齢は、58歳(43~68)であり、67%が男性であった。診断からの平均期間は、6年(1.3~8.6)であった。事前の治療ラインの平均数は、6(4~10)であり、100%の患者が少なくとも1つの事前の自家幹細胞移植を受け、67%が事前のダラツムマブまたはCD38マブを受け、89%が事前のレナリドミドを受け、78%が事前のポマリドミドを受け、100%が事前のボルテゾミブを受け、78%が事前のカルフィルゾミブを受けた。
抗BCMA02CAR T細胞は、2つのCRおよび6か月での進行中の臨床応答を含み、5.0×107のCAR+T細胞を上回る用量レベルで顕著な有効性を示した。他のCAR T細胞療法での結果とは対照的に、抗BCMA02CAR T細胞の有効性は、意外と軽度で対処可能なCRSを伴い、≧50%の骨髄障害を有する患者におけるものを含む。これらのデータは、再発性/難治性多発性骨髄腫に対する抗BCMA02CAR T細胞の治療有効性を支持する。
抗BCMA02CAR T細胞は、再発性/難治性多発性骨髄腫のヒト臨床試験において治療活性を示し続ける。
21人の患者を、5.0×107のCAR+T細胞(3人の患者)、15.0×107のCAR+T細胞(6人の患者)、45.0×107のCAR+T細胞(9人の患者)、および80.0×107のCAR+T細胞(3人の患者)の3つの用量コホートにおいて抗BCMA02CAR T細胞で注入した。細胞を採取し、すべての患者において製造および放出が成功した。9人の注入された対象の登録時の平均年齢は、58歳(37~74)であり、62%が男性であった。診断からの平均期間は、5年(1.0~16.0)であった。事前の治療ラインの平均数は、7(3~14)であり、100%の患者が少なくとも1つの事前の自家幹細胞移植を受け、100%が以前にレナリドミドおよびボルテゾミブで治療され、91%が以前にポマリドミドおよびカルフィルゾミブで治療され、71%が以前にダラツムマブで治療され、29%の患者がペンタ難治性(ボルテゾミブ、レナリドミド、カルフィルゾミブ、ポマリドミド、ダラツムマブ)であった。
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