JP7488534B2 - 新規ながん免疫療法抗体組成物 - Google Patents
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Description
本出願は、2018年8月20日出願の同時係属中の米国仮特許出願第62/720,015号(これは、その全体において本明細書に参考として援用される)の優先権およびその利益を主張する。
本発明は、ヒトPD-L1を結合する抗原結合ポリペプチド、その医薬組成物およびその使用に関する。本発明の局面はまた、このような抗原結合ポリペプチドまたは抗体を生成する発現系に関する。本発明の記載される抗原結合ポリペプチドまたは医薬組成物は、病的な状態(例えば、哺乳動物のがん、感染など)に関して処置を必要とする被験体を処置するために有用である。
免疫細胞は、それらの細胞表面上に膜結合および可溶性リガンドと相互作用する共刺激および阻害レセプターを有する。これらのレセプターは、免疫細胞活性化または阻害の閾値および継続期間を変化させることによって、免疫応答の有効性、継続期間、およびタイプを調節するように働く。これらはしばしば、まとめて、免疫チェックポイントといわれる。これらのチェックポイント分子のうちの多くは、分子のB7スーパーファミリーまたは腫瘍壊死因子(TNF)スーパーファミリーのいずれかのメンバーである。
CTLA-4抗体は、FDA承認を勝ち取る、免疫チェックポイント遮断に基づく免疫療法のクラスのうちの最初のものであった。他の遮断標的(例えば、PD1およびその関連分子)は、臨床状況において抗腫瘍免疫を増強するためにより多くのかつ異なる機会を提供する。
本発明は、PD-L1、好ましくは、ヒトPD-L1を結合する抗原結合ポリペプチド(または交換可能に「抗PD-L1ポリペプチド(複数可)」、「PD-L1結合ポリペプチド」)を提供する;上記ポリペプチドは、以下の特徴のうちの一方または両方を有する:(a)PD-L1に結合し、PD1と相互作用するその能力を阻害する;ならびに(b)ADCCおよび/またはCDCを誘発し得るアイソタイプまたは定常領域を有する。得られる抗体は、2つの相乗作用的経路--T細胞抑制解除および直接的細胞傷害性を通じて、腫瘍細胞を殺滅し得る。本発明のポリペプチドは、腫瘍を単独で、あるいは(a)他の免疫抑制経路を標的とする抗体;(b)化学療法もしくは放射線療法;(c)免疫抑制経路を遮断する他の機構、例えば、アプタマーもしくはRNAi;または(d)他の免疫治療剤、例えば、サイトカイン、標的治療剤などとの組み合わせにおいて処置するために使用され得る。
別段注記されなければ、技術用語は、従来の使用法に従って使用される。
ある特定の実施形態において、本発明の結合ポリペプチドは、翻訳後修飾をさらに含み得る。例示的な翻訳後タンパク質修飾としては、リン酸化、アセチル化、メチル化、ADP-リボシル化、ユビキチン化、グリコシル化、カルボニル化、SUMO化(sumoylation)、ビオチン化またはポリペプチド側鎖もしくは疎水性基の付加が挙げられる。結果として、その修飾された可溶性ポリペプチドは、非アミノ酸エレメント(例えば、脂質、ポリサッカリドもしくはモノサッカリド、およびホスフェート)を含み得る。グリコシル化の好ましい形態は、シアル化であり、これは、そのポリペプチドに1つまたはこれより多くのシアル酸部分を結合体化する。シアル酸部分は、タンパク質の起こり得る免疫原性をも低減すると同時に、溶解度および血清半減期を改善する。Rajuら Biochemistry. 2001 31; 40(30):8868-76を参照のこと。ポリペプチドの機能性に対するこのような非アミノ酸エレメントの効果は、PD-L1またはPD-1機能のおけるその拮抗的な役割、例えば、血管新生または腫瘍成長に対するその阻害効果に関して試験され得る。
本開示は、PD-L1生物学的活性の阻害に応答する状態を処置するかまたは前状態(pre-condition)を防止するための方法をさらに特徴とする。好ましい例は、細胞過剰増殖および感染の持続によって特徴づけられる状態である。投与のための技術および投与量は、具体的なポリペプチドのタイプおよび処置され具体的な状態に依存して変動する。規制当局は、治療剤として使用されるタンパク質試薬が、受容可能に低レベルの発熱物質とともに製剤化されることを要求することから、本発明の治療用製剤は、実質的に発熱物質がないことに関して他の製剤から区別され得るか、または適切な規制当局(例えば、米国FDA)によって決定されるような発熱物質の受容可能なレベル以下を少なくとも含み得る。
実施例1: 抗体コード: 4-1A2
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Claims (12)
- 重鎖可変ドメインおよび軽鎖可変ドメインを含む、ヒトPD-L1エピトープに結合する抗原結合ポリペプチドであって、ここで前記重鎖可変ドメインは配列番号18の配列を有し、前記軽鎖可変ドメインは配列番号20の配列を有する抗原結合ポリペプチド。
- 前記ポリペプチドは、完全ヒト抗体またはヒト化抗体である、請求項1に記載の抗原結合ポリペプチド。
- 前記抗体は、ヒト定常領域をさらに含み、ここで前記ヒト定常領域は、ADCCおよび/またはCDC活性を有する、請求項2に記載の抗原結合ポリペプチド。
- 請求項1に記載の抗原結合ポリペプチドをコードする核酸分子であって、ここで前記核酸分子は、DNA分子またはRNA分子である、核酸分子。
- 前記核酸分子は、重鎖可変ドメインおよび軽鎖可変ドメインをコードするDNA配列を含み、前記重鎖可変ドメインをコードするDNA配列は、配列番号17からなる配列を有し、前記軽鎖可変ドメインをコードするDNA配列は、配列番号19からなる配列を有する、請求項4に記載の核酸分子。
- 請求項1に記載の重鎖可変ドメインおよび軽鎖可変ドメインの対を含む、ヒトPD-L1エピトープに結合する抗体。
- 請求項1~3のいずれか一項に記載の抗原結合ポリペプチドまたは請求項6に記載の抗体、および薬学的に受容可能な賦形剤、キャリアまたは希釈剤を含む、医薬組成物。
- 状態に関して処置を必要とする被験体を治療的に処置するのに使用するための医薬組成物であって、前記医薬組成物は、治療上有効な量の請求項1~3のいずれか一項に記載の抗原結合ポリペプチドまたは請求項6に記載の抗体を包含する、医薬組成物。
- 状態に関して処置を必要とする被験体を治療的に処置するのに使用するための医薬組成物であって、治療上有効な量の請求項1~3のいずれか一項に記載の抗原結合ポリペプチドまたは請求項6に記載の抗体を包含する前記医薬組成物は、(a)他の免疫抑制経路を標的とする抗体;(b)化学療法もしくは放射線療法;または(c)他の免疫治療剤と組み合わせて前記被験体に投与される、医薬組成物。
- 前記状態は、卵巣がん、結腸がん、乳がん、肺がん、骨髄腫、神経芽細胞由来CNS腫瘍、単球性白血病、B細胞に由来する白血病、T細胞に由来する白血病、B細胞に由来するリンパ腫、T細胞に由来するリンパ腫、マスト細胞に由来する腫瘍、黒色腫、膀胱がん、胃がん、肝臓がん、尿路上皮癌、皮膚癌、腎がん、頭頸部がん、膵臓がん、およびこれらの組み合わせからなる群より選択される哺乳動物のがんである、請求項8または9に記載の医薬組成物。
- 前記哺乳動物のがんは、検出可能な量のPD-L1を発現する腫瘍細胞の少なくとも一部を有する、請求項10に記載の医薬組成物。
- 請求項1~3のいずれかに記載の抗原結合ポリペプチドを生成する哺乳動物発現系。
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EP3841126A1 (en) | 2021-06-30 |
KR20210046725A (ko) | 2021-04-28 |
CN112839963A (zh) | 2021-05-25 |
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AU2019324388A1 (en) | 2021-03-18 |
SG11202101757QA (en) | 2021-03-30 |
BR112021003182A2 (pt) | 2021-05-11 |
CN116063519A (zh) | 2023-05-05 |
EP3841126A4 (en) | 2022-08-10 |
WO2020038379A1 (en) | 2020-02-27 |
CN112839963B (zh) | 2023-02-10 |
CN116410320A (zh) | 2023-07-11 |
CA3110138A1 (en) | 2020-02-27 |
US20210332138A1 (en) | 2021-10-28 |
JP2021534750A (ja) | 2021-12-16 |
MX2021002077A (es) | 2021-05-27 |
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