JP7053037B2 - 治療薬 - Google Patents
治療薬 Download PDFInfo
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- JP7053037B2 JP7053037B2 JP2018503642A JP2018503642A JP7053037B2 JP 7053037 B2 JP7053037 B2 JP 7053037B2 JP 2018503642 A JP2018503642 A JP 2018503642A JP 2018503642 A JP2018503642 A JP 2018503642A JP 7053037 B2 JP7053037 B2 JP 7053037B2
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Description
(i)第二世代キメラ抗原受容体であって、
(a)シグナル伝達領域;
(b)共刺激シグナル伝達領域;
(c)膜貫通ドメイン;および
(d)標的抗原上の第1のエピトープと特異的に相互作用する結合エレメント
を含む第二世代キメラ抗原受容体と、
(ii)キメラ共刺激受容体であって、
(e)(b)の共刺激シグナル伝達領域と異なる共刺激シグナル伝達領域;
(f)膜貫通ドメイン;および
(g)標的抗原上の第2のエピトープと特異的に相互作用する結合エレメント
を含むキメラ共刺激受容体と
を発現する免疫応答細胞を提供する。
の220アミノ酸のタンパク質であり、膜貫通ドメインを太字で示す。
EQKLISEEDL(配列番号5)
のタグである。
RGDLX5X6L(配列番号7)、または
RGDLX5X6I(配列番号8)
を含み、LX5X6LまたはLX5X6Iは、αヘリックス構造内に含まれ、X5およびX6は、[α]-ヘリックスの中央に見られるために1.0より大きい配座優先性を有するヘリックス促進残基である(Creighton,1993 and Pace C.N.and Scholtz J.M.(1998),Biophysical Journal,Vol.75,pages 422-427から)。特に、そうした残基は、独立に、Glu、Ala、Leu、Met、Gln、Lys、Arg、Val、Ile、Trp、PheおよびAspからなる群から選択される。
YTASARGDLAHLTTTHARHL(配列番号9)
GFTTGRRGDLATIHGMNRPF(配列番号10)、もしくは
NAVPNLRGDLQVLAQKVART(配列番号11)
またはそれらの変異体が挙げられる。
ホジキンリンパ腫、未分化大細胞リンパ腫、およびたとえばトリプルネガティブ乳癌などの一部の固形腫瘍に過剰発現するCSF-1受容体(c-FMSによりコードされる)を標的とする一連のCARを調製した。これらを概略的に図1に示す。これらの一連のCARは、標的化部分として2つの天然リガンドCSF-1またはIL-34の何れかを有する第二世代および第三世代CARの両方を含んでいた。CSF-1およびIL-34の両方がCSF-1受容体に結合するが、IL-34の方がかなり高い親和性(CSF-1より34倍高い)で結合する。
in vivoでの作用の解析
上記の実施例1に使用した一連のCARについて、CSF-1受容体標的を低レベルで発現し、かつ疾患がリンパ節全体に散在する、高悪性度in vivo異種移植モデルを用いて抗腫瘍活性を試験した(図7)。腫瘍細胞にホタルルシフェラーゼタグを付加し、疾患負荷の非侵襲的モニタリングを可能にした。
・C4B群:20×106個のC4B T細胞 IV
・C34B群:20×106個のC34B T細胞 IV
・43428Bz:20×106個の43428Bz T細胞 IV
・34CB群:20×106個の34CB T細胞 IV
・UT(形質導入していない)群:20×106個の形質導入していないT細胞 IV
・NT(無処置)群:200μL PBS IV
の1つで処置した。
αvβ6依存性にT細胞活性化を誘導するpCARを操作するための標的化部分の選択
αvβ6インテグリンを単独または伸長(extended)ErbBファミリーと一緒に標的とする一連のCARを調製した。これらを図14に概略的に示す。この事例に使用した結合エレメントは、口蹄疫ウイルス(血清型01 BFS)由来のカプシドタンパク質VP1のGHループに由来するA20ペプチド(配列番号11)であった(米国特許第8,927,501号明細書)。これをCD124シグナルペプチドの下流に置き、CD28およびCD3ζ細胞内ドメインと融合して第二世代CAR、A20-28ζを形成した。同様のコンストラクトを含むが、重要なRGDLモチーフをAAAAで置き換えてスクランブルした標的化ペプチド(C20と命名される)を用いて対照(C20-28ζ)を調製した。第2の対照は、CD28切断細胞内ドメインと融合したA20(A20-Tr)を含んでいた。
機能的pCARを操作するための代替のTNF受容体ファミリーメンバーCD27の使用
A20-28z/T1E-41BB pCARを出発材料として使用して、41BBモジュールをTNF受容体ファミリーの代替メンバー、すなわちCD27またはCD40で置き換えた別のpCARを操作した。細胞内ドメインを切断した(tr)対照pCARを操作した。αvβ6を発現する(Bxpc3)または欠いている(Panc1)標的細胞を24ウェルプレートの1ウェルあたり5×104細胞の密度で蒔いた。24時間後、5×104個のpCAR T細胞を、外来性サイトカイン添加物を用いずに標的細胞または空ウェル(「刺激していない」)に加えた。さらに72時間後、T細胞をウェルから回収し、カウントした(図19A)。MTTアッセイを行って残存標的細胞の生存割合を判定し、T細胞を添加せずに蒔いてあった対照標的細胞と比較した(図19B)。各刺激サイクル後にT細胞が増殖した場合、上記の通りに新鮮な標的細胞上で再刺激した。pCAR T細胞の増殖(図19A)およびMTTアッセイ(図19B)は、前の場合と同様に72時間後に行った。pCAR T細胞の反復再刺激および標的細胞殺傷の評価は、このように72時間の各サイクル期間にわたりT細胞がもはや増殖しなくなるまで継続した。
Claims (25)
- 免疫応答細胞であって、
(i)第二世代キメラ抗原受容体であって、
(a)シグナル伝達領域;
(b)共刺激シグナル伝達領域;
(c)膜貫通ドメイン;および
(d)標的抗原上の第1のエピトープと特異的に相互作用する結合エレメント
を含む第二世代キメラ抗原受容体と、
(ii)キメラ共刺激受容体であって、
(e)(b)の共刺激シグナル伝達領域と異なる共刺激シグナル伝達領域;
(f)膜貫通ドメイン;および
(g)標的抗原上の第2のエピトープと特異的に相互作用する結合エレメント
を含むキメラ共刺激受容体と
を発現し、
(b)または(e)の共刺激シグナル伝達領域の一方がCD28であり、他方の共刺激シグナル伝達領域が4-1BB、CD27、またはOX40であり、
前記免疫応答細胞が、T細胞およびナチュラルキラー(NK)細胞から選択される
ことを特徴とする免疫応答細胞。 - 請求項1に記載の免疫応答細胞において、細胞傷害性T細胞またはヘルパーT細胞であることを特徴とする免疫応答細胞。
- 請求項1または2に記載の免疫応答細胞において、前記シグナル伝達領域(a)は、ヒトCD3[ゼータ]鎖の細胞内ドメインまたはその変異体を含むことを特徴とする免疫応答細胞。
- 請求項1乃至3の何れか1項に記載の免疫応答細胞において、(b)はCD28であることを特徴とする免疫応答細胞。
- 請求項4に記載の免疫応答細胞において、(e)は4-1BBまたはCD27であることを特徴とする免疫応答細胞。
- 請求項1乃至5の何れか1項に記載の免疫応答細胞において、(c)および(f)の前記膜貫通ドメインは、CD8α膜貫通ドメインおよびCD28膜貫通ドメインから選択されることを特徴とする免疫応答細胞。
- 請求項1乃至6の何れか1項に記載の免疫応答細胞において、前記第1および第2のエピトープは、同一の受容体または抗原と関連付けられていることを特徴とする免疫応答細胞。
- 請求項1乃至7の何れか1項に記載の免疫応答細胞において、キメラサイトカイン受容体を共発現することを特徴とする免疫応答細胞。
- 請求項8に記載の免疫応答細胞において、前記キメラサイトカイン受容体は4αβであることを特徴とする免疫応答細胞。
- 請求項1乃至9の何れか1項に記載の免疫応答細胞において、結合エレメント(d)または結合エレメント(g)の少なくとも1つは、ErbB2量体のリガンド、コロニー刺激因子-1の受容体(CSF-1R)またはαvβ6インテグリン特異的結合剤であることを特徴とする免疫応答細胞。
- 請求項1乃至10の何れか1項に記載の免疫応答細胞において、結合エレメント(d)はCSF-1を含み、結合エレメント(g)はIL-34を含むことを特徴とする免疫応答細胞。
- 請求項1乃至10の何れか1項に記載の免疫応答細胞において、結合エレメント(d)は、αvβ6インテグリン特異的結合剤であって、配列モチーフ
RGDLX5X6L(配列番号7)、または
RGDLX5X6I(配列番号8)
を含むペプチドであり、LX5X6LまたはLX5X6Iは、αヘリックス構造内に含まれ、X5およびX6はヘリックス促進残基である、αvβ6インテグリン特異的結合剤であり、結合エレメント(g)はTIEペプチドであることを特徴とする免疫応答細胞。 - 請求項1乃至12の何れか1項に記載の免疫応答細胞において、結合エレメント(d)の結合親和性は結合エレメント(g)の結合親和性より低いことを特徴とする免疫応答細胞。
- 請求項1乃至13の何れか1項に記載の免疫応答細胞を調製するための方法であって、請求項1に定義された構造(i)のCARをコードする第1の核酸および請求項1に定義された構造(ii)のCCRをコードする第2の核酸を細胞に形質導入するステップを備えることを特徴とする方法。
- 請求項14に記載の方法において、前記免疫応答細胞はキメラサイトカイン受容体を含み、増殖ステップは、サイトカインの存在下で行われることを特徴とする方法。
- 組み合わせであって、請求項1に定義された(i)のCARをコードする第1の核酸と、請求項1に定義された(ii)のCCRをコードする第2の核酸との組み合わせであることを特徴とする組み合わせ。
- ベクターまたはベクターの組み合わせであって、請求項16に記載の組み合わせを含むことを特徴とするベクターまたはベクターの組み合わせ。
- キットであって、請求項16または17に記載の組み合わせを含むことを特徴とするキット。
- 標的細胞集団に対するT細胞性免疫応答の刺激を、それを必要とする患者において行うための、請求項1乃至13の何れか1項に記載の免疫応答細胞であって、前記結合エレメント(d)および(g)は標的細胞に特異的であることを特徴とする免疫応答細胞。
- 標的細胞集団に対するT細胞性免疫応答を刺激するための医薬の調製における、請求項1乃至13の何れか1項に記載の免疫応答細胞の使用であって、前記結合エレメント(d)および(g)は前記標的細胞に特異的であることを特徴とする使用。
- 必要とする患者に療法を提供するための医薬の調製における、請求項1乃至13の何れか1項に記載の免疫応答細胞の使用。
- 癌の治療のための医薬の調製における、請求項1乃至13の何れか1項に記載の免疫応答細胞の使用。
- 必要とする患者の療法に用いるための、請求項1乃至13の何れか1項に記載の免疫応答細胞。
- 必要とする患者の癌の治療に用いるための、請求項1乃至13の何れか1項に記載の免疫応答細胞。
- 請求項24に記載の免疫応答細胞において、前記癌は、前立腺癌、乳癌、神経芽細胞腫、メラノーマ、小細胞または非小細胞性肺癌、肉腫、および脳腫瘍からなる群から選択されることを特徴とする免疫応答細胞。
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RU2747733C1 (ru) | 2021-05-13 |
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HK1256383A1 (zh) | 2019-09-20 |
CN107735407B (zh) | 2022-08-16 |
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CN107735407A (zh) | 2018-02-23 |
US20200331981A1 (en) | 2020-10-22 |
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US10899818B2 (en) | 2021-01-26 |
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JP2021168675A (ja) | 2021-10-28 |
ES2883633T3 (es) | 2021-12-09 |
GB201513540D0 (en) | 2015-09-16 |
US20200277353A1 (en) | 2020-09-03 |
US20210095000A1 (en) | 2021-04-01 |
KR102411571B1 (ko) | 2022-06-21 |
AU2016303355B2 (en) | 2020-08-06 |
US20190002521A1 (en) | 2019-01-03 |
EP3328880B1 (en) | 2021-07-07 |
US20240076348A1 (en) | 2024-03-07 |
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US11802143B2 (en) | 2023-10-31 |
US10865231B2 (en) | 2020-12-15 |
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