JP7420751B2 - I型インターフェロン及びcd40-配位子を用いる腫瘍溶解性ウイルス又は抗原提示細胞媒介性癌治療 - Google Patents
I型インターフェロン及びcd40-配位子を用いる腫瘍溶解性ウイルス又は抗原提示細胞媒介性癌治療 Download PDFInfo
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Description
本出願は、2018年6月19日出願の米国仮出願第62/687,076号の優先権を主張するものであり、内容を参照することにより組み込まれる。
本発明は、NCI Skin Specialized Programs of Research Excellenceによって授与されたグラント番号5P50CA168536-03の下で政府の支援を受けてなされた。米国政府は、本発明においてある種の権利を有する。
好ましい実施形態において、悪性腫瘍に罹患している対象は、チェックポイント阻害剤を用いた治療に不応である。
配列番号7
MIETYSQPSPRSVATGLPASMKIFMYLLTVFLITQMIGSVLFAVYLHRRLDKVEEEVNLHEDFVFIKKLKRCNKGEGSLSLLNCEEMRRQFEDLVKDITLNKEEKKENSFEMQRGDEDPQIAAHVVSEANSNAASVLQWAKKGYYTMKSNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREPSSQRPFIVGLWLKPSSGSERILLKAANTHSSSQLCEQQSVHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL
配列番号8:
MIETYNQTSPRSAATGLPISMKIFMYLLTVFLITQMIGSALFAVYLHRRLDKIEDERNLHEDFVFMKTIQRCNTGERSLSLLNCEEIKSQFEGFVKDIMLNKEETKKDEDPQIAAHVVSEANSNAASVLQWAKKGYYTMKSNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREPSSQRPFIVGLWLKPSSGSERILLKAANTHSSSQLCEQQSVHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL
配列番号9
MIETYSQPSPRSVATGLPASMKIFMYLLTVFLITQMIGSVLFAVYLHRRLDKVEEEVNLHEDFVFIKKLKRCNKGEGSLSLLNCEEMRRQFEDLVKDITLNKEEKKENSFEMQRGDEDPQIAAHVVSEANSNAASVLQWAKKGYYTMKSNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIVGLWLKPSSGSERILLKAANTHSSSQLCEQQSVHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL
配列番号10
MIETYNQTSPRSAATGLPISMKIFMYLLTVFLITQMIGSALFAVYLHRRLDKIEDERNLHEDFVFMKTIQRCNTGERSLSLLNCEEIKSQFEGFVKDIMLNKEETKKDEDPQIAAHVVSEANSNAASVLQWAKKGYYTMKSNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIVGLWLKPSSGSERILLKAANTHSSSQLCEQQSVHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL
配列番号11
MIETYSQPSPRSVATGLPASMKIFMYLLTVFLITQMIGSVLFAVYLHRRLDKVEEEVNLHEDFVFIKKLKRCNKGEGSLSLLNCEEMRRQFEDLVKDITLNKEEKKENSFEMQRGDEDPQIAAHVVSEANSNAASVLQWAKKGYYTMKSNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIVGLWLKPSSGSERILLKAANTHSSSQLCEQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL
配列番号12
MIETYNQTSPRSAATGLPISMKIFMYLLTVFLITQMIGSALFAVYLHRRLDKIEDERNLHEDFVFMKTIQRCNTGERSLSLLNCEEIKSQFEGFVKDIMLNKEETKKDEDPQIAAHVVSEANSNAASVLQWAKKGYYTMKSNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIVGLWLKPSSGSERILLKAANTHSSSQLCEQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL
配列番号13
MIETYSQPSPRSVATGLPASMKIFMYLLTVFLITQMIGSVLFAVYLHRRLDKVEEEVNLHEDFVFIKKLKRCNKGEGSLSLLNCEEMRRQFEDLVKDITLNKEEKKENSFEMQRGDEDPQIAAHVVSEANSNAASVLQWAKKGYYTMKSNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIVGLWLKPSSGSERILLKAANTHSSAKPCGQQSIHLGGVFELQPGASCFVNVTDPSQVSHGTGFTSFGLLKL
配列番号14
MIETYNQTSPRSAATGLPISMKIFMYLLTVFLITQMIGSALFAVYLHRRLDKIEDERNLHEDFVFMKTIQRCNTGERSLSLLNCEEIKSQFEGFVKDIMLNKEETKKDEDPQIAAHVVSEANSNAASVLQWAKKGYYTMKSNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIVGLWLKPSSGSERILLKAANTHSSAKPCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL
配列番号15
MIETYSQPSPRSVATGLPASMKIFMYLLTVFLITQMIGSVLFAVYLHRRLDKVEEEVNLHEDFVFIKKLKRCNKGEGSLSLLNCEEMRRQFEDLVKDITLNKEEKKENSFEMQRGDEDPQIAAHVVSEANSNAASVLQWAKKGYYTMKSNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREPSSQRPFIVGLWLKPSSGSERILLKAANTHSSSQLCEQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL
配列番号16
MIETYNQTSPRSAATGLPISMKIFMYLLTVFLITQMIGSALFAVYLHRRLDKIEDERNLHEDFVFMKTIQRCNTGERSLSLLNCEEIKSQFEGFVKDIMLNKEETKKDEDPQIAAHVVSEANSNAASVLQWAKKGYYTMKSNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREPSSQRPFIVGLWLKPSSGSERILLKAANTHSSSQLCEQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL
配列番号17
MIETYSQPSPRSVATGLPASMKIFMYLLTVFLITQMIGSVLFAVYLHRRLDKVEEEVNLHEDFVFIKKLKRCNKGEGSLSLLNCEEMRRQFEDLVKDITLNKEEKKENSFEMQRGDEDPQIAAHVVSEANSNAASVLQWAKKGYYTMKSNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREPSSQRPFIVGLWLKPSSGSERILLKAANTHSSAKPCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL
配列番号18
MIETYNQTSPRSAATGLPISMKIFMYLLTVFLITQMIGSALFAVYLHRRLDKIEDERNLHEDFVFMKTIQRCNTGERSLSLLNCEEIKSQFEGFVKDIMLNKEETKKDEDPQIAAHVVSEANSNAASVLQWAKKGYYTMKSNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREPSSQRPFIVGLWLKPSSGSERILLKAANTHSSAKPCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL
IFNβとCD40-Lの組み合わせのようなI型IFNとCD40-Lの組み合わせを送達するために、又はIFNβとCD40-Lの組み合わせのようなI型IFNとCD40-Lの組み合わせをコードする核酸配列を送達して、本発明のAPC、特定のDC、又は腫瘍溶解性ウイルスを生成するために、種々の方法が使用される。
APCは、効果的な免疫応答を誘発するのに重要である。APCは、抗原特異的受容体をもつT細胞に抗原を提示するだけでなく、T細胞の活性化に必要なシグナルを提供する。このようなシグナルは完全には定義されていないが、種々の細胞表面分子及びサイトカイン又は成長因子を含むことが知られている。ナイーブ又は無感作T細胞の活性化に必要な因子は、以前の感作メモリーT細胞の再活性化に必要な因子とは異なる可能性がある。単球及びB細胞は、コンピテントAPCであることが示されているが、それらの抗原提示能は、以前の感作T細胞の再活性化に限定されるようである。従って、これらは、機能的にナイーブ又は無感作T細胞集団を直接活性化することはできない。一方、DCは、ナイーブと以前に無感作のT細胞の両方を活性化することができる。
「含む(comprising)」、「からなる(consisting of)」及び「実質的にからなる(consisting of)」という用語は、それらの標準的な意味に従って定義される。これらの用語は各用語に関連する特定の意味をつけるために、本出願を通じて互いに代替されてもよい。
樹状細胞生成及びペプチドプールローディング。DCは、無血清XVIVO-15培地(ロンザ、アレンダレ、ニュージャージー州)中に7~11×106PBMC/mLを懸濁し、続いて25cm2細胞培養フラスコ(コーニング、コーニング、ニューヨーク州)中で3時間培養することによって生成することができる。次いで、細胞をPBS中で2回洗浄して、非接着細胞を除去することができる。接着細胞は、GM-CSF及びIL-4(R&Dシステムズ、ミネアポリス、ミネソタ州)のそれぞれ1000単位/mlを添加した無血清X-VIVO培地中で6日間培養することができる。次いで、DCを収集し、洗浄し、そしてカウントする。1μg/ペプチド/mlを補充した100μlのXVIVO-15培地中で37℃で1時間インキュベートすることによって、DCに示されたペプチドプールをロードすることができる。
実施形態1 外因性I型インターフェロン及び外因性CD40-Lの組み合わせ、又は外因性I型IFNと外因性CD40-Lの組み合わせをコードする1つ以上の異種核酸配列を含む、抗原提示細胞(APC)。
実施形態2 実施形態1に記載のAPCであって、
a)前記I型IFNは、ヒトIFNα(配列番号1)に対して少なくとも80%の配列同一性を有するIFNα、ヒトIFNβ(配列番号2)に対して少なくとも80%の配列同一性を有するIFNβ、ヒトIFNε(配列番号3)に対して少なくとも80%の配列同一性を有するIFNε、ヒトIFNκ(配列番号4)に対して少なくとも80%の配列同一性を有するIFNκ、又はヒトIFNω(配列番号5)に対して少なくとも80%の配列同一性を有するIFNωであり、及び/又は
b)前記CD40-Lは、ヒトCD40-L(配列番号6)に対して少なくとも80%の配列同一性、配列番号7~18から選択される配列を有するキメラCD40-Lに対して少なくとも80%の配列同一性、又は配列番号12の配列を有するキメラCD40-Lに対して少なくとも80%の配列同一性を有し、及び/又は
c)前記I型IFNは、ヒトIFNβ(配列番号2)に対して少なくとも80の配列同一性を有するIFNβであり、かつ、前記CD40-Lは、配列番号12の配列を有するキメラCD40-Lに対して少なくとも80%の配列同一性を有する、APC。
実施形態3 実施形態1又は2に記載のAPCであって、
I型IFNとCD40-Lの組合せをコードする1つ以上の異種核酸配列は、1つ以上のウイルス構築物中にある、APC。
実施形態4 実施形態3に記載のAPCであって、1つ以上のウイルス構築物の各々が、独立して、アデノウイルス構築物、アデノ随伴ウイルス構築物(AAV)、ポックスウイルス構築物、レンチウイルス構築物、アルファウイルス構築物、ヘルペスウイルス構築物、レトロウイルス構築物、ワクシニアウイルス構築物、水疱性口内炎ウイルス構築物、又は単純ヘルペスウイルス構築物である、APC。
実施形態5 前記APCは、ヒトAPCである、前述の実施形態のいずれか1つに記載のAPC。
実施形態6 前記APCがDCである、前述の実施形態のいずれか1つに記載のAPC。
実施形態7 前述の実施形態のいずれか1つに記載のAPCと、薬学的に許容される担体とを含む組成物。
実施形態8 アジュバントをさらに含む、実施形態7に記載の組成物。
実施形態9 悪性腫瘍を処置する方法であって、該処置を必要とする対象に、前述の実施形態のいずれか1つに記載の有効量のAPCを投与することを含む、悪性腫瘍を処置する方法。
実施形態10 前記APCは、自家細胞である実施形態9に記載の方法。
実施形態11 前記方法は、1つ以上の追加の抗癌剤を対象に投与することをさらに含む、実施形態9又は10のいずれか1つに記載の方法。
実施形態12 前記方法は、化学療法薬(例えば、メルファラン)、免疫調節薬、アジュバント、貧血薬(例えば、エリスロポエチン)、放射線療法、幹細胞移植、キメラ抗原受容体(CAR)-発現T細胞(CAR T細胞)、又は前述のもののうちの2つ以上の組み合わせを投与することをさらに含む、実施形態9~11のいずれか1つに記載の方法。
実施形態13 前記APCを投与する前に放射線療法を処方することを含む、実施形態9~12のいずれか1つに記載の方法。
実施形態14 前記対象は、ヒトである、実施形態9~13のいずれか1つに記載の方法。
実施形態15 前記APCは、皮内注射、腫瘍内注射、又は腫瘍内に流出するリンパ節への注射によって投与される、実施形態9~14のいずれか1つに記載の方法。
実施形態16 前記皮内注射は、前記対象の腋窩及び/又は鼠径リンパ節流域に流れ出る解剖学的部位にある、実施形態15に記載の方法。
実施形態17 前記APCは、数日間にわたって複数回投与される、実施形態9~16のいずれか1つに記載の方法。
実施形態18 前記方法は、前記対象に対して造血細胞移植(例えば、骨髄、末梢血、又は臍帯血からの造血幹細胞又は前駆細胞)を実施することをさらに含む、実施形態9~17のいずれか1つに記載の方法。
実施形態19 前記造血細胞移植は、自家である、実施形態18記載の方法。
実施形態20 前記APCは、前記造血細胞移植の前後に投与される、実施形態18又は19に記載の方法。
実施形態21 前記対象上で幹細胞動員(例えば、G-CSFを使用)を行い、自己造血細胞移植の前に前記対象から造血細胞を収集することをさらに含む、実施形態18~20のいずれか1つに記載の方法。
実施形態22 前記APCを投与する前に、前記対象に投与される前記APCの産生のために前記対象から前記APCを収集することをさらに含む、実施形態9~21のいずれか1つに記載の方法。
実施形態23 前記APCは、前記投与の前に凍結保存される、実施形態22に記載の方法。
実施形態24 前記APCの投与前、投与中、又は投与後に、化学療法剤(例えば、メルファラン)を投与することをさらに含む、実施形態9~23のいずれか1つに記載の方法。
実施形態25 前記造血細胞移植中に化学療法剤(例えば、メルファラン)を投与することをさらに含む、実施形態24に記載の方法。
実施形態26 チェックポイント阻害剤を前記対象に投与することをさらに含む、実施形態9~24のいずれかに記載の方法。
実施形態27 前記チェックポイント阻害剤は、細胞毒性T-白血球抗原4(CTLA4、CD152としても知られる)、プログラム細胞死タンパク質1(PD-1、CD279としても知られる)又はプログラム細胞死1配位子1(PD-L1、CD274としても知られる)の阻害剤である、実施形態26記載の方法。
実施形態28 CTLA4の前記阻害剤は、CTLA4に結合する抗体であり、PD-1の前記阻害剤は、PD-1に結合する抗体であり、PD-L1の前記阻害剤は、PD-L1に結合する抗体である、実施形態27に記載の方法。
実施形態29 I型インターフェロンとCD40Lの組み合わせ、又はI型IFNとCD40-Lの組み合わせをコードする1つ以上の核酸配列を含む腫瘍溶解性ウイルス。
実施形態30 実施形態29に記載の腫瘍溶解性ウイルスであって、
a)前記I型IFNは、ヒトIFNα(配列番号1)に対して少なくとも80%の配列同一性を有するIFNα、ヒトIFNβ(配列番号2)に対して少なくとも80%の配列同一性を有するIFNβ、ヒトIFNε(配列番号3)に対して少なくとも80%の配列同一性を有するIFNε、ヒトIFNκ(配列番号4)に対して少なくとも80%の配列同一性を有するIFNκ、又はヒトIFNω(配列番号5)に対して少なくとも80%の配列同一性を有するIFNω、及び/又は
b)前記CD40-Lは、ヒトCD40-L(配列番号6)に対して少なくとも80%の配列同一性、又は配列番号7~18から選択される配列を有するキメラCD40-Lに対して少なくとも80%の配列同一性を有し、及び/又は
c)前記I型IFNは、ヒトIFNβ(配列番号2)に対して少なくとも80%の配列同一性を有するIFNβであり、前記CD40-Lは、配列番号12の配列を有するキメラCD40-Lに対して少なくとも80%の配列同一性を有する、腫瘍溶解性ウイルス。
実施形態31 前記腫瘍溶解性ウイルスは、アデノウイルス、レオウイルス、ヘルペスウイルス、ピコルナウイルス(例えば、コクサッキーウイルス、ポリオウイルス、及びセネカバレーウイルス)、パラミクソウイルス(例えば、麻疹ウイルス及びニューカッスル病ウイルス)、パルボウイルス、ラブドウイルス(例えば、水疱性口内炎ウイルス)、ワクシニアウイルス、ポックスウイルス、シンドビスウイルス、粘液腫ウイルス、マラバウイルス、インフルエンザウイルス、ムンプスウイルス、アレナウイルス、ワクシニアウイルス、又はE1Aデルタ-24欠失、E1b-55K欠失、及びE3領域欠失を含む組換えアデノウイルスである、実施形態29~30のいずれかに記載の腫瘍溶解性ウイルス。
実施形態32 実施形態29~31のいずれか1つに記載の腫瘍溶解性ウイルスと、薬学的に許容される担体とを含む組成物。
実施形態33 アジュバントをさらに含む、実施形態32に記載の組成物。
実施形態34 悪性腫瘍を処置する方法であって、該処置を必要とする対象に、実施形態29~31のいずれか1つの腫瘍溶解性ウイルス又は実施形態31又は32の組成物の有効量を投与することを含む、悪性腫瘍を処置する方法。
実施形態35 前記方法は、1つ以上の追加の抗癌剤を前記対象に投与することをさらに含む、実施形態34に記載の方法。
実施形態36 前記方法は、化学療法薬(例えば、メルファラン)、免疫調節薬、アジュバント、貧血薬(例えば、エリスロポエチン)、放射線療法、幹細胞移植、キメラ抗原受容体(CAR)-発現T細胞(CAR T細胞)、又は前述のものの2つ以上の組み合わせを投与することをさらに含む、実施形態35に記載の方法。
実施形態37 前記対象は、ヒトである、実施形態34~36のいずれか1つに記載の方法。
実施形態38 前記腫瘍溶解性ウイルスは、数日間にわたって複数回投与される、実施形態34~37のいずれか1つに記載の方法。
実施形態39 前記腫瘍溶解性ウイルスは、皮内注射、腫瘍内注射、静脈内注射、又は腫瘍内に流出するリンパ節への注射によって投与される、実施形態34~38のいずれか1つに記載の方法。
実施形態40 前記皮内注射は、前記対象の腋窩及び/又は鼠径リンパ節流域に流れ出る解剖学的部位にある、実施形態39に記載の方法。
実施形態41 前記方法は、前記対象に対して造血細胞移植(例えば、骨髄、末梢血、又は臍帯血からの造血幹細胞又は前駆細胞)を実施することをさらに含む、実施形態34~40のいずれか1つに記載の方法。
実施形態42 前記造血細胞移植は、自家である、実施形態41記載の方法。
実施形態43 前記腫瘍溶解性ウイルスは、前記造血細胞移植の前後に投与される、実施形態41又は42に記載の方法。
実施形態44 前記対象上で幹細胞動員(例えば、G-CSFを使用)を行い、自己造血細胞移植の前に前記対象から前記造血細胞を収集することをさらに含む、実施形態34~43のいずれか1つに記載の方法。
実施形態45 前記腫瘍溶解性ウイルスを投与する前、投与中、又は投与後に化学療法剤(例えば、メルファラン)を投与することをさらに含む、実施形態34~44のいずれか1つに記載の方法。
実施形態46 前記造血細胞移植中に化学療法剤(例えば、メルファラン)を投与することをさらに含む、実施形態43~45のいずれかに記載の方法。
実施形態47 チェックポイント阻害剤を前記対象に投与することをさらに含む、実施形態34~46のいずれかに記載の方法。
実施形態48 前記チェックポイント阻害剤は、細胞毒性T-白血球抗原4(CTLA4、CD152としても知られる)、プログラム細胞死タンパク質1(PD-1、CD279としても知られる)又はプログラム細胞死1配位子1(PD-L1、CD274としても知られる)の阻害剤である、実施形態47記載の方法。
実施形態49 CTLA4の前記阻害剤は、CTLA4に結合する抗体であり、PD-1の前記阻害剤は、PD-1に結合する抗体であり、PD-L1の前記阻害剤は、PD-L1に結合する抗体である、実施形態48に記載の方法。
CMVプロモーター、MEM40ヌクレオチド配列、及びポリアデニル化配列を含むMEM40の発現カセットにより、腫瘍溶解性アデノウイルス5型を構築した。発現カセットを、24ヌクレオチド欠失を含むアデノウイルスE1A遺伝子領域の上流に挿入した。さらに、SV40プロモーター、IFNβヌクレオチド配列、及びポリアデニル化配列を含むIFNβの第2の発現カセットを、アデノウイルスE3領域が欠失されたアデノウイルスゲノム位置に挿入した。アデノウイルスゲノムのE1b 55k領域も欠失している。図2は、CD40-L及びIFNβをコードする二重発現カセットを有する例示された腫瘍溶解性アデノウイルスの概略構成を示す。
腫瘍溶解性アデノウイルス5型を、CMVプロモーター、内部リボソーム侵入部位により分離されたMEM40及びIFNβヌクレオチド配列、ならびにポリアデニル化配列を含むMEM40及びIFNβの発現カセットで構築した。発現カセットを、24ヌクレオチド欠失を含むアデノウイルスE1A遺伝子領域の上流に挿入した。アデノウイルスは、E3及びE1b 55k領域欠失を含む。図3は、内部リボソーム侵入部位(IRES)により分離されたCD40-L及びIFNβをコードする単一の発現カセットを有する例示された腫瘍溶解性ウイルスの概略構成を示す。
攻撃性B16皮下メラノーマを有するマウスの腫瘍増殖に対するIFNβ及びMEM40発現の個別及び複合効果を試験した。IFNβを発現する樹状細胞(IFNβを発現するレンチウイルスにより形質導入された106細胞)及びMEM40を発現する複製欠損アデノウイルス(Ad-MEM40、1010ウイルス粒子)を、図4Aに示すように腫瘍に注射した。重要なのは、いずれかの薬剤単独と比較して、組み合わせた処置は、腫瘍増殖を大幅に減少させたことである(図4A)。図4Bに示すように、両剤による処置の後、攻撃的なB16メラノーマ腫瘍細胞を移植したマウスは、実験終了時に全て生存していた。対照的に、Ad-MEM40での処置後、B16メラノーマ腫瘍細胞を移植したマウスのいずれも、実験終了時には生存していなかった。そしてIFNβのみを発現するDCでの処置後、B16メラノーマ腫瘍細胞を移植したマウスで、実験終了時に生存していたのは僅か17%であった。
配列番号1は、ヒト野生型インターフェロンα(UniProtKB参照番号P05014)のアミノ酸配列である。
MALSFSLLMAVLVLSYKSICSLGCDLPQTHSLGNRRALILLAQMGRISHFSCLKDRHDFGFPEEEFDGHQFQKAQAISVLHEMIQQTFNLFSTEDSSAAWEQSLLEKFSTELYQQLNDLEACVIQEVGVEETPLMNEDSILAVRKYFQRITLYLTEKKYS PCAWEVVRAE IMRSLSFSTN LQKRLRRKD
配列番号2は、ヒト野生型インターフェロン-β(UniProtKB参照番号P01574)のアミノ酸配列である。
MTNKCLLQIALLLCFSTTALSMSYNLLGFLQRSSNFQCQKLLWQLNGRLEYCLKDRMNFDIPEEIKQLQQFQKEDAALTIYEMLQNIFAIFRQDSSSTGWNETIVENLLANVYHQINHLKTVLEEKLEKEDFTRGKLMSSLHLKRYYGRILHYLKAKEYSHCAWTIVRVEILRNFYFINRLTGYLRN
配列番号3は、ヒト野生型インターフェロン-ε(UniProtKB参照番号Q86WN2)のアミノ酸配列である。
MIIKHFFGTVLVLLASTTIFSLDLKLIIFQQRQVNQESLKLLNKLQTLSIQQCLPHRKNFLLPQKSLSPQQYQKGHTLAILHEMLQQIFSLFRANISLDGWEENHTEKFLIQLHQQLEYLEALMGLEAEKLSGTLGSDNLRLQVKMYFRRIHDYLENQDYSTCAWAIVQVEISRCLFFVFSLTEKLSKQGRPLNDMKQELTTEFRSPR
配列番号4は、ヒト野生型インターフェロン-κ(UniProtKB参照番号Q9P0W0)のアミノ酸配列である。
MSTKPDMIQKCLWLEILMGIFIAGTLSLDCNLLNVHLRRVTWQNLRHLSSMSNSFPVECLRENIAFELPQEFLQYTQPMKRDIKKAFYEMSLQAFNIFSQHTFKYWKERH LKQIQIGLDQQAEYLNQCLEEDKNENEDMKEMKENEMKPSEARVPQLSSLELRRYFHRIDNFLKEKKYSDCAWEIVRVEIRRCLYYFYKFTALFRRK
配列番号5は、ヒト野生型インターフェロンω(UniProtKB参照番号P05000)のアミノ酸配列である。
MALLFPLLAALVMTSYSPVGSLGCDLPQNHGLLSRNTLVLLHQMRRISPFLCLKDRRDFRFPQEMVKGSQLQKAHVMSVLHEMLQQIFSLFHTERSSAAWNMTLLDQLHTGLHQQLQHLETCLLQVVGEGESAGAISSPALTLRRYFQGIRVYLKEKKYSDCAWEVVRMEIMKSLFLSTNMQERLRSKDRDLGSS
配列番号6は、ヒトCD40-L(UniProtKB参照番号P29965)のアミノ酸配列である。
MIETYNQTSPRSAATGLPISMKIFMYLLTVFLITQMIGSALFAVYLHRRLDKIEDERNLHEDFVFMKTIQRCNTGERSLSLLNCEEIKSQFEGFVKDIMLNKEETKKENSFEMQKGDQNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL
配列番号7~18は、キメラCD40-Lアミノ酸配列の例である。
配列番号19~23は、キメラヒト/マウスCD40-Lをコードする核酸配列である。
配列番号24は、キメラヒト/マウスCD40-L MEM40をコードする核酸配列である。
配列番号25~30は、キメラヒト/マウスCD40-Lをコードする核酸配列である。
Claims (45)
- 外因性I型インターフェロン及び外因性CD40-Lの組み合わせ、又は外因性I型IFNと外因性CD40-Lの組み合わせをコードする1つ以上の異種核酸配列を含み、
(a)前記I型IFNは、ヒトIFNβ(配列番号2)に対して少なくとも90%の配列同一性を有するヒトIFNβであり、
(b)前記CD40-Lは、配列番号7~18から選択される配列に対して少なくとも90%の配列同一性を有するキメラCD40-Lである、抗原提示細胞(APC)。 - 請求項1に記載のAPCであって、
前記I型IFNとCD40-Lの組合せをコードする前記1つ以上の異種核酸配列は、1つ以上のウイルス構築物中にある、APC。 - 請求項2に記載のAPCであって、前記1つ以上のウイルス構築物の各々が、独立して、アデノウイルス構築物、アデノ随伴ウイルス構築物(AAV)、ポックスウイルス構築物、レンチウイルス構築物、アルファウイルス構築物、ヘルペスウイルス構築物、レトロウイルス構築物、ワクシニアウイルス構築物、水疱性口内炎ウイルス構築物、又は単純ヘルペスウイルス構築物である、APC。
- 前記APCは、ヒトAPCである、請求項1~3のいずれか一項に記載のAPC。
- 前記APCがDCである、請求項1~4のいずれか一項に記載のAPC。
- 請求項1~5のいずれか1項に記載のAPCと、薬学的に許容される担体とを含む組成物。
- アジュバントをさらに含む、請求項6に記載の組成物。
- 悪性腫瘍を処置する方法であって、
該処置を必要とするヒト以外の対象に、請求項1~7のいずれか一項に記載の有効量のAPCを投与することを含む、悪性腫瘍を処置する方法。 - APCは、自家細胞である請求項8に記載の方法。
- 前記方法は、1つ以上の追加の抗癌剤を前記ヒト以外の対象に投与することをさらに含む、請求項8又は9のいずれか一項に記載の方法。
- 前記方法は、化学療法薬、免疫調節薬、アジュバント、貧血薬、放射線療法、幹細胞移植、キメラ抗原受容体(CAR)-発現T細胞(CAR T細胞)、又は前述のもののうちの2つ以上の組み合わせを処方することをさらに含む、請求項8~10のいずれか一項に記載の方法。
- 前記APCを投与する前に放射線療法を処方することを含む、請求項8~11のいずれか一項に記載の方法。
- 前記APCは、皮内注射、腫瘍内注射、又は腫瘍内に流出するリンパ節への注射によって投与される、請求項8~12のいずれか一項に記載の方法。
- 前記皮内注射は、前記ヒト以外の対象の腋窩リンパ節流域及び/又は鼠径リンパ節流域に流れ出る解剖学的部位にある、請求項13に記載の方法。
- 前記APCは、数日間にわたって複数回投与される、請求項8~14のいずれか一項に記載の方法。
- 前記方法は、前記ヒト以外の対象に対して造血細胞移植(造血幹細胞移植又は前駆細胞移植)を実施することをさらに含む、請求項8~15のいずれか一項に記載の方法。
- 前記造血細胞移植は、自家である、請求項16記載の方法。
- 前記APCは、前記造血細胞移植の前後に投与される、請求項16又は17に記載の方法。
- 前記ヒト以外の対象上で幹細胞動員を行い、自己造血細胞移植の前に前記ヒト以外の対象から造血細胞を収集することをさらに含む、請求項16~18のいずれか一項に記載の方法。
- 前記APCを投与する前に、前記ヒト以外の対象に投与される前記APCの産生のために前記対象から前記APCを収集することをさらに含む、請求項8~19のいずれか一項に記載の方法。
- 前記APCは、前記投与の前に凍結保存される、請求項20に記載の方法。
- 前記APCの投与前、投与中、又は投与後に、化学療法剤を投与することをさらに含む、請求項8~21のいずれか一項に記載の方法。
- 前記造血細胞移植中に化学療法剤を投与することをさらに含む、請求項22に記載の方法。
- チェックポイント阻害剤を前記ヒト以外の対象に投与することをさらに含む、請求項8~22のいずれか一項に記載の方法。
- 前記チェックポイント阻害剤は、細胞毒性T-白血球抗原4(CTLA4、CD152としても知られる)、プログラム細胞死タンパク質1(PD-1、CD279としても知られる)又はプログラム細胞死1配位子1(PD-L1、CD274としても知られる)の阻害剤である、請求項24記載の方法。
- CTLA4の前記阻害剤は、CTLA4に結合する抗体であり、PD-1の前記阻害剤は、PD-1に結合する抗体であり、PD-L1の前記阻害剤は、PD-L1に結合する抗体である、請求項25に記載の方法。
- I型インターフェロンとCD-40Lの組み合わせ、又はI型IFNとCD40-Lの組み合わせをコードする1つ以上の核酸配列を含み、
(a)前記I型IFNは、ヒトIFNβ(配列番号2)に対して少なくとも90%の配列同一性を有するヒトIFNβであり、
(b)前記CD40-Lは、配列番号7~18から選択される配列に対して少なくとも90%の配列同一性を有するキメラCD40-Lである、腫瘍溶解性ウイルス。 - 前記腫瘍溶解性ウイルスは、アデノウイルス、レオウイルス、ヘルペスウイルス、ピコルナウイルス、パラミクソウイルス、パルボウイルス、ラブドウイルス、ワクシニアウイルス、ポックスウイルス、シンドビスウイルス、粘液腫ウイルス、マラバウイルス、インフルエンザウイルス、ムンプスウイルス、アレナウイルス、ワクシニアウイルス、又はE1Aデルタ-24欠失、E1b-55K欠失、及びE3領域欠失を含む組換えアデノウイルスである、請求項27に記載の腫瘍溶解性ウイルス。
- 請求項27又は28に記載の腫瘍溶解性ウイルスと、薬学的に許容される担体とを含む組成物。
- アジュバントをさらに含む、請求項29に記載の組成物。
- 悪性腫瘍を処置する方法であって、
該処置を必要とするヒト以外の対象に、請求項27又は28に記載の腫瘍溶解性ウイルス又は請求項29又は30の組成物の有効量を投与することを含む、悪性腫瘍を処置する方法。 - 前記方法は、1つ以上の追加の抗癌剤を前記ヒト以外の対象に投与することをさらに含む、請求項31に記載の方法。
- 前記方法は、化学療法薬、免疫調節薬、アジュバント、貧血薬、放射線療法、幹細胞移植、キメラ抗原受容体(CAR)-発現T細胞(CAR T細胞)、又は前述のものの2つ以上の組み合わせを処方することをさらに含む、請求項32に記載の方法。
- 前記腫瘍溶解性ウイルスは、数日間にわたって複数回投与される、請求項31~33のいずれか一項に記載の方法。
- 前記腫瘍溶解性ウイルスは、皮内注射、腫瘍内注射、静脈内注射、又は腫瘍内に流出するリンパ節への注射によって投与される、請求項31~34のいずれか一項に記載の方法。
- 前記皮内注射は、前記ヒト以外の対象の腋窩リンパ節流域及び/又は鼠径リンパ節流域に流れ出る解剖学的部位にある、請求項35に記載の方法。
- 前記方法は、前記ヒト以外の対象に対して造血細胞移植(造血幹細胞移植又は前駆細胞移植)を実施することをさらに含む、請求項31~36のいずれか一項に記載の方法。
- 前記造血細胞移植は、自家である、請求項37記載の方法。
- 前記腫瘍溶解性ウイルスは、前記造血細胞移植の前後に投与される、請求項37又は38に記載の方法。
- 前記ヒト以外の対象上で幹細胞動員を行い、自己造血細胞移植の前に前記ヒト以外の対象から前記造血細胞を収集することをさらに含む、請求項31~39のいずれか一項に記載の方法。
- 前記腫瘍溶解性ウイルスを投与する前、投与中、又は投与後に化学療法剤を投与することをさらに含む、請求項31~40のいずれか一項に記載の方法。
- 前記造血細胞移植中に化学療法剤を投与することをさらに含む、請求項39~41のいずれか一項に記載の方法。
- チェックポイント阻害剤を前記ヒト以外の対象に投与することをさらに含む、請求項31~42のいずれか一項に記載の方法。
- 前記チェックポイント阻害剤は、細胞毒性T-白血球抗原4(CTLA4、CD152としても知られる)、プログラム細胞死タンパク質1(PD-1、CD279としても知られる)又はプログラム細胞死1配位子1(PD-L1、CD274としても知られる)の阻害剤である、請求項43に記載の方法。
- 前記CTLA4の前記阻害剤は、CTLA4に結合する抗体であり、PD-1の前記阻害剤は、PD-1に結合する抗体であり、PD-L1の前記阻害剤は、PD-L1に結合する抗体である、請求項44に記載の方法。
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