JP7125197B2 - ヒト対象において抗体免疫応答を誘導するために低投与体積b細胞エピトープ組成物を使用する方法 - Google Patents
ヒト対象において抗体免疫応答を誘導するために低投与体積b細胞エピトープ組成物を使用する方法 Download PDFInfo
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Description
[0035]一実施形態では、本開示は、ヒト対象において抗体免疫応答を誘導する方法であって、ヒト対象にB細胞エピトープを含む抗原、両親媒性化合物及び疎水性担体を含む組成物の低投与体積を非経口的に投与することを含み、組成物の低投与体積が、100μl未満であり、ヒト対象においてB細胞エピトープに対する抗体免疫応答を誘導する方法に関する。
[0059]本明細書において、用語「ワクチン」、「ワクチン組成物」又は「組成物」は、文脈が要求するように同義的に使用され得る。
[0064]本明細書において開示される組成物は、1種又はそれ以上の抗原を含む。少なくとも1種の抗原は、少なくとも1種のB細胞エピトープを含む。B細胞エピトープを含む場合も含まない場合もある他の抗原が、組成物中に含まれ得る。
MENTSITIEFSSKFWPYFTLIHMITTIISLLIIISIMIAILNKLCEYNVFHNKTFELPRARVNT(配列番号4)
ヒトRSV SH(サブグループB):
MGNTSITIEFTSKFWPYFTLIHMILTLISLLIIITIMIAILNKLSEHKTFCNKTLEQGQMYQINT(配列番号5)
[0094]SHの機能は、何年も不明確であったが、最近の証拠は、SHが、RSV感染の際に、ビロポリン(viroporin)として機能するようであり、インフラマソーム活性化をシグナル伝達し、イオン又は小分子に対する膜透過性を誘導することを示唆する。可能性があるワクチン候補としてのSH抗原の使用は、ベルギーのヘント大学、独立研究機関Vlaams Instituutvoor Biotechnologie(VIB;ベルギー、フランダース)及びベイラー医科大学(テキサス州、ヒューストン)に本拠地を置く研究者による前臨床研究において調査されている。VIBグループは、SHeとして知られるSHタンパク質の23個のアミノ酸のエクトドメイン部分を具体的に調べた(例えば、国際公開第2012/065997号を参照のこと)。しかし、SHeは小ペプチドであり、SHe単独の免疫原性は限定される。
NKLCEYNVFHNKTFELPRARVNT(配列番号1)
サブグループBヒトRSV SHe(RSV SHe B):
NKLSEHKTFCNKTLEQGQMYQINT(配列番号2)
[0096]したがって、いくつかの実施形態では、本明細書において開示される組成物は、アミノ酸配列NKLCEYNVFHNKTFELPRARVNT(配列番号1)を含む、若しくはからなる抗原又はその断片を含む。いくつかの実施形態では、本明細書において開示される組成物は、アミノ酸配列NKLSEHKTFCNKTLEQGQMYQINT(配列番号2)を含む、若しくはからなる抗原又はその断片を含む。
[00132]抗原配列に対して実質的な同一性を有するポリペプチド又はペプチドを使用してもよい。2種の配列は、最適にアラインされた場合に(ギャップが許可されて)、それらが少なくともおよそ50%の配列同一性を共有する場合に、又は配列が定義された機能的モチーフを共有する場合に、実質的同一性を有すると考えられる。代替実施形態では、最適にアラインされた配列は、それらが、指定の領域にわたって、少なくとも60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%の同一性を共有する場合に、実質的に同一である(すなわち、実質的同一性を有する)と考えられる。用語「同一性」とは、2つのポリペプチド分子間の配列類似性を指す。同一性は、アラインされた配列中の各位置を比較することによって決定され得る。アミノ酸配列間の同一性の程度は、例えば、指定の領域にわたる配列によって共有される位置の同一の又は対応するアミノ酸の数の関数である。同一性の比較のための配列の最適アラインメントは、当技術分野で公知であるように、http://clustalw.genome.ad.jpで入手可能なClustalWプログラム、Smith及びWaterman(1981)の局所相同性アルゴリズム、Needleman及びWunsch(1970)の相同性アラインメントアルゴリズム、Pearson及びLipman(1988)の類似性の検索方法及びこれらのアルゴリズム(Wisconsin Geneticsソフトウェアパッケージ、Genetics Computer Group、米国、ウィスコンシン州、マディソン中のGAP、BESTFIT、FASTA及びTFASTAなど)のコンピュータ化された実行を含む、種々のアルゴリズムを使用して実施してもよい。配列同一性はまた、Altschulら(1990)に記載されたBLASTアルゴリズム(公開されたデフォルト設定を使用して)を使用して決定してもよい。例えば、国立バイオテクノロジー情報センター(National Center for Biotechnology Information)によって入手可能な(http://www.ncbi.nlm.nih.gov/ BLAST/bl2seq/wblast2.cgiでインターネットによって)「BLAST2 Sequences」ツールを、以下のデフォルト設定で「blastp」プログラムを選択して使用してもよい:期待閾値(expect threshold)10、ワードサイズ(word size)3、マトリックス(matrix)BLOSUM62、ギャップコスト存在(gap costs existence)11、拡張(extension)1。別の実施形態では、当業者ならば、任意の所与の配列を容易に、適切にアラインし、単に目視検査によって、配列同一性及び/又は相同性を推定できる。
[00144]「両親媒性化合物」とは、親水性及び疎水性(親油性)両方の部分又は特徴を有する化合物である。用語「両親媒性化合物」とは、「両親媒性物質(amphiphile)」又は「両親媒性物質(amphiphilic)」と同義的に使用され得る。いくつかの実施形態では、適した両親媒性化合物はまた、本明細書において以下に記載されるものなどの乳化剤も含み得る。用語「両親媒性化合物」によって本明細書において包含される乳化剤の例示的実施形態として、限定するものではないが、ポリソルベート(例えば、モノオレイン酸ソルビタン)、マンニドオレエート(mannideoleate)(Arlacel(商標)A)、レシチン、Tween(商標)80及びSpans(商標)20、80、83及び85が挙げられる。両親媒性化合物は、親水性親和性を有するワクチン構成成分の、水の非存在下でオイルなどの疎水性担体への組込みを促進し得る。ワクチン構成成分は、制限するものではないが、抗原及び/又はアジュバント及び/又は免疫応答の生成を促進し得る他の成分を含み得る。
[00165]本明細書において開示される組成物は、疎水性担体、好ましくは、液体疎水性物質を含む。
[00173]本明細書において開示される組成物は、当技術分野で公知のような1種又は複数のさらなる構成成分をさらに含み得る(例えば、Remington’s Pharmaceutical Sciences、Mack Publishing Company、米国、ペンシルバニア州、イーストン 1985年及び1999年に公開された米国薬局方:国民医薬品集(USP 24 NF19)を参照のこと)。
[00176]いくつかの実施形態では、本明細書において開示される組成物は、1種又は複数のアジュバントを含み得る。
[00200]いくつかの実施形態では、本明細書において開示される組成物は、1種又は複数の乳化剤を含み得る。乳化剤は、純粋な乳化剤又は乳化剤の混合物であり得る。乳化剤(複数可)は、医薬上及び/又は免疫学的に許容されなければならない。
[00206]いくつかの実施形態では、本明細書において開示される組成物はまた、少なくとも1種のTヘルパーエピトープ又はTヘルパー抗原を含み得る。これは、CTLエピトープを有するさらなる抗原を含む組成物と特に関連し得るが、以下に記載されるように、Tヘルパーエピトープはまた、B細胞を含む免疫応答の媒介に関与する。
[00217]一実施形態では、本明細書において開示される組成物は、水を含まない、又は実質的に水を含まない、すなわち、組成物はエマルジョンではない。
[00221]組成物は、本開示を考慮して当技術分野で公知の方法によって調製され得る。本明細書において開示される組成物を調製するための例示的実施形態を、制限するものではないが、実施例においてを含め以下に記載する。
抗原を水中の10%DMSO/0.5%酢酸(w/w)の混合物中に溶解し、37℃で一晩加熱することによって二量体化された抗原を調製することと、
≦110nmの大きさの合成脂質/コレステロールナノ粒子を用いて一定の大きさの脂質混合物を調製することと、
リン酸ナトリウムバッファー(100mM、pH6.0)中で二量体化された抗原を、合成脂質/コレステロールナノ粒子及びアジュバントを混合することと、
混合物を凍結乾燥して、ドライケーキを形成することと、
ドライケーキを疎水性担体中に再懸濁することと
によって組成物を調製してもよい。
[00235]本開示は、本明細書において記載されるようなB細胞エピトープを含む抗原を含む組成物の低投与体積を使用する、ヒト対象において抗体免疫応答を誘導する方法、対応する使用並びにこのような方法において使用され得る組成物及びキットに関する。
[00262]本明細書において開示される組成物は、任意選択で、キットとしてユーザーに提供される。例えば、本開示のキットは、本明細書において開示される組成物の1種又は複数の構成成分を含有する。キットは、1種又は複数のさらなる試薬、包装材料、キットの構成成分を保持するための容器及びキット構成成分を使用する好ましい方法を詳述する使用説明書セット又はユーザーマニュアルをさらに含み得る。一実施形態では、容器はバイアルである。
[00273]当業者ならば、キットの代替配置が可能であり、本明細書における開示によって包含されることは理解するであろう。
[00276]本開示の特定の実施形態として、制限するものではないが、以下が挙げられる:
[00277](1)ヒト対象において抗体免疫応答を誘導する方法であって、ヒト対象に
B細胞エピトープを含む抗原、
両親媒性化合物、及び
疎水性担体
を含む組成物の低投与体積を非経口的に投与することを含み、
組成物の低投与体積が、100μl未満であり、ヒト対象においてB細胞エピトープに対する抗体免疫応答を誘導する方法。
アミノ酸配列NKLCEYNVFHNKTFELPRARVNT(配列番号1)を含むペプチド、
ジオレオイルホスファチジルコリン(DOPC)及びコレステロールを含む脂質混合物、
PAM3Cys-Ser-(Lys)4(配列番号3)である、短い合成リポペプチド、
モンタナイド(登録商標)ISA 51 VG
を含む、段落(1)~(53)のいずれか1つの方法。
両親媒性化合物と、
疎水性担体と
を含む組成物の低投与体積の使用であって、組成物が非経口的投与のためのものであり、組成物の低投与体積が、100μl未満である、使用。
[00342]カナダにおいて実施されたCI1204と呼ばれた第1相試験(NCT番号02472548)は、呼吸器合胞体ウイルス(RSV)小疎水性エクトドメイングループA(SHe A)ペプチド抗原に対する免疫応答を誘導するための、オイルベース製剤の低投与体積投与の安全性及び免疫効力を、アラムベース製剤と比較して評価した。試験は、無作為化された、観察者盲検の、プラセボ対照の、用量漸増試験であった。試験には、2つのステップが含まれ、第1のステップは、低ペプチド用量製剤を評価し、第2のステップは、高ペプチド用量製剤を評価した。
[00345]この試験に使用したアラムベースワクチンは、1ミリリットルあたり0.2ミリグラム(低ペプチド)又は1ミリリットルあたり0.5ミリグラム(高ペプチド)のRSV SHe Aペプチド抗原からなっていた。低及び高ペプチドアラムベースワクチンの両方とも、1ミリリットルあたり10ミリグラムのアルミニウムのAlhydrogel(登録商標)2%(Brenntag Biosector A/S、デンマーク)を含有していた。アラムベースのワクチンを製剤化するために、二量体化されたRSV SHe Aペプチド抗原を、酢酸ナトリウムバッファー(10ミリモル、pH7.0)を用いて希釈し、バイアル中に詰めた。注射の直前に、ワクチンを、1ミリリットルのワクチン製剤あたり1ミリグラムのアルミニウムでAlhydrogel(登録商標)2%(高ペプチド)と、又はAlhydrogel(登録商標)2%/水(低ペプチド)と混合した。
[00347]臨床治験に登録された対象は、年齢50~64歳の間の健常成人であった。平均年齢は、55.3歳であり、72.5%が女性であった。4つの対象群(n=8)に、以下のとおりにワクチン接種した:1)試験0及び56日目に50マイクロリットルの低ペプチドオイルベース製剤、2)試験0日目に50マイクロリットルの低ペプチドアラムベース製剤と、それに続く、試験56日目に50マイクロリットルの生理食塩水プラセボ、3)試験0及び56日目に50マイクロリットルの高ペプチドオイルベース製剤並びに4)試験0日目に50マイクロリットルの高ペプチドアラムベース製剤と、それに続く、試験56日目に50マイクロリットルの生理食塩水プラセボ。5番目の対象群(n=8)には、試験0及び56日目に50マイクロリットルの投与体積の生理食塩水プラセボ(0.9%塩化ナトリウム)を与えた。
[00350]非自発的及び自発的有害事象によって安全性をモニタリングし、測定した。試験0日目の第1の投与及び試験56日目の第2の投与後に事象を1週間毎日記録した。
[00355]ワクチンの免疫原性を、試験中一定間隔での血清採取によって臨床治験中のすべての対象についてモニタリングした。RSV SHeA抗原に対する抗体を、酵素結合免疫吸着測定法(ELISA)によって検出した。
[00359]試験56日目に、すべての群に単回免疫処置を施した。低ペプチドオイルベース製剤の対象の平均エンドポイント力価は、試験56日目に1.87であった(8人のうち検出限界を上回る力価を有する4人の対象)。低ペプチドアラムベース製剤の対象の平均log10エンドポイント力価は、試験56日目に0.73であった(8人のうち検出限界を上回る力価を有する2人の対象)。高ペプチドオイルベース製剤の対象の平均log10エンドポイント力価は、試験56日目に2.08であった(8人のうち検出限界を上回る力価を有する5人の対象)。高ペプチドアラムベース製剤の対象の平均log10エンドポイント力価は、試験56日目に0.44であった(8人のうち検出限界を上回る力価を有する1人の対象)。試験56日目のプラセボ群の対象の平均log10エンドポイント力価(試験の各アームからプールされた)は、0であった(8人のうち検出限界を上回る力価を有する0人の対象)。
[00362]病原体フリーの雌のCD1マウス、6~8週齢を、Charles River Laboratories(カナダ、ケベック州、サン・コンスタン)から入手し、フィルター制御空気循環下で水及び食物を自由に用いて、施設のガイドラインに従って飼育した。
[00368]
[00369]アジュバント添加オイルベース製剤は、RSV SHe A(p<0.01)及びRSV SHe B(p<0.001)ペプチド抗原の両方に対して、アラムベース製剤と比較して有意に高い力価を誘導した。アジュバント非添加オイルベース製剤は、SHe Bペプチド抗原に対して、アラムベース製剤と比較して有意に高い力価(p<0.001)を誘導した。アジュバント非添加オイルベース製剤は、SHe Aペプチド抗原に対して、水ベース製剤よりも高い力価を誘導したが、統計的に有意ではなかった。これらの結果は、RSV SHe A又はRSV SHe Bペプチド抗原を含有するアジュバント添加オイルベース製剤は、水ベースワクチンよりも有意に強力であった抗体反応を有効に誘導できることを実証する。これらの結果はまた、オイルベース製剤が、複数のペプチドに対して水ベースワクチンを上回るより強力な免疫応答を誘導することを実証する。
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Claims (11)
- ヒト対象において抗体免疫応答を誘導するための治療方法において使用するための組成物であって、前記方法が、前記ヒト対象に、前記組成物の低投与体積を筋肉内注射によって非経口的に投与することを含み、
前記組成物が、
B細胞エピトープを含む抗原10μg~25μg、
ジオレオイルホスファチジルコリン(DOPC)及びコレステロールを含む脂質混合物、
PAM 3 Cys-Ser-(Lys)4(配列番号3)である短い合成リポペプチド、及び
鉱油溶液中のマンニドオレエートである疎水性担体
を含み、
前記抗原がアミノ酸配列NKLCEYNVFHNKTFELPRARVNT(配列番号1)を含むペプチドであり、
前記組成物の前記低投与体積が、50μL~100μLであり、前記ヒト対象において前記B細胞エピトープに対する抗体免疫応答を誘導する、組成物。 - 前記低投与体積が、50μL、60μL、70μL、80μL又は90μLである、請求項1に記載の組成物。
- 前記低投与体積が、50μLである、請求項1又は2に記載の組成物。
- 前記方法が、(i)前記組成物の単回投与のみを投与するステップ又は(ii)前記組成物の単回初回刺激投与及び単回追加免疫投与のみを投与するステップを含む、請求項1~3のいずれか一項に記載の組成物。
- 前記単回追加免疫投与が、前記単回初回刺激投与の、1週間、2週間、3週間、4週間、5週間、6週間、7週間、8週間、9週間、10週間、11週間、12週間若しくはそれ以上後に前記ヒト対象に提供され、又は
前記単回追加免疫投与が、前記単回初回刺激投与の56日後に前記ヒト対象に提供される、請求項4に記載の組成物。 - 前記組成物の前記低投与体積が、
前記組成物の第1の投与の少なくとも早ければ28日後に前記ヒト対象において検出可能である抗体免疫応答を誘導する、
前記組成物の第1の投与後少なくとも84日若しくは少なくとも236日間前記ヒト対象において持続する抗体免疫応答を誘導する、
投与後56日目、84日目若しくは236日目までに、前記ヒト対象の少なくとも75%、少なくとも80%、少なくとも85%、少なくとも90%、少なくとも95%若しくは少なくとも100%において抗体免疫応答を誘導する、
投与後少なくとも84日目若しくは236日目までに、治療されたヒト対象の100%において抗体免疫応答を誘導する、並びに/又は
アラム組成物に製剤化された抗原を投与されたヒト対象において誘導された抗体免疫応答と比較して増強された抗体免疫応答を誘導し、前記アラム組成物が、前記抗原、アラムアジュバント、無機アジュバント及び水性担体を含む、
請求項1~5のいずれか一項に記載の組成物。 - 前記組成物の前記低投与体積が、前記アラム組成物を投与されたヒト対象において誘導された前記抗体免疫応答と比較して増強された抗体免疫応答を誘導し、
前記組成物及び前記アラム組成物の各々が、10μgの抗原を含み、前記組成物を用いる平均抗原特異的抗体エンドポイント力価が、(i)投与後28日目で前記アラム組成物よりも少なくとも123.2倍高い及び/若しくは(ii)56日目で前記アラム組成物よりも少なくとも16.7倍高い、
前記組成物及び前記アラム組成物の各々が、25μgの抗原を含み、前記組成物の平均抗原特異的抗体エンドポイント力価が、(i)投与後28日目で前記アラム組成物よりも少なくとも35.3倍高い及び/若しくは(ii)56日目で前記アラム組成物よりも少なくとも13.1倍高い、
前記組成物及び前記アラム組成物の各々が、10μgの抗原を含み、前記組成物を用いて治療された場合に検出可能な抗原特異的抗体免疫応答を有するヒト対象のパーセンテージが、投与後56日目で前記アラム組成物を用いた場合よりも少なくとも2.0倍高い、
前記組成物及び前記アラム組成物の各々が、25μgの抗原を含み、前記組成物を用いて治療された場合に検出可能な抗原特異的抗体免疫応答を有するヒト対象のパーセンテージが、投与後56日目で前記アラム組成物を用いた場合よりも少なくとも5.0倍高い、並びに/又は
前記組成物が、非自発的総全身性有害事象及び/若しくは自発的総有害事象について容認できる安全性プロファイルを有する、
請求項6に記載の組成物。 - 前記ヒト対象が、0~2歳、50~64歳又は65歳を超える年齢である、請求項1~7のいずれか一項に記載の組成物。
- 前記組成物が、水を含まない又は実質的に水を含まない、請求項1~8のいずれか一項に記載の組成物。
- 前記ヒト対象における感染性疾患の治療又は予防のためのものである、請求項1~9のいずれか一項に記載の組成物。
- 請求項1~10のいずれか一項に記載の組成物を含む、ヒト対象において抗体免疫応答を誘導するための治療方法において使用するためのキット。
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CN106310293A (zh) * | 2007-09-27 | 2017-01-11 | 免疫疫苗技术有限公司 | 在包括连续疏水相的载体中的脂质体在体内输送多核苷酸中的应用 |
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