JP7405434B2 - ストレス関連障害および癌を治療するための材料および方法 - Google Patents
ストレス関連障害および癌を治療するための材料および方法 Download PDFInfo
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Description
本発明は、米国国立衛生研究所によって授与されたCA195563の下で政府の支援を受けてなされた。政府は、本発明におけるある特定の権利を有する。
本出願は、2018年6月11日に出願された米国仮特許出願第62/683,369号、2018年12月10日に出願された米国仮特許出願第62/777,572号、および2019年5月6日に出願された米国仮特許出願第62/843,677号に対する優先権の利益を主張し、それらの開示は、それらの全体が参照により本明細書に組み込まれる。
本出願は、本開示の別個の部分として、その全体が参照により組み込まれるコンピュータ可読形式の配列表(ファイル名:52978_Seqlisting.txt、サイズ:15,132バイト、作成日:2019年6月7日)を含む。
本開示はまた、抗CRH抗体を提供する。「抗体」という用語は、無傷の免疫グロブリン分子(完全長の重鎖および/または軽鎖を有するポリクローナル、モノクローナル、キメラ、ヒト化、および/またはヒトバージョンを含む)を指す。抗体は、当該技術分野で知られている任意の種類の抗体、すなわち免疫グロブリンであり得る。例示的な実施形態では、抗体は、クラスまたはアイソタイプIgA、IgD、IgE、IgG、またはIgMの抗体である。例示的な実施形態では、本明細書に記載の抗体は、1つ以上のα重鎖、Δ重鎖、ε重鎖、γ重鎖、および/またはμ重鎖を含む。例示的な実施形態では、本明細書に記載の抗体は、1つ以上のκまたは軽鎖を含む。例示的な態様では、抗体は、IgG抗体であり、任意選択で、IgG1、IgG2、IgG3およびIgG4の4種のヒトサブクラスの1種である。また、いくつかの実施形態における抗体は、モノクローナル抗体である。他の実施形態では、抗体はポリクローナル抗体である。いくつかの態様では、抗体は、キメラ抗体またはヒト化抗体である。抗体に関して使用される場合、「ヒト化」という用語は、非ヒト供給源由来の少なくともCDR領域を有し、元の供給源抗体よりも真のヒト抗体により類似した構造および免疫機能を有するように操作されている抗体を指す。例えば、ヒト化は、マウス抗体などの非ヒト抗体からヒト抗体フレームワークへのCDRの移植を含み得る。ヒト化は、非ヒト配列をよりヒト配列らしくするアミノ酸置換を選択することも含み得る。
抗体を作製する好適な方法は当該技術分野で知られている。例えば、標準的なハイブリドーマ法は、例えば、Harlow and Lane(編)、Antibodies:A Laboratory Manual、CSH Press(1988)、およびCA.Janeway et al.(編)、Immunobiology.第5版,Garland Publishing、New York,NY(2001))に記載されている。本開示の方法で使用するためのモノクローナル抗体は、培養中の連続細胞株による抗体分子の産生を提供する任意の技術を使用して調製することができる。これらには、KoehlerおよびMilsteinによって最初に記述されたハイブリドーマ技術(Nature 256:495-497、1975)、ヒトB細胞ハイブリドーマ技術(Kosbor et al.,Immunol Today 4:72、1983;Cote et al.,Proc Natl Acad Sci 80:2026-2030、1983)およびEBV-ハイブリドーマ技術(Cole et al.,Monoclonal Antibodies and Cancer Therapy,Alan R Liss Inc,New York NY,pp 77-96,(1985)が挙げられるが、これらに限定されない。あるいは、他の方法、例えば、EBVハイブリドーマ法(Haskard and Archer,J.Immunol.Methods,74(2)、361-67(1984)、およびRoder et al.,Methods Enzymol.,121,140-67(1986))、およびバクテリオファージベクター発現システム(例えば、Huse et al.,Science,246,1275-81(1989)を参照されたい)は当該技術分野で知られている。さらに、非ヒト動物において抗体を産生する方法は、例えば、米国特許第5,545,806号、同第5,569,825号、および同第5,714,352号、ならびに米国特許出願公開第2002/0197266A1号に記載されている。抗体はまた、リンパ球集団においてインビボ産生を誘導することによって、またはOrlandi et al(Proc Natl Acad Sci 86:3833-3837;1989)、ならびにWinter GおよびMilstein C(Nature 349:293-299,1991)に開示されているように、組換え免疫グロブリンライブラリーまたは高度に特異的な結合試薬のパネルをスクリーニングすることによって産生され得る。抗体または抗原結合フラグメントの完全な配列が知られている場合、組換えタンパク質を産生する方法を使用することができる。たとえば、“Protein production and purification”Nat Methods 5(2):135-146(2008)を参照されたい。いくつかの実施形態では、抗体(または抗原結合フラグメント)は、インビボで生成される場合、細胞培養物または生体試料から単離される。
試料中のCRHの存在を検出したり、CRHの量を測定したりすることが望ましいときがある。これに関して、本開示は、試料中のCRHの量を測定するために、本明細書に記載の抗体またはそのフラグメントを使用する方法を提供する。CRHの測定値を決定するために、哺乳動物対象由来の生体試料を、免疫複合体を形成させるのに十分な時間、本明細書に記載の抗CRH抗体(またはその抗原結合フラグメント)と接触させる。次に、試料中の抗体とCRHの間に形成された免疫複合体が検出される。生体試料中のCRHの量は、抗体とCRHの間に形成される免疫複合体の量を測定することによって任意選択で定量化される。例えば、抗体が検出可能な標識を有する場合、抗体を定量的に測定することができ、または二次抗体を使用して免疫複合体を定量化することができる。
本明細書に記載のすべてのタンパク質ベースの治療法(例えば、抗体)について、遺伝子発現構築物の送達による投与が一実施形態として企図される。任意の好適なベクターを使用して、本明細書に記載のタンパク質ベースの治療薬をコードするポリヌクレオチドを宿主に導入することができる。文献に記載されている例示的なベクターとしては、レンチウイルスベクターを含むがこれらに限定されない複製欠損レトロウイルスベクター[Kim et al.,J.Virol.,72(1):811-816(1998);Kingsman&Johnson,Scrip Magazine,October,1998,pp.43 46.];アデノ随伴ウイルス(AAV)ベクター[米国特許第5,474,935号、米国特許第5,139,941号、米国特許第5,622,856号、米国特許第5,658,776号、米国特許第5,773,289号、米国特許第5,789,390号、米国特許第5,834,441号、米国特許第5,863,541号、米国特許第5,851,521号、米国特許第5,252,479号、Gnatenko et al.,J.Invest.Med.,45:87 98(1997)];アデノウイルス(AV)ベクター[例えば、米国特許第5,792,453号、米国特許第5,824,544号、米国特許第5,707,618号、米国特許第5,693,509号、米国特許第5,670,488号、米国特許第5,585,362号、Quantin et al.,Proc.Natl.Acad.Sci.USA、89:2581 2584(1992);Stratford Perricadet et al.,J.Clin.Invest.,90:626 630(1992);およびRosenfeld et al.,Cell、68:143 155(1992)を参照されたい];アデノウイルスアデノ随伴ウイルスキメラ(例えば、米国特許第5,856,152号を参照されたい)またはワクシニアウイルスもしくはヘルペスウイルス(例えば、米国特許第5,879,934号、米国特許第5,849,571号、米国特許第5,830,727号、米国特許第5,661,033号、米国特許第5,328,688号を参照されたい);リポフェクチン媒介遺伝子導入(BRL);リポソームベクター[例えば、米国特許第5,631,237号(Sendaiウイルスタンパク質を含むリポソーム)を参照されたい];およびそれらの組み合わせが挙げられる。前述の文書のすべては、参照によりそれらの全体が本明細書に組み込まれる。複製欠損アデノウイルスベクターは、好ましい実施形態を構成する。
本明細書に記載の抗体またはその抗原結合フラグメント、CRHペプチドフラグメント、および医薬組成物は、CRH調節不全または視床下部下垂体副腎(HPA)軸の活性化に関連する障害(例えば、ストレス関連障害および/または癌)を治療または予防するのに有用である。HPA軸には、視床下部、下垂体、および神経内分泌系を形成する副腎の3つの内分泌腺間の正および負のフィードバック相互作用が含まれる。内分泌腺から放出されるホルモンは、ストレスへの反応、消化などの身体プロセスの調節、免疫系、気分と感情、セクシュアリティおよびエネルギーの保存と消費を制御する。HPA軸は、数種類の精神病や神経精神病において、ならびにアルコール依存症や脳卒中において調節不全になる。HPA軸バイオマーカーの例としては、ACTHおよびコルチゾールが挙げられる。コルチゾールはコルチコトロピン放出ホルモン(CRH)の分泌を阻害し、ACTH分泌のフィードバック阻害になる。この通常のフィードバックループは、ヒトが慢性的なストレスに曝されると崩壊することがあり得、うつ病の根本的な原因となり得る。
様々な実施形態では、本明細書に記載の抗CRH抗体またはそのフラグメントは、HPA軸活性化に関連する状態または障害(例えば、癌)を治療するために有用な追加の治療薬と組み合わせて投与される。
医薬組成物は調製されると、液剤、懸濁剤、ゲル剤、乳剤、固形剤、結晶剤として、または脱水粉末または凍結乾燥粉末として、滅菌バイアルに保存され得る。特定の実施形態では、そのような製剤は、すぐに使用可能な形態、または投与前に再構成される形態(例えば、凍結乾燥形態)のいずれかで保存され得る。本発明はまた、単回投与ユニットを生成するためのキットを提供する。本開示のキットは、各々、乾燥タンパク質を含有する第1の容器と水性製剤を含有する第2の容器の両方を含み得る。特定の実施形態では、単一チャンバーおよび複数チャンバーのプレフィルドシリンジ(例えば、液体シリンジおよびリオシリンジ)を含むキットが提供される。
野生型マウスに、200μLの完全フロイントアジュバントに乳化させた200μgのN末端CRHペプチドフラグメント(ペプチドA:SEEPPISLDLTFHLL(配列番号1または配列番号2のアミノ酸1~15)またはペプチドB:SEEPPISLDLTFHLLREVLEM(配列番号1または配列番号3のアミノ酸1~21)のいずれか)を皮下注射し、続いて不完全フロイントアジュバントに乳化させた200μgのペプチドの追加免疫を2回、2週間間隔で腹腔内注射した。最終ブーストに続いて、血清を収集し、直接ELISAによって抗CRH力価についてアッセイした。図1を参照されたい。
マウス群(n=17)に、CRH-OVAワクチンまたはOVAのみのいずれかを投与し、実施例1に記載のように2回の追加ブーストを投与した。次いで、マウスを90分間の急性拘束ストレスに曝した。血漿を3時点で採取し、ラジオイムノアッセイによってコルチコステロンレベルについてアッセイした。CRH活性ワクチンおよび対照は、急性ストレスに対するコルチコステロン応答を同程度にブロックした。
本明細書に記載のN末端CRHペプチドに結合する抗体は、CRHに対して高い親和性を示す。配列番号2に結合する抗CRH抗体(抗体A)は、標的に対してピコモルレベルの親和性を示した(Kdは1×10-12未満)。配列番号3(抗体B)に結合する抗CRH抗体は、標的に対してナノモルレベルの親和性を示した(Kd=2.09×10-8)。
野生型マウス群(n=9)に、30分間の拘束ストレスに曝す12時間前に、25mg/kgの抗CRH抗体Aまたは生理食塩水のいずれかを腹腔内注射した。血漿を4時点(0、30、90、および150分)で採取し、ラジオイムノアッセイによってコルチコステロンレベルについてアッセイした。より大きい野生型マウス群(n=10)を利用したことを除いて、同じ実験を抗CRH抗体Bで繰り返した。図4Bに示すように、抗CRH抗体Bは急性ストレスに対するコルチコステロン応答をブロックした。抗体Bの投与により、30分でコルチコステロンのレベルが少なくとも4分の1に低下し、拘束ストレスを取り除いた時点で、コルチコステロンのレベルは対照マウスにおいて最高であった。
野生型マウスにAAV8-CRHを脳室内に注射した結果、脳内でCRHが過剰発現し、クッシング様表現型(すなわち、脱毛、皮膚の赤み、肥満)を誘発した。図5に示すように、抗CRH抗体B(0.3mg)を1回腹腔内注射すると、観察された脱毛が元に戻った。
ScFvコンストラクトは、AAVベクターを介して脳に送達されることが可能であるという利点を提供する。リンカーペプチドによって結合された、抗体Aおよび抗体Bの重可変領域および軽可変領域から構成されるScFvのDNAコンストラクトを生成した。抗体Aおよび抗体BのscFvのアミノ酸配列は、それぞれ、配列番号22および23に記載する。次いで、DNAコンストラクトをヒト胎児由来腎臓(HEK)293t細胞にトランスフェクトし、48時間インキュベートした。次いで、細胞を溶解し、直接CRH ELISAによってCRH結合について分析した。図6に示すように、結果として得られるScFvは、抗体Aまたは抗体Bに結合したCRHの重可変領域と軽可変領域を含む。
図7は、抗CRH抗体Bの可変領域と同様のヒト可変フレームワークとの比較を示す。強調表示されているのは、抗体Bの相補性決定領域(CDR)である。抗体Bの可変領域のフレームワークは、抗体BのCDRを変えることなく、ヒトフレームワークの可変領域と適合するように変えることができる。
CRHR1安定過剰発現H4神経膠腫細胞を、PBS中で合成CRH(Bachem)または精製抗体B(QED bio)の組み合わせとともに10分間インキュベートした。処理後、細胞を0.1M HClおよび1%Tritonで溶解し、競合ELISAキット(Thermo Fisher EMSCAMPL)によりサイクリックAMPレベルについて分析した。図8に示すように、抗体Bは、CRH誘発性サイクリックAMPの増加を低下させることができた。
野生型(C3B6H)マウスを2ヶ月間単独飼育した(軽度のストレス)。次いで、マウスを様々な用量の抗体Bで処置し(1群あたりn=4、雄雌均衡)、30分間の急性拘束ストレスに曝した。図9に示すように、抗体Bで処置したマウスは、明確な用量反応型の効果プロファイルを示し(左)、低用量(1.5mg/kg)の抗体Bでも、2ヶ月間単独飼育したマウスのベースラインコルチコステロンレベルを下げることができた。
2.5ヶ月齢の野生型(C3B6)マウスを2週間の慢性変動ストレスに曝した。毎日2種のストレッサーを各1時間ずつ。マウスを25mg/kgの抗体BまたはマウスIgG1アイソタイプ対照(上記のn数、雄雌均衡)で処置した。図10を参照されたい。
マウス(n=6M C57BL/6Jマウス)を抗体BまたはマウスIgG1対照抗体のいずれかで2.5週間、25mg/kgの初回腹腔内注射に続いて12.5mg/kgの週1回の腹腔内注射で処置した。
上記の実施例11(抗体Bによる2.5週間後の処置)で記載と同じマウスからの脾臓を、すりガラススライドで処理し、濾過(70ミクロン)して、単一細胞懸濁液を作製した。赤血球を塩化アンモニウム-カリウム溶解緩衝液で、氷上で5分間溶解し、残りの細胞をリン酸緩衝生理食塩水(PBS)で洗浄してから染色した。試料あたり1×106個の細胞を死細胞の排除のために修正可能ライブ/デッド・近赤外サーモフィッシャー(Waltham,MA,USA)で染色した。細胞をFcブロック(2.4G2;BD Biosciences)とともに氷上で5分間インキュベートした後、次の抗体を適切な濃度で、氷上で30分間染色した:CD4-PerCP-Cy5.5(RM4-5;eBioscience)、CD8a-PE-Cy7(53-6.7;Biolegend)、CD3e-BV605(145-2C11;Biolegend)、NK1.1-APC(PK136;eBioscience)、CD19-BV711(6D5;Biolegend)、Ly6G-BV421(1A8;BD Biosciences)、Ly6C-PE(HK1.4;eBioscience)、CD11b-AF488(M1/70;eBioscience)。LSR Fortessa(BD Biosciences)でデータを取得し、FlowJo(v10.5.0;Tree Star)、BioLegend(San Diego,CA,USA)、eBioscience(San Diego,CA,USA)を使用して分析する前に、試料を1回洗浄した。図13に示すように、抗体Bで処置すると、B細胞およびT細胞が増加し、生脾細胞の量が大幅に増加する。
1:1のPBS:メチルセルロース溶液中の10,000個のGL261細胞を、8~12週齢の成体雌C57Bl6/Jマウス(1群あたりN=8)に定位注射を使用して、頭蓋骨の3mm下およびブレグマの外側2mmの点に2.5uLの容量で頭蓋内注射した。次いで、UFIACUC201607966に記載されているように、人道的エンドポイントへの進行についてマウスをモニターした。処置したマウスに、腫瘍移植の5日後に400ugの抗PD1抗体、400μgの抗体B、またはその両方(Clone RMP1-14、BioXCell)を腹腔内注射し、次いで、5日ごとに200μgの抗PD1および200μgの抗体Bを計5投与量で投与した。図14に示すように、抗体B(および抗体Bと抗PD1抗体の組み合わせ)による処置により、GL261頭蓋内マウス神経膠腫モデルの生存を高め、未処置の動物より2倍超長く生存した。
1uM(左)または10uM(右)のCRFまたはCRFファミリー神経ペプチドウロコルチン(UCN)1、UCN2、またはUCN3をポリカーボネート96ウェルELISAプレートにコーティングした直接ELISA。次いで、抗体Bを13.33nMで添加し、2時間インキュベートした後、抗マウスIgG-HRP結合検出抗体を添加した。次いで、TMB試薬を使用してELISAを発色させ、分光光度計を使用して450nMで読み取った。
Claims (19)
- 配列番号1のアミノ酸1~21を含むコルチコトロピン放出ホルモン(CRH)の領域に特異的に結合する抗体又はその抗原結合フラグメントであって、
(a)配列番号12のアミノ酸配列で表されるCDR-H1、
配列番号13のアミノ酸配列で表されるCDR-H2、および
配列番号14のアミノ酸配列で表されるCDR-H3
を含む、重鎖可変領域、並びに
(b)配列番号15のアミノ酸配列で表されるCDR-L1、
配列番号16のアミノ酸配列で表されるCDR-L2、および
配列番号17のアミノ酸配列で表されるCDR-L3
を含む、軽鎖可変領域
を含む、抗体またはその抗原結合フラグメント。 - 配列番号19に記載のアミノ酸配列を含む重鎖可変領域;および配列番号18に記載のアミノ酸配列を含む軽鎖可変領域を含む、請求項1に記載の抗体またはその抗原結合フラグメント。
- 配列番号1のアミノ酸1~21を含むコルチコトロピン放出ホルモン(CRH)の領域に特異的に結合する抗体又はその抗原結合フラグメントであって、
(a)配列番号4のアミノ酸配列で表されるCDR-H1、
配列番号5のアミノ酸配列で表されるCDR-H2、および
配列番号6のアミノ酸配列で表されるCDR-H3
を含む、重鎖可変領域、並びに
(b)配列番号7のアミノ酸配列で表されるCDR-L1、
配列番号8のアミノ酸配列で表されるCDR-L2、および
配列番号9のアミノ酸配列で表されるCDR-L3
を含む、軽鎖可変領域
を含む、抗体またはその抗原結合フラグメント。 - 配列番号11に記載のアミノ酸配列を含む重鎖可変領域;および配列番号10に記載のアミノ酸配列を含む軽鎖可変領域を含む、請求項3に記載の抗体またはその抗原結合フラグメント。
- モノクローナル抗体である、請求項1~4のいずれか一項に記載の抗体またはその抗原結合フラグメント。
- ヒト化抗体である、請求項1~5のいずれか一項に記載の抗体またはその抗原結合フラグメント。
- IgGである、請求項1~6のいずれか一項に記載の抗体またはその抗原結合フラグメント。
- 前記抗原結合フラグメントがFabフラグメントまたはscFvである、請求項1~7のいずれか一項に記載の抗体またはその抗原結合フラグメント。
- 前記scFvが、配列番号22または配列番号23に記載のアミノ酸配列を含む、請求項8に記載の抗体または抗原結合フラグメント。
- 対象におけるストレスに対するコルチコステロン応答を阻害するための、請求項1または請求項3に記載の抗体またはその抗原結合フラグメントを含む医薬組成物。
- 対象におけるストレス関連障害を治療するための、請求項1または請求項3に記載の抗体またはその抗原結合フラグメントを含む医薬組成物。
- 前記ストレス関連障害が、不安、うつ病、アルツハイマー病、心的外傷後ストレス障害、全般性不安障害、大うつ病、神経性食欲不振症、副腎障害、メタボリックシンドローム、1型糖尿病、サルコペニアおよび多発性硬化症からなる群から選択される、請求項11に記載の医薬組成物。
- 対象における癌を治療するための、請求項1または請求項3に記載の抗体またはその抗原結合フラグメントを含む医薬組成物。
- 前記対象に癌免疫療法を投与することをさらに含む、請求項13に記載の医薬組成物。
- 前記癌免疫療法が、抗PD1抗体および抗CTLA4抗体である、請求項14に記載の医薬組成物。
- 前記癌が癌腫、黒色腫、肉腫、骨髄腫、白血病、またはリンパ腫である、請求項13に記載の医薬組成物。
- 前記癌が脳癌、乳癌、または結腸癌である、請求項13に記載の医薬組成物。
- 前記乳癌がトリプルネガティブ乳癌である、請求項17に記載の医薬組成物。
- 対象における視床下部下垂体副腎(HPA)軸を阻害するための、請求項1または請求項3に記載の抗体またはその抗原結合フラグメントを含む医薬組成物。
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