JP6014116B2 - ヒト・プログラム死受容体pd−1に対する抗体の安定製剤および関連治療 - Google Patents
ヒト・プログラム死受容体pd−1に対する抗体の安定製剤および関連治療 Download PDFInfo
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Description
本出願は、2011年3月31日付け出願の米国仮特許出願第61/470,121号(その全体を参照により本明細書に組み入れることとする)の利益を主張するものである。
本発明は、ヒト・プラグラム死受容体PD−1に対する抗体またはその抗原結合性フラグメントの安定製剤に関する。本発明は更に、ヒトPD−1に対する抗体またはその抗原結合性フラグメントの安定製剤での種々の癌および慢性感染の治療方法を提供する。
PD−1は免疫調節および末梢性免疫寛容の維持における重要な担い手として認識されている。マウスにおいて、これは、PD−1細胞質ドメイン内のITIM配列が関わるT細胞活性化を負にモジュレーションするためには、末梢組織上のPD−L1発現および潜在的に自己反応性のT細胞上のPD−1の結合を要することが示された(1,4)。
本発明はヒト・プログラム死受容体PD−1に対する抗体またはその抗原結合性フラグメントの安定製剤に関する。本発明は更に、ヒト・プログラム死受容体PD−1に対する抗体またはその抗原結合性フラグメントの安定製剤での種々の癌および慢性感染症の治療方法を提供する。
本発明は、抗PD−1抗体の製剤、ならびに種々の癌および感染症の治療のためのその使用を提供する。
本明細書中で用いる「抗体」なる語は、所望の生物活性を示す抗体の任意の形態を意味する。したがって、それは最も広義に用いられ、特に、所望の生物活性を示すモノクローナル抗体(完全長モノクローナル抗体を含む)、ポリクローナル抗体、多重特異性抗体(例えば、二重特異性抗体)、キメラ抗体、ヒト化抗体、完全ヒト抗体などを含む。
本明細書中で用いる「アジュバント」なる語は、抗原に対する免疫応答を増強する化合物または混合物を意味する。アジュバントは、該抗原を徐々に放出する組織デポーとして、そしてまた、該免疫応答を非特異的に増強するリンパ系活性化因子として働きうる(Hoodら,Immunology,Second Ed.,1984,Benjamin/Cummings:Menlo Park,California,p.384)。しばしば、アジュバントの非存在下の抗原のみでの一次チャレンジは体液性または細胞性免疫応答を惹起しないであろう。アジュバントには、完全フロイントアジュバント、不完全フロイントアジュバント、サポニン、無機ゲル、例えば水酸化アルミニウム、界面活性物質、例えばリゾレシチン、プルロニックポリオール、ポリアニオン、ペプチド、油または炭化水素エマルション、キーホールリンペットヘモシアニン、および潜在的に有用なヒトアジュバント、例えばN−アセチル−ムラミル−L−トレオニル−D−イソグルタミン(thr−MDP)、N−アセチル−ノル−ムラミル−L−アラニル−D−イソグルタミン、N−アセチルムラミル−L−アラニル−D−イソグルタミニル−L−アラニン−2−(1’−2’−ジパルミトイル−sn−グリセロ−3−ヒドロキシホスホリルオキシ)−エチルアミン、BCG(bacille Calmette−Guerin)およびコリネバクテリウム・パルブム(Corynebacterium parvum)が含まれるが、これらに限定されるものではない。好ましくは、該アジュバントは医薬上許容されるものである。
「サイトカイン」なる語は、1つの細胞集団により放出される、細胞間メディエーターとして別の細胞に作用するタンパク質の総称である。そのようなサイトカインの例としては、リンホカイン、モノカイン、ケモカインおよび伝統的なポリペプチドホルモンが挙げられる。典型的なサイトカインには、ヒトIL−2、IFN−γ、IL−6、TNFα、IL−17およびIL−5が含まれる。
本明細書中で用いる「細胞毒性物質」なる語は、細胞の機能を抑制もしくは妨害し、および/または細胞の破壊を引き起こす物質を意味する。該用語は、放射活性同位体(例えば、I131、I125、Y90およびRe186)、化学療法剤、および毒素、例えば、細菌、真菌、植物または動物由来の酵素的に活性な毒素、またはそれらの断片を含むと意図される。
PD−1遮断物質には、ヒトPD−1に特異的に結合し、免疫応答を増大、増強、刺激またはアップレギュレーションするために使用可能であるものが含まれる。望ましい対象には、癌および/または慢性ウイルス感染を有する患者を含む、免疫応答の増強を要するヒト患者が含まれる。
「癌」、「癌性」または「悪性」なる語は、無制御な細胞増殖により典型的に特徴づけられる、哺乳動物における生理的状態を意味し又は示す。癌の例には、癌腫、リンパ腫、白血病、芽腫および肉腫が含まれるが、これらに限定されるものではない。そのような癌の更に詳細な例には、扁平上皮癌、骨髄腫、小細胞肺癌、非小細胞肺癌、神経膠腫、ホジキンリンパ腫、非ホジキンリンパ腫、胃腸(管)癌、腎臓癌、卵巣癌、肝臓癌、リンパ芽球性白血病、リンパ性白血病、結腸直腸癌、子宮内膜癌、腎臓癌、前立腺癌、甲状腺癌、メラノーマ、軟骨肉腫、神経芽細胞腫、膵臓癌、多形性膠芽腫、子宮頸癌、脳の癌、胃癌、膀胱癌、肝癌、乳癌、結腸癌および頭頸部癌が含まれる。
「化学療法剤」は、癌の治療に有用な化合物である。抗PD−1抗体はいずれかの1以上の適当な化学療法剤と共に使用されうる。そのような化学療法剤の例には以下のものが含まれる:アルキル化剤、例えばチオテパ(thiotepa)およびシクロスホスファミド(cyclosphosphamide);アルキルスルホナート、例えばブスルファン(busulfan)、イムプロスルファン(improsulfan)およびピポスルファン(piposulfan);アジリジン、例えばベンゾドーパ(benzodopa)、カルボコン(carboquone)、メツレドーパ(meturedopa)およびウレドーパ(uredopa);エチレンイミンおよびメチルアメルアミン(methylamelamine)、例えばアルトレタミン(altretamine)、トリエチレンメラミン、トリエチレンホスホルアミド(trietylenephosphoramide)、トリエチレンチオホスルアミド(triethylenethiophosphaoramide)およびトリメチロロメラミン(trimethylolomelamime);アセトゲニン(特にブルラタシン(bullatacin)およびブルラタシノン(bullatacinone);カンプトテシン(合成類似体トポテカン(topotecan)を含む);ブリオスタチン(bryostatin);カルリスタチン(callystatin);CC−1065(そのアドゼレシン(adozelesin)、カルゼレシン(carzelesin)およびビゼレシン(bizelesin)合成類似体を含む);クリプトフィシン(cryptophycin)(特にクリプトフィシン1およびクリプトフィシン8);ドラスタチン(dolastatin);デュオカルマイシン(duocarmycin)(合成類似体KW−2189およびCBI−TMIを含む);エロイテロビン(eleutherobin);パンクラチスタチン(pancratistatin);サルコジクチイン(sarcodictyin);スポンジスタチン(spongistatin);ナイトロジェンマスタード、例えばクロラムブシル(chlorambucil)、クロルナファジン(chlornaphazine)、クロロホスファミド(cholophosphamide)、エストラムスチン(estramustine)、イフォスファミド(ifosfamide)、メクロルエタミン(mechlorethamine)、メクロルエタミンオキシド塩酸塩、メルファラン(melphalan)、ノベムビチン(novembichin)、フェネステリン(phenesterine)、プレドニムスチン(prednimustine)、トロフォスファミド(trofosfamide)、ウラシルマスタード(uracil mustard);ニトロソ尿素、例えばカルムスチン(carmustine)、クロロゾトシン(chlorozotocin)、フォテムスチン(fotemustine)、ロムスチン(lomustine)、ニムスチン(nimustine)、ラニムスチン(ranimustine);抗生物質、例えばエンジイン抗生物質(例えば、カリケアマイシン(calicheamicin)、特にカリケアマイシン ガンマ1Iおよびカリケアマイシン ファイI1;例えば、Agnew,Chem.Intl.Ed.Engl.,33:183−186(1994)を参照されたい);ダイネマイシン(dynemicin)、例えばダイネマイシンA;ビスホスホナート、例えばクロドロナート(clodronate);エスペラマイシン(esperamicin);およびネオカルジノスタチン(neocarzinostatin)発色団および関連色素タンパク質エンジイン抗生物質発色団)、アクラシノマイシン(aclacinomysin)、アクチノマイシン(actinomycin)、オースラマイシン(authramycin)、アザセリン(azaserine)、ブレオマイシン(bleomycin)、カクチノマイシン(cactinomycin)、カラビシン(carabicin)、カルミノマイシン(carminomycin)、カルジノフィリン(carzinophilin)、クロモマイシン(chromomycin)、ダクチノマイシン(dactinomycin)、ダウノルビシン(daunorubicin)、デトルビシン(detorubicin)、6−ジアゾ−5−オキソ−L−ノルロイシン、ドキソルビシン(doxorubicin)(モルホリノ−ドキソルビシン、シアノモルホリノ−ドキソルビシン、2−ピロリノ−ドキソルビシンおよびデオキシドキソルビシンを含む)、エピルビシン(epirubicin)、エソルビシン(esorubicin)、イダルビシン(idarubicin)、マルセロマイシン(marcellomycin)、マイトマイシン(mitomycin)、例えばマイトマイシンC、ミコフェノール酸、ノガラマイシン(nogalamycin)、オリボマイシン(olivomycin)、ペプロマイシン(peplomycin)、ポトフィロマイシン(potfiromycin)、ピューロマイシン(puromycin)、クエラマイシン(quelamycin)、ロドルビシン(rodorubicin)、ストレプトニグリン(streptonigrin)、ストレプトゾシン(streptozocin)、ツベルシジン(tubercidin)、ウベニメックス(ubenimex)、ジノスタチン(zinostatin)、ゾルビシン(zorubicin);代謝拮抗物質、例えばメトトレキセート(methotrexate)および5−フルオロウラシル(5−FU);葉酸類似体、例えばデノプテリン(denopterin)、メトトレキセート(methotrexate)、プテロプテリン(pteropterin)、トリメトレキセート(trimetrexate);プリン類似体、例えばフルダラビン(fludarabine)、6−メルカプトプリン、チアミプリン(thiamiprine)、チオグアニン(thioguanine);ピリミジン類似体、例えばアンシタビン(ancitabine)、アザシチジン(azacitidine)、6−アザウリジン、カルモフール(carmofur)、シタラビン(cytarabine)、ジデオキシウリジン(dideoxyuridine)、ドキシフルリジン(doxifluridine)、エノシタビン(enocitabine)、フロクスリジン(floxuridine);アンドロゲン、例えばカルステロン(calusterone)、ドロモスタノロン(dromostanolone)プロピオナート、エピチオスタノール(epitiostanol)、メピチオスタン(mepitiostane)、テストラクトン(testolactone);抗アドレナール、例えばアミノグルテチミド(aminoglutethimide)、ミトタン(mitotane)、トリロスタン(trilostane);葉酸補充物、例えばフロリン酸(frolinic acid);アセグラトン(aceglatone);アルドホスファミド(aldophosphamide)グリコシド;アミノレブリン酸;エニルウラシル(eniluracil);アムサクリン(amsacrine);ベストラブシル(bestrabucil);ビサントレン(bisantrene);エダトラキセート(edatraxate);デフォファミン(defofamine);デメコルシン(demecolcine);ジアジクオン(diaziquone);エルフォルニチン(elfornithine);酢酸エリプチニウム(elliptinium);エポチロン(epothilone);エトグルシド(etoglucid);硝酸ガリウム;ヒドロキシ尿素;レンチナン(lentinan);ロニダミン(lonidamine);メイタンシノイド、例えばメイタンシン(maytansine)およびアンサミトシン(ansamitocin);ミトグアゾン(mitoguazone);ミトザントロン(mitoxantrone);モピダモール(mopidamol);ニトラクリン(nitracrine);ペントスタチン(pentostatin);フェナメット(phenamet);ピラルビシン(pirarubicin);ロソザントロン(losoxantrone);ポドフィリン酸(podophyllinic acid);2−エチルヒドラジド;プロカルバジン(procarbazine);ラゾキサン(razoxane);リゾキシン(rhizoxin);シゾフラン(sizofuran);スピロゲルマニウム(spirogermanium);テヌアゾン酸(tenuazonic acid);トリアジクオン(triaziquone);2,2’,2’’−トリクロロトリエチルアミン;トリコテセン(trichothecene)(特にT−2毒素、ベルラクリン(verracurin)A)、ロリジン(roridin)Aおよびアングイジン(anguidine);ウレタン;ビンデシン(vindesine);ダカルバジン(dacarbazine);マンノムスチン(mannomustine);ミトブロニトール(mitobronitol);ミトラクトール(mitolactol);ピポブロマン(pipobroman);ガシトシン(gacytosine);アラビノシド(arabinoside)(「Ara−C」);シクロホスファミド(cyclophosphamide);チオテパ(thiotepa);タキソイド、例えばパクリタキセル(paclitaxel)およびドキセタキセル(doxetaxel);クロラムブシル(chlorambucil);ゲムシタビン(gemcitabine);6−チオグアニン;メルカプトプリン(mercaptopurine);メトトレキセート(methotrexate);白金類似体、例えばシスプラチン(cisplatin)およびカルボプラチン(carboplatin);ビンブラスチン(vinblastine);白金;エトポシド(etoposide)(VP−16);イフォスファミド(ifosfamide);マイトマイシンC;ミトザントロン(mitoxantrone);ビンクリスチン(vincristine);ビノレルビン(vinorelbine);ノバントロン(novantrone);テニポシド(teniposide);エダトレキセート(edatrexate);ダウノマイシン(daunomycin);アミノプテリン(aminopterin);キセロダ(xeloda);イバンドロネート(ibandronate);CPT11;トポイソメラーゼインヒビターRFS 2000;ジフルオロメチルオルニチン(difluoromethylornithine)(DMFO);レチノイド、例えばレチノイン酸;カペシタビン(capecitabine);ならびに前記のいずれかのものの医薬上許容される塩、酸または誘導体。また、以下のものも含まれる:腫瘍に対するホルモン作用を調節または抑制するよう作用する抗ホルモン剤、例えば抗エストロゲンおよび選択的エストロゲン受容体モジュレーター(SERM)、例えばタモキシフェン(tamoxifen)、ラロキシフェン(raloxifene)、ドロロキシフェン(droloxifene)、4−ヒドロキシタモキシフェン(hydroxytamoxifen)、トリオキシフェン(trioxifene)、ケオキシフェン(keoxifene)、LY117018、オナプリストン(onapristone)およびトレミフェン(toremifene)(Fareston);副腎内のエストロゲン産生を調節する酵素アロマターゼを阻害するアロマターゼインヒビター、例えば4(5)−イミダゾール、アミノグルテチミド(aminoglutethimide)、酢酸メゲストロール(megestrol
)、エクセメスタン(exemestane)、ホルメスタン(formestane)、ファドロゾール(fadrozole)、ボロゾール(vorozole)、レトロゾール(letrozole)およびアナストロゾール(anastrozole);ならびに抗アンドロゲン、例えばフルタミド(flutamide)、ニルタミド(nilutamide)、ビカルタミド(bicalutamide)、ロイプロリド(leuprolide)およびゴセレリン(goserelin);ならびに前記のいずれかのものの医薬上許容される塩、酸または誘導体。
本明細書中で用いる「増殖(成長)抑制物質」は、細胞、特に、本明細書中で特定されている遺伝子のいずれかを過剰発現する癌細胞の増殖(成長)をインビトロまたはインビボのいずれかで抑制する化合物または組成物を意味する。したがって、増殖抑制物質は、S期において該遺伝子を過剰発現する細胞の比率を有意に減少させるものである。増殖抑制物質の例には、細胞周期の進行を(S期以外の時点で)阻止する物質、例えば、G1停止およびM期停止を誘導する物質が含まれる。古典的なM期ブロッカーには、ビンカ(ビンクリスチン(vincristine)およびビンブラスチン(vinblastine)) タキサン、およびトポIIインヒビター、例えばドキソルビシン(doxorubicin)、エピルビシン(epirubicin)、ダウノルビシン(daunorubicin)およびエトポシド(etoposide)が含まれる。G1を停止する物質、例えばDNAアルキル化剤、例えばダカルバジン(dacarbazine)、メクロレタミン(mechlorethamine)およびシスプラチン(cisplatin)は、S期停止にも及ぶ。更なる情報はThe Molecular Basis of Cancer,MendelsohnおよびIsrael編,Chapter 1,題名“Cell cycle regulation,oncogens,and antineoplastic drugs”,Murakamiら(WB Saunders:Philadelphia,1995)に見出されうる。
抗PD−1抗体または抗体フラグメントは、単独で、または他の抗腫瘍物質もしくは免疫原性物質(例えば、弱毒化癌細胞、腫瘍抗原(組換えタンパク質、ペプチドおよび炭水化物分子を含む))、腫瘍提示細胞、例えば、腫瘍由来抗原もしくは核酸が添加された樹状細胞、免疫刺激性サイトカイン(例えば、IL−2、IFNα2、GM−CSF)および免疫刺激性サイトカイン(限定的なものではないが、例えば、GM−CSF)をコードする遺伝子でトランスフェクトされた細胞、標準的な癌治療(例えば、化学療法、放射線療法または手術)、あるいは他の抗体(限定的なものではないが、VEGF、EGFR、Her2/neu、VEGF受容体、他の増殖因子受容体、CD20、CD40、CD−40L、CTLA−4、OX−40、4−1BBおよびICOSに対する抗体を含む)と組合せて使用されうる。
アンタゴニスト抗PD−1抗体または抗体フラグメントは、感染および感染症を予防または治療するためにも使用されうる。これらの物質を、単独で、またはワクチンと組合せて使用して、病原体、毒素および自己抗原に対する免疫応答を刺激することが可能である。該抗体またはその抗原結合性フラグメントは、ヒトに対して感染性であるウイルス、例えばヒト免疫不全ウイルス、A、BおよびC型肝炎ウイルス、エプスタインバーウイルス、ヒトサイトメガロウイルス、ヒトパピローマウイルスならびにヘルペスウイルス(これらに限定されるものではない)に対する免疫応答を刺激するために使用されうる。アンタゴニスト抗PD−1抗体または抗体フラグメントは、細菌または真菌寄生生物および他の病原体による感染に対する免疫応答を刺激するために使用されうる。このうち、B型およびC型肝炎ならびにHIVによるウイルス感染は、慢性ウイルス感染だとみなされる感染である。
「増量剤」なる語は、該凍結乾燥産物の構造を与える物質を含む。増量剤に使用される一般的な例には、マンニトール、グリシン、ラクトースおよびスクロースが含まれる。医薬上優美なケークを与えることに加えて、増量剤は、崩壊温度の改変、凍結−融解保護の提供、および長期貯蔵にわたるタンパク質安定性の増強に関する有用な品質をも与えうる。これらの物質は等張性改変剤としても働きうる。
製品安定性を評価するのに適した分析方法には、サイズ排除クロマトグラフィー(SEC)、動的光散乱試験(DLS)、示差走査熱量測定(DSC)、iso−asp定量、効力、340nmにおけるUV、UV分光法およびFTIRが含まれる。SEC(J.Pharm.Scien.,83:1645−1650,(1994);Pharm.Res.,11:485(1994);J.Pharm.Bio.Anal.,15:1928(1997);J.Pharm.Bio.Anal.,14:1133−1140(1986))は産物中の単量体の比率を測定し、可溶性凝集物の量の情報を与える。DSC(Pharm.Res.,15:200(1998);Pharm.Res.,9:109(1982))は、タンパク質変性温度およびガラス転移温度の情報を与える。DLS(American Lab.,November(1991))は平均拡散係数を測定し、可溶性および不溶性凝集物の量の情報を与える。340nmにおけるUVは340nmにおける散乱光強度を測定し、可溶性および不溶性凝集物の量に関する情報を与える。UV分光法は278nmにおける吸光度を測定し、タンパク質濃度の情報を与える。FTIR(Eur.J.Pharm.Biopharm.,45:231(1998);Pharm.Res.,12:1250(1995);J.Pharm.Scien.,85:1290(1996);J.Pharm.Scien.,87:1069(1998))はアミドオン領域のIRスペクトルを測定し、タンパク質二次構造の情報を与える。
ヒト化抗体h409A11、h409A16およびh409A17の重鎖および軽鎖の可変領域をコードするDNA構築物はWO2008/156712に記載されている。
本発明の製剤は、還元された場合に又は液体形態で生物学的に活性である抗体およびそのフラグメントを含む。本明細書中で用いる「生物学的に活性」なる語は、所望の抗原エピトープに結合し直接的または間接的に生物学的効果を発揮しうる抗体または抗体フラグメントに関するものである。典型的には、これらの効果は、PD−1がそのリガンドに結合できないことにより生じる。「特異的」なる語は標的抗原エピトープへの該抗体の選択的結合を意味する。抗体は、ある与えられた組合せの条件下でPD−1への結合を無関係な抗原または抗原混合物への結合と比較することにより、結合の特異性に関して試験されうる。
治療用タンパク質の凍結乾燥製剤は幾つかの利点をもたらす。凍結乾燥製剤は一般に、溶液製剤より良好な化学的安定性、したがって増加した半減期をもたらす。凍結乾燥製剤は、投薬または投与の経路のような臨床的要因に応じて、種々の濃度で還元されうる。例えば、凍結乾燥製剤は、皮下投与のために必要に応じて高濃度(すなわち、小容量)で、あるいは静脈内投与の場合にはより低い濃度で還元されうる。また、特定の対象に対しては、特に、注射容量を最小にしなければならない皮下投与の場合には、高濃度が必要かもしれない。1つのそのような凍結乾燥抗体製剤は米国特許第6,267,958号(その全体を参照により本明細書に組み入れることとする)に開示されている。もう1つの治療用タンパク質の凍結乾燥製剤が米国特許第7,247,707号(その全体を参照により本明細書に組み入れることとする)に開示されている。
液体抗体製剤は、薬物(例えば、抗ヒト化PD−1)を取り、精製プロセスの最終工程としてそれを所望のバッファー中にバッファー交換することにより製造されうる。この実施形態においては、凍結乾燥工程は存在しない。最終バッファー中の薬物を所望の濃度まで濃縮する。賦形剤、例えばスクロースおよびポリソルベート80を該薬物に加え、適当なバッファーを使用して、それを最終タンパク質濃度まで希釈する。該最終製剤化薬物を、0.22μm フィルターを使用して濾過し、最終容器(例えば、ガラスバイアル)内に充填する。そのような液体製剤は、10mM ヒスチジン(pH5.5)、7% スクロース、0.02% ポリソルベート80および25mg/mL h409A11を含む最終液体製剤により例示される。
実施例1
抗体の製造
h409A11は、ヒトPD−1に結合しPD−1とそのリガンドPDL1およびPDL2との相互作用を遮断するヒト化モノクローナル抗体である。該抗体は、Fc領域内の安定化S228P配列改変を伴うIgG4/カッパイソタイプである。表2はCDR配列の一覧を示す。グリコシル化を除外すると、該アミノ酸配列に由来する重鎖および軽鎖の理論分子量は、それぞれ49.3kDaおよび23.7kDaである。マウスをhPD−1 DNAで免疫化することにより、親抗体(hPD−1.09A)を製造した。同時係属WO2008/156712に記載されているとおり、CDRグラフティング技術(例えば、米国特許第5,225,539号)を用いて、Medical Research Council(Cambridge,UK)により、該親マウス抗ヒトPD−1抗体のヒト化により、h409A11抗体が製造された。
h409A11は、ヒトPD−1とそのリガンドPD−L1およびPD−L2との相互作用を遮断する高選択性ヒト化モノクローナル抗体である。h409A11は、各重鎖のFcドメイン内のアスパラギン297において異種グリコシル化されていて、付加されたグリカン鎖に応じて典型的には148.9〜149.5kDaの範囲の分子量を示す。h409A11の重鎖および軽鎖のアミノ酸配列は配列番号31および配列番号36に見出される。リーダー配列を伴わない軽鎖は配列番号36のアミノ酸残基20−237を含み、リーダー配列を伴わない重鎖は配列番号31のアミノ酸残基20−466を含む。
ある実施形態においては、安定なヒト化PD−1、例えばh409A11は、凍結条件(温度範囲は典型的には約2〜8℃であるが、ある状況下では、該水性製剤は、約25℃および約40℃を含む他の温度で約12か月間までの期間にわたって安定性を示しうる)下で貯蔵される、10mM ヒスチジンバッファー(pH5.0〜6.0)中の25mg/mL以上の濃度の水溶液である。ある実施形態においては、安定なヒト化PD−1、例えばh409A11は、10mM ヒスチジンバッファー(pH5.0〜6.0)中の約25mg/mLの濃度の水溶液である。該安定製剤(すなわち、薬物)は、典型的には、透明ないしオパール色の溶液であり、粒子を含有しうる。
ヒト化抗PD−1抗体の生物活性を、ヒトPD−1への結合においてPD−L1(PD−1の天然リガンド)と競合するその能力により測定され、参照物質と比較して競合ELISAにおいて定量する。本明細書に記載されている安定製剤は、長期間、例えば少なくとも約18カ月間にわたって生物活性を示す。種々の貯蔵条件下のh409A11の幾つかのバッチの安定性を図1〜9に示す。
抗PD−1抗体の凍結乾燥製剤を以下のとおりに製造する。h409A11抗体の典型的なバッチ製剤を表3に示す。抗体の最終濃度は25mg/mLである。このバッチ製剤は、後記表4に関して記載されているとおり、凍結乾燥された50mg/バイアルの単位を製造するために使用されうる。植物由来のポリソルベート80を使用する。pHを約5.5(±0.2)の所望の値に調節するために、追加的な塩酸または水酸化ナトリウムを加えることが可能である。該成分を無菌注射用水(WFI)で14Lの最終容量にする。表3に一覧されている量の比例的減少により、より小さな対応ロットを製造することが可能である。
ヒト化抗PD−1抗体の凍結乾燥製剤の安定性試験
図1〜9は種々の貯蔵条件下のヒト化抗ヒトPD−1抗体の凍結乾燥製剤の安定性試験のデータを示す。バイアルを直立配置で貯蔵した。後記に更に詳しく記載されているとおり、本発明の製剤は、pH5.5(ヒスチジンバッファー)で凍結乾燥された抗体および類似液体製剤に関しては、少なくとも24カ月間にわたる安定性を示す。
進行充実性腫瘍を有する患者におけるh409A11(抗PD−1モノクローナル抗体)の第1相研究
第1相治験はh409A11の安全性、PK、PDおよび抗腫瘍活性を検査した。標準的な化学療法に治療抵抗性である進行悪性疾患を有する患者において、非盲検・用量増加研究を行った。最初の患者の組合せにおいては、進行充実性腫瘍を有する患者を、本明細書に記載されている安定h409A11製剤で治療した。手術に関する制限/制約は無かったが、患者は現在、手術の候補者ではなかった。3〜6名の患者のコホートを1、3または10mg/kgのIV用量において登録した(3+3の計画)。初期投与および28日間のサイクルの後、患者に2週間ごとに複数用量を投与した。第1相のA部においては、3名の患者を1mg/kgで治療し、3名の患者を3mg/kgで治療し、9名の患者を10mg/kgで治療し、全員に2週間ごとに投与した。患者内用量増加は行わなかった。RECIST 1.1指針を用いて、8週間ごとに放射線評価を行った。
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Claims (15)
- 再構成された場合に、
a)25〜100mg/mLの抗ヒトPD−1抗体、
b)約70mg/mLのスクロース、
c)約0.2mg/mLのポリソルベート80、および
d)pH5.0〜6.0の約10mMのヒスチジンバッファーを含む、抗ヒトPD−1抗体の安定な凍結乾燥医薬製剤であって、該抗体が、
i)配列番号36のアミノ酸残基20〜237を含む軽鎖と、
ii)配列番号31のアミノ酸残基20〜466を含む重鎖を含む、前記凍結乾燥医薬製剤。 - 該抗ヒトPD−1抗体が再構成溶液中に約25mg/mLで存在する、請求項1記載の安定な凍結乾燥医薬製剤。
- 再構成溶液が約5.5のpHを有する、請求項1記載の安定な凍結乾燥医薬製剤。
- 再構成溶液が、25.0mg/mlの抗ヒトPD−1抗体、1.55mg/mlのヒスチジン、0.2mg/mlのポリソルベート80、70mg/mlのスクロースを含み、pH5.5であることを特徴とする、請求項1記載の安定な凍結乾燥医薬製剤。
- 該抗体が、h409A11である、請求項1記載の安定な凍結乾燥医薬製剤。
- a)25〜100mg/mLの抗ヒトPD−1抗体、
b)約70mg/mLのスクロース、
c)約0.2mg/mLのポリソルベート80、および
d)pH5.0〜6.0の約10mMのヒスチジンバッファーを含む、抗ヒトPD−1抗体の安定な液体医薬製剤であって、該抗体が、
i)配列番号36のアミノ酸残基20〜237を含む軽鎖と、
ii)配列番号31のアミノ酸残基20〜466を含む重鎖を含む、安定な液体医薬製剤。 - 10mMのヒスチジン(pH5.5)、7%のスクロース、0.02%のポリソルベート80及び25.0mg/mlの抗ヒトPD−1抗体を含む、請求項6記載の安定な液体医薬製剤。
- 該抗体が、h409A11である、請求項6記載の安定な液体医薬製剤。
- 癌の治療を必要とするヒト対象において癌を治療する方法のための医薬製剤の製造における抗ヒトPD−1抗体の使用であって、該方法は抗ヒトPD−1抗体の安定な医薬製剤の有効量を投与することを含み、当該医薬製剤は、
a)25〜100mg/mLの抗ヒトPD−1抗体、
b)約70mg/mLのスクロース、
c)約0.2mg/mLのポリソルベート80、および
d)pH5.0〜6.0の約10mMのヒスチジンバッファーを含み、該抗体が、
i)配列番号36のアミノ酸残基20〜237を含む軽鎖と、
ii)配列番号31のアミノ酸残基20〜466を含む重鎖を含み、
前記安定な医薬製剤は、凍結乾燥医薬製剤から再構成されるか、または、予め凍結乾燥されていない液体医薬製剤であることを特徴とする、前記使用。 - 前記有効量が、治療の経過にわたって約14日または約21日の間隔で投与される約1.0、3.0および10.0mg/kgからなる群から選択される用量を含む、請求項9記載の使用。
- 前記有効量が、治療の経過にわたって2週間または3週間ごとの間隔で投与される5.0または10.0mg/kgの用量を含む、請求項9記載の使用。
- 該対象がメラノーマに罹患しており、前記有効量が、治療の経過にわたって3週間ごとの間隔で投与される3.0mg/kgの用量を含む、請求項9記載の使用。
- 対象が治療未経験である、請求項9記載の使用。
- 該医薬製剤が30分間の静脈内注射によって投与される、請求項9記載の使用。
- 該対象がメラノーマに罹患している、請求項9記載の使用。
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