JP6842926B2 - Il−15ベース分子及びその使用方法 - Google Patents
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Description
本出願は、2014年6月30日に出願された米国特許仮出願第62/018,899号の35U.S.C.§119(e)に基づく優先権の恩典を主張する。この仮出願は、引用によりその全体が本明細書に組み込まれる。
本発明は、一般に、癌及び感染性因子の処置のための治療薬の分野に関する。
(1)被験体の新生物又は感染を処置するための方法であって、前記被験体に有効量の抗体又は抗体様分子と、IL−15N72D:IL−15RαSu/Fc複合体(ALT−803)を含む有効量の医薬組成物とを投与し、ここで、前記ALT−803は、ダイマー型IL−15RαSu/Fcと2分子のIL−15N72Dを含むものであり、それにより、該新生物又は感染を処置すること、を含む方法。
(2)IL−15N72D分子が配列番号3を含むものである、前記(1)に記載の方法。
(3)IL−15RαSu/Fcが配列番号6を含むものである、前記(1)に記載の方法。
(4)新生物が、膠芽腫、前立腺癌、造血器の癌、B細胞腫瘍、多発性骨髄腫、B細胞リンパ腫、ホジキンリンパ腫、慢性リンパ性白血病、急性骨髄性白血病、皮膚T細胞リンパ腫、T細胞リンパ腫、固形腫瘍、尿路上皮/膀胱癌、黒色腫、肺癌、腎細胞癌、乳癌、胃及び食道の癌、頭頸部癌、結腸直腸癌、卵巣癌、非小細胞肺癌、B細胞性非ホジキンリンパ腫、並びに頭頸部扁平上皮癌からなる群より選択される、前記(1)に記載の方法。
(5)感染が、ヒト免疫不全ウイルス(HIV)によるウイルス感染である、前記(1)に記載の方法。
(6)有効量の前記ALT−803を毎日投与する、前記(1)に記載の方法。
(7)前記ALT−803の有効量が0.1μg/kg〜100mg/kgである、前記(6)に記載の方法。
(8)有効量の前記ALT−803が1週間に1回又は2回投与される、前記(1)に記載の方法。
(9)前記ALT−803の有効量が0.1μg/kg〜1mg/kgである、前記(8)に記載の方法。
(10)該医薬組成物を全身、静脈内、皮下、筋肉内、膀胱内投与するか、又は点滴によって投与する、前記(1)に記載の方法。
(11)前記抗体が腫瘍特異的抗体又は抗ウイルス抗体である、前記(1)に記載の方法。
(12)前記抗体が免疫チェックポイント阻害薬である、前記(1)に記載の方法。
(13)前記抗体が、抗gp75抗体、抗CD20抗体、抗HER2抗体、抗EGFR抗体、抗細胞傷害性Tリンパ球抗原4(CTLA−4)抗体、抗プログラム細胞死−1(PD−1)抗体、抗プログラム細胞死−リガンド1(PD−L1)抗体又は抗プログラム細胞死−リガンド2(PD−L2)抗体を含む、前記(1)に記載の方法。
(14)前記被験体の腫瘍細胞又は感染細胞に対する前記抗体によって媒介される抗体依存性細胞媒介性細胞傷害(ADCC)又は抗体依存性細胞食作用(ADCP)が、前記投与後、少なくとも5%増大する、前記(11)に記載の方法。
(15)前記抗体と前記ALT−803により、血中のNK細胞、T細胞、好中球又は単球のカウント数又は活性のレベルが増大する、前記(1)に記載の方法。
(16)前記抗体と前記ALT−803がCD4+又はCD8+ T細胞を刺激して腫瘍細胞又は感染細胞を死滅させる、前記(1)に記載の方法。
(17)前記抗体と前記ALT−803がNK細胞を刺激して腫瘍細胞又は感染細胞を死滅させる、前記(1)に記載の方法。
(18)前記抗体と前記ALT−803が好中球又は単核球細胞を刺激して腫瘍細胞又は感染細胞を死滅させる、前記(1)に記載の方法。
(19)前記投与により腫瘍細胞又は感染細胞の数の減少がもたらされる、前記(1)に記載の方法。
(20)前記投与により新生物又は感染の疾患進行の低減がもたらされる、前記(1)に記載の方法。
(21)前記投与により、未処置の被験体と比べて前記被験体の生存期間の長期化がもたらされる、前記(1)に記載の方法。
(22)前記被験体がヒトである、前記(1)に記載の方法。
(23)前記抗体と前記ALT−803が同時又は逐次投与される、前記(1)に記載の方法。
(24)前記投与により前記新生物又は感染の将来の再発が予防される、前記(1)に記載の方法。
(25)新生物の処置のためのキットであって、有効量のALT−803、抗体、及び新生物の処置のための該キットの使用説明書を備えているキット。
(26)ウイルスの処置のためのキットであって、有効量のALT−803、抗体、及びウイルスの処置のための該キットの使用説明書を備えているキット。
(27)標的抗原を発現している疾患細胞を死滅させるための方法であって:免疫細胞を有効量のIL−15N72D:IL−15RαSu/Fc複合体(ALT−803)で処理すること、ALT−803処理した該免疫細胞を、該標的抗原に特異的な抗体及び前記標的抗原を発現している疾患細胞と混合すること、該疾患細胞を、ALT−803処理した該免疫細胞と該標的抗原特異的抗体によって媒介されるADCC又はADCPによって死滅させること、を含む方法。
(28)疾患細胞の死滅レベルが、ALT−803で処理しなかった免疫細胞によって媒介されるレベルと比べて少なくとも5%増大する、前記(27)に記載の方法。
(29)前記抗体と前記ALT−803により血中サイトカインレベルが増大する、前記(1)に記載の方法。
(30)前記サイトカインがIFN−γ及び/又はIL−6を含む、前記(29)に記載の方法。
本発明の他の特色及び利点は、その好ましい実施形態の以下の説明及び特許請求の範囲から自明となろう。特に定義していない限り、本明細書で用いる科学技術用語はすべて、本発明が属する技術分野の当業者に一般的に理解されているものと同じ意味を有する。本明細書に記載のものと同様又は同等の方法及び材料が本発明の実施又は試験において使用され得るが、好適な方法及び材料を以下に記載する。本明細書で挙げた外国の公開特許及び特許出願はすべて、引用により本明細書に組み込まれる。本明細書に記載した受託番号によって示されるGenbank及びNCBIの寄託物は引用により本明細書に組み込まれる。本明細書で挙げた他の既刊の参考文献、文献、手稿及び科学文献はすべて、引用により本明細書に組み込まれる。矛盾する場合は、本明細書(定義を含む)に支配される。また、材料、方法及び実施例は実例にすぎず、限定を意図するものではない。
ALT−803は、IL−2Rβγに対する増大した結合能及び増強された生物活性を有するIL−15変異型を含むものである(米国特許第8,507,222号,引用により本明細書に組み込まれる)。IL−15のこのスーパーアゴニスト変異型は刊行物(J Immunol 2009 183:3598)に報告され、米国特許庁により該スーパーアゴニストに対する特許が発行されており、いくつかの特許出願が係属中である(例えば、米国特許出願第12/151,980号及び同第13/238,925号)。このIL−15スーパーアゴニストを可溶性IL−15α受容体融合タンパク質(IL−15RαSu/Fc)と組み合わせると、インビトロ及びインビボで非常に強力なIL−15活性を有するタンパク質複合体がもたらされる(Han et al.,2011,Cytokine,56:804−810;Xu,et al.,2013 Cancer Res.73:3075−86,Wong,et al.,2013,OncoImmunology 2:e26442)。このIL−15スーパーアゴニスト複合体(IL−15N72D:IL−15RαSu/Fc)はALT−803と称される。薬物動態解析により、該複合体は、マウスにおいてi.v.投与後25時間の半減期を有することが示された。ALT−803は、免疫適格マウスの侵襲性の固形腫瘍モデル及び造血器腫瘍モデルに対して見事な抗腫瘍活性を示す。これは、単独療法として週2回又は毎週のi.v.投薬レジメンを用いて投与してもよく、抗体との併用療法薬として投与してもよい。また、ALT−803の抗腫瘍応答は永続的である。また、ALT−803での処置後に治癒した腫瘍担持マウスは、同じ腫瘍細胞での再負荷刺激に対して高度に耐性であり、ALT−803が、再導入された腫瘍細胞に対して有効な免疫学的記憶応答を誘導することが示された。
インターロイキン−15(IL−15)は、エフェクターNK細胞及びCD8+記憶T細胞の発生、増殖及び活性化のための重要なサイトカインである。IL−15はIL−15受容体α(IL−15Rα)に結合し、エフェクター細胞上のIL−2/IL−15受容体β−共通γ鎖(IL−15Rβγc)複合体に対してトランス型で提示される。IL−15とIL−2はIL−15Rβγcに対する結合を共有しており、STAT3経路及びSTAT5経路を介してシグナル伝達する。しかしながら、IL−2はまた、CD4+CD25+FoxP3+ 制御性T(Treg)細胞の維持も補助し、活性化CD8+ T細胞の細胞死を誘導する。このような効果は、腫瘍に対するIL−2の治療活性を制限し得る。IL−15は、このような免疫抑制活性をIL−2と共有していない。さらに、IL−15は、エフェクターCD8+ T細胞に抗アポトーシスシグナル伝達をもたらすことが知られている唯一のサイトカインである。IL−15は単独又はIL−15Rαとの複合体のいずれかで投与すると、実験動物モデルにおいて、充分に確立された固形腫瘍に対して強力な抗腫瘍活性を示し、したがって、潜在的に癌を治癒し得る将来最も有望な免疫療法薬の1つであると認定されている。
ALT−803は、IL−15N72D:IL−15RαSu/Fc融合複合体を含むものである。IgGのFc領域と別のタンパク質(種々のサイトカイン及び可溶性受容体など)のドメインを合わせた融合タンパク質が報告されている(例えば、Capon et al.,Nature,337:525−531,1989;Chamow et al.,Trends Biotechnol.,14:52−60,1996);米国特許第5,116,964号及び同第5,541,087号を参照のこと)。このプロトタイプの融合タンパク質は、IgG Fcのヒンジ領域内のシステイン残基によって連結され、重鎖の可変ドメインとCH1ドメイン及び軽鎖がないIgG分子と同様の分子になっているホモダイマータンパク質である。Fcドメインを含む融合タンパク質のダイマー型の性質は、他の分子との高次相互作用(すなわち、二価結合又は二重特異性結合)をもたらすのに好都合であり得る。構造的相同性のため、Fc融合タンパク質は、同様のアイソタイプを有するヒトIgGのものと同等のインビボ薬物動態プロフィールを示す。免疫グロブリンの中でもIgGクラスは、ヒト血液中に最も多いタンパク質であり、その循環半減期は21日間という長いものであり得る。IL−15若しくはIL−15融合タンパク質の循環半減期を長くするため、及び/又はその生物活性を高めるため、ヒト重鎖IgGタンパク質のFc部分と共有結合させたIL−15RαSuと非共有結合させたIL−15ドメインを含有する融合タンパク質複合体が作製された(例えば、ALT−803)。
本発明によりALT−803を提供し、これはIL−15N72DとIL−15RαSu/Fc間のタンパク質複合体である。一部の特定の実施形態では、ALT−803ポリペプチドは、他のタンパク質ドメインとの融合のための骨格としての機能を果たし得る。かかる融合タンパク質複合体では、第1の融合タンパク質が、インターロイキン−15(IL−15)又はその機能性断片と共有結合させた第1の生物活性ポリペプチドを含むものであり;第2の融合タンパク質が、可溶性インターロイキン−15受容体アルファ(IL−15Rα)ポリペプチド又はその機能性断片と共有結合させた第2の生物活性ポリペプチドを含むものであり、第1の融合タンパク質のIL−15ドメインを第2の融合タンパク質の可溶性IL−15Rαドメインと結合させて可溶性融合タンパク質複合体が形成されている。また、本発明の融合タンパク質複合体は、第1及び第2の融合タンパク質の一方又は両方と連結させた免疫グロブリンのFcドメイン又はその機能性断片も含んでいる。好ましくは、第1と第2の融合タンパク質と連結させたFcドメインが相互作用して融合タンパク質複合体を形成したものである。かかる複合体は、免疫グロブリンのFcドメイン間でのジスルフィド結合の形成によって安定化され得る。一部の特定の実施形態では、本発明の可溶性融合タンパク質複合体は、IL−15ポリペプチド、IL−15変異体又はその機能性断片と可溶性IL−15Rαポリペプチド又はその機能性断片を含み、IL−15及びIL−15Rαポリペプチドの一方又は両方がさらに、免疫グロブリンFcドメイン又はその機能性断片を含むものである。
本発明により、治療薬としての使用のためのALT−803を含む医薬組成物を提供する。一態様において、ALT−803は、例えば、薬学的に許容され得るバッファー、例えば生理食塩水で製剤化して全身投与される。好ましい投与経路としては、例えば、連続的持続レベルの該組成物を患者にもたらす膀胱内への点滴、皮下、静脈内、腹腔内、筋肉内又は皮内注射が挙げられる。ヒト患者又は他の動物の処置は、治療有効量の本明細書において確認される治療薬を生理学的に許容され得る担体に含めて用いて行われる。好適な担体及びその製剤は、例えば、E.W.MartinによるRemington’s Pharmaceutical Sciencesに記載されている。投与される治療用薬剤の量は、投与様式、患者の年齢及び体重、並びに新生物又は感染の臨床症状に応じて異なる。一般的に、該量は、新生物又は感染と関連している他の疾患の処置に使用される他の薬剤で使用されるものの範囲内であるが、一部の特定の場合では、該化合物の高い特異性のため、必要とされる量はより少ない。該化合物は、被験体の免疫応答を増強させる投薬量で、又は当業者に知られた方法によって測定される新生物細胞の増殖、生存若しくは浸潤性が低減される投薬量で投与される。或いはまた、該化合物は、対象のウイルス又は他の病原体による感染が低減される投薬量で投与される。
新生物又は感染の処置ためのALT−803の投与は、他の成分と併せて新生物又は感染の改善、低減又は安定化に有効な濃度の該治療薬がもたらされる任意の適切な手段によるものであり得る。ALT−803は、任意の適切な量で任意の適切な担体物質中に含有され得、一般的に、組成物の総重量の1〜95重量%の量で存在させる。該組成物は、非経口(例えば、皮下、静脈内、筋肉内、膀胱内又は腹腔内)投与経路に適した投薬形態で提供され得る。医薬組成物は慣用的な製薬実務に従って製剤化され得る(例えば、Remington:The Science and Practice of Pharmacy(第20版),A.R.Gennaro編,Lippincott Williams&Wilkins,2000並びにEncyclopedia of Pharmaceutical Technology,J.Swarbrick及びJ.C.Boylan編,1988−1999,Marcel Dekker,New Yorkを参照のこと)。
ALT−803を含む医薬組成物は、注射、輸注又は埋込み(皮下、静脈内、筋肉内、膀胱内、腹腔内など)により、慣用的な無毒性の薬学的に許容され得る担体及びアジュバントを含有している投薬形態、製剤で、又は適切な送達デバイス若しくは埋入物によって非経口投与され得る。かかる組成物の製剤化及び調製は医薬品製剤化の当業者によく知られている。製剤化は、Remington:The Science and Practice of Pharmacy(上掲)において知得され得る。
好ましくは、ALT−803は、抗新生物治療薬又は抗感染治療薬、例えば抗体、例えば、腫瘍特異的抗体又は免疫チェックポイント阻害薬と併用して投与される。抗体とALT−803は同時に投与しても逐次投与してもよい。一部の実施形態では、抗体での処置は該疾患の適応症に確立された治療であり、この抗体レジメンにALT−803での処置を加えることにより、患者に対する治療上の有益性が改善される。かかる改善は、個々の患者ベースでの応答の増大又は患者集団における応答の増大として測定され得る。また、併用療法により、より低用量又はより低頻度での用量の抗体で改善された応答がもたらされ、耐容性がより良好な処置レジメンがもたらされ得る。記載のように、ALT−803と抗体の併用療法により、種々の機構、例えば、ADCC、ADCP及び/又はNK細胞、T細胞、好中球若しくは単核球細胞レベル或いは免疫応答の増大によって臨床的活性の増強がもたらされ得る。
ALT−803を含む医薬組成物を新生物又は感染の処置における使用のためのキット又は医薬品システムに一体化してもよい。本発明のこの態様によるキット又は医薬品システムは、内部に1つ以上の容器、例えばバイアル、チューブ、アンプル、ボトル、シリンジ又はバッグが密封されている持ち運び手段、例えば、ボックス、カートン、チューブを備えたものである。また、本発明のキット又は医薬品システムは、ALT−803の使用のための使用説明書を付随して備えていてもよい。
一般に、本発明の融合タンパク質複合体(例えば、ALT−803の成分)の調製は、本明細書に開示した手順及び認知されている組換えDNA手法によって行われ得る。
本発明により、さらに、本発明のタンパク質(例えば、ALT−803の成分)をコードしている核酸配列、特にDNA配列を提供する。好ましくは、該DNA配列を、染色体外複製に適合させたベクター、例えば、ファージ、ウイルス、プラスミド、ファージミド、コスミド、YAC又はエピソームに担持させる。特に、所望の融合タンパク質をコードしているDNAベクターは、本明細書に記載の調製方法を容易にするため、及び有意な量の融合タンパク質を得るために使用され得る。該DNA配列を適切な発現ベクターに、すなわち、挿入したタンパク質コード配列の転写及び翻訳のために必要なエレメントを含むベクターに挿入してもよい。さまざまな宿主−ベクター系が、タンパク質コード配列を発現させるために使用され得る。このようなものとしては、ウイルス(例えば、ワクシニアウイルス、アデノウイルスなど)に感染させた哺乳動物細胞系;ウイルス(例えば、バキュロウイルス)に感染させた昆虫細胞系;微生物、例えば、酵母ベクターを含有している酵母、又はバクテリオファージDNA、プラスミドDNA若しくはコスミドDNAで形質転換した細菌が挙げられる。使用される宿主−ベクター系に応じて、いくつかの適切な転写エレメント及び翻訳エレメントのうちのいずれか1つが使用され得る。Sambrook et al.(上掲)及びAusubel et al.(上掲)を参照のこと。
ALT−803を発現させるために、いくつかのストラテジーが使用され得る。例えば、ALT−803をコードしている構築物が適切なベクター内に、該ベクター内に該構築物を挿入した後、ライゲーションするための切断部を作製するための制限酵素を用いて組み込まれ得る。遺伝子構築物を含有しているベクターは次いで、融合タンパク質の発現のために適切な宿主内に導入される。一般的には、Sambrook et al.(上掲)を参照のこと。好適なベクターの選択は、クローニングプロトコルに関連する要素に基づいて経験的に行われ得る。例えば、ベクターは、使用される宿主と適合性でであり、適正なレプリコンを有するものであるのがよい。ベクターは、発現させる融合タンパク質複合体をコードしているDNA配列に適応できるものでなければならない。好適な宿主細胞としては、真核生物細胞及び原核生物細胞、好ましくは、容易に形質転換され得、培養培地中で急速な増殖を示し得る細胞が挙げられる。具体的には、好ましい宿主細胞としては、例えば大腸菌、枯草菌などの原核生物、及び動物細胞及び酵母株、例えば出芽酵母などの真核生物が挙げられる。哺乳動物細胞、特に、J558、NSO、SP2−O又はCHOが一般的に好ましい。他の適切な宿主としては、例えばSf9などの昆虫細胞が挙げられる。慣用的な培養条件が使用される。Sambrook(上掲)を参照のこと。安定な形質転換細胞株又はトランスフェクト細胞株が次いで、選択され得る。本発明の融合タンパク質複合体を発現している細胞は、既知の手順によって判定され得る。例えば、免疫グロブリンと連結させた融合タンパク質複合体の発現は、連結させた免疫グロブリンに特異的なELISA及び/又はイムノブロッティングによって調べることができる。IL−15又はIL−15Rαドメインと連結させた生物活性ポリペプチドを含む融合タンパク質の発現を検出するための他の方法は本実施例に開示している。
正常個体由来のヒト血液バフィーコートを使用し、Histopaque−1077を用いて末梢血単核球(PBMC)を単離した。PBMCを、37℃で5%CO2にてRPMI−10培地(RPMI−1640,2−メルカプトエタノール,ペニシリン−ストレプトマイシン−グルタミン,非必須アミノ酸、ピルビン酸ナトリウム及び10%ウシ胎仔血清)中で、種々の量のALT−803とともに培養した。「ALT−803」により、ダイマー型IL−15RαSu/Fc融合タンパク質と非共有結合により結合しているIL−15N72Dを含むものである複合体を意図し、ここで、前記複合体は免疫賦活活性を示すものである。任意選択で、IL−15N72D及び/又はIL−15RαSu/Fc融合タンパク質は、参照配列と比べて1、2、3、4つ、又はそれ以上のアミノ酸変異を含むものである。例示的なIL−15N72Dアミノ酸配列を以下に示す(例えば、米国特許出願第13/769,179号(引用により本明細書に組み込まれる)を参照のこと)。
(リーダーペプチド)
(リーダーペプチド)
(IL−15N72D)
(リーダーペプチド)
(リーダーペプチド)
(IL−15RαSu)
ALT−803が細胞媒介性細胞傷害に影響を及ぼすかどうかを評価するため、血液バフィーコート由来のヒト単離PBMCをエフェクター細胞として使用した。DaudiヒトB細胞リンパ腫細胞及びK562ヒト骨髄性白血病細胞を標的細胞として使用し、RPMI−10中5μMのCelltrace Violetで37℃にて20分間、製造業者による説明のとおりに標識した。エフェクター細胞をバイオレット標識標的細胞と混合し、37℃で5%CO2にてRPMI−10中、ALT−803とともに又はなしで、表示した期間インキュベートした。一部の実験では、Daudi細胞の表面上に発現されるCD20に特異的な抗CD20 Ab(リツキシマブ,10nM)を、エフェクター:Daudi細胞培養液に添加し、抗CD20 Ab媒介性抗体依存性細胞傷害(ADCC)に対するALT−803の効果を調べた。エフェクター細胞と標的細胞の混合物を遠心分離によって収集し、フェノールレッドなしで2μg/mlのヨウ化プロピジウムを含めたRPMI−10中に再懸濁させた。標的細胞に対するエフェクター細胞の細胞傷害性をフローサイトメトリーによって、ヨウ化プロピジウム陽性染色後の死滅したバイオレット標識標的細胞のパーセンテージを調べることにより評価した。
ALT−803が抗CD20 mAbの抗腫瘍活性を増大させる能力を、Daudi腫瘍を担持させたSCIDマウスにおいてさらに評価した。このマウスは、おそらく腫瘍に対するADCC応答を媒介する機能性のNK細胞を有している。この試験のため、Fox Chase SCID雌マウス(Harlan,C.B−17/IcrHsd−Prkdc−scid:6週齢)にDaudi細胞(10×106/マウス)(3マウス/群)を静脈内(i.v.)移植した。腫瘍担持マウスをPBS、ALT−803(0.2mg/kg)、リツキシマブ(10mg/kg)又はALT−803(0.2mg/kg)+リツキシマブ(10mg/kg)で、腫瘍移植後15日目及びその3日後にi.v.処置した。2回目の処置の4日後にマウスを致死させ、骨髄中のDaudi細胞レベルを調べた。大腿骨の骨髄細胞のうちのDaudi細胞のパーセンテージを、PEコンジュゲート抗ヒトHLA−DR抗体(Biolegend)での染色及びフローサイトメトリー分析後に評価した。図10に示す結果は、ALT−803及び抗CD20 mAbの単独療法で、腫瘍担持マウスの骨髄中のDaudi細胞のパーセンテージが低減され得ることを示す。しかしながら、ALT−803+抗CD20 mAbの併用で最も大きな抗腫瘍活性がもたらされ、骨髄のDaudi細胞は、対照マウスにおける38%からALT−803+リツキシマブ処置マウスにおける5%まで低減された。このモデルでの用量応答試験により、0.02mg/kgという少ないALT−803で抗CD20 mAbの抗腫瘍活性が増大され得ることが確認された(図11)。
免疫チェックポイントブロッカー、例えば、CTLA−4、PD−1、PD−L1、PD−L2、B7−H3、B7−H4、LAG−3、BTLA、TIM−3、VISTA、IDO、A2aR、HVEM、KIRs、NKG2A、NKG2D、CEACAM−1、2B4、CD200R及びそのリガンド並びに本明細書に記載の他の標的に対する抗体により、免疫抑制シグナルを阻害することによって免疫応答を向上させることが可能であり得る。上記のように、ALT−803は、NK細胞とT細胞の増殖及び活性を向上させる免疫賦活分子である。しかしながら、その有効性は、阻害性チェックポイント及び免疫応答を減弱させ得る経路によって制限される場合があり得る。このような負の調節因子を排除してALT−803の活性を増強させるストラテジーにより、治療上の有益性がもたらされ得よう。
動物におけるALT−803の安全性プロフィール及び治療指数を評価するため、並びに安全で有効なヒト用量を推定するため、反復用量のALT−803での処置の毒性試験をマウスとカニクイザルにおいて行った。C57BL/6Nマウス(10匹のマウス/性別/群)に0.1、1.0又は4.0mg/kgのALT−803又はPBSを尾静脈から、毎週、連続4週間投与した。最後の注射の4日後(26日目)、身体検査、血液化学検査、血液検査、肉眼検死、体重及び器官重量の測定並びに組織病理検査を含む評価を行った(5匹のマウス/性別/群)。最後の処置の14日後(36日目)、残ったマウスに対して同様の評価を行った。第2の試験において、C57BL/6Nマウス(15匹のマウス/性別/群)を0.1又は1.0mg/kgのALT−803又はPBSの4回の毎週のi.v.注射で処置した。上記のような毒性評価を、最後の注射の4日後(26日目)(10匹のマウス/性別/群)又は4週間後(50日目)(5匹のマウス/性別/群)に行った。
優良試験所基準(Good Laboratory Practice)の規定の下、ALT−803の反復用量のi.v.投与の効果を評価するための試験をカニクイザルにおいて行った。動物(5匹のサル/性別/群)を毎週、連続4週間(1、8、15及び22日目)、0.03若しくは0.1mg/kgのALT−803で処置するか、又はPBSを約3分間のi.v.注射で投与した。試験中の生存期間を通して、動物を、臨床観察結果及び行動の観察結果、食料消費、体重、心臓及び目の機能について評価した。血液検査、化学的評価及び凝固評価(投与前並びに投与後5、26及び36日目)並びに免疫細胞分析のために採血した。免疫原性試験のために血清を得、定量的酵素結合イムノソルベントアッセイ(ELISA)方法を用いてPK解析を行った。尿検査のために採尿した(投与前並びに4、25及び35日目)。身体検査、肉眼検死、器官重量測定及び組織病理検査を含む臨床病理学評価を、最後の注射の4日後(26日目)(3匹の動物/性別/群)及び2週間後(36日目)(2匹の動物/性別/群)に行った。
組換えヒトIL−15(rhIL−15)製剤品を用いた進行中の治験で得られているデータは、高Cmax並びに耐容性に影響を及ぼす二次サイトカイン放出(IL−6及びIFN−γ)が誘導されるため、静脈内投与はIL−15に最適でなく、したがって限定的と思われることを示唆している。IL−2を用いた前臨床試験及び臨床試験では、皮下投与の方が安全であり、ずっと良好な耐容性がもたらされることが示されている。例えば、Waldmann及び同僚らは、連続12日間の毎日の静脈内ボーラス輸注を用いて、ヒトにおけるrhIL−15の最初の固形腫瘍での治験を実施した(Conlon et al.,2015.J.Clin.Oncol.,33:74−82)。3.0及び1.0μg/kg/日のコホートで観察された用量制限毒性は、グレード3の低血圧症、血小板減少症、及びアラニントランスアミナーゼ(ALT)とアスパラギン酸トランスアミナーゼ(AST)の上昇であった。最大耐用量(MTD)は0.3μg/kg/日と示された。静脈内投与での同じ用量レベルと比べたときのCmaxの低下、及びrIL−15製剤品のより持続的な循環レベルの結果、皮下投与での耐容性の増大が予想される。Cmaxが低下すると、全体的により多くの薬物送達が可能になる。
実施例4に記載の試験に加え、ALT−803と免疫チェックポイントブロッカーとの併用の抗腫瘍活性を、同所性MB49luc膀胱腫瘍を担持しているマウスにおいて評価した。C57BL/6マウス(n=6/群)に、ポリリシンで膀胱を前処置した後、試験の0日目にMB49luc細胞(3×104個の細胞/膀胱)を膀胱内点滴した。PBS、ALT−803(0.2mg/kg,i.v.)又はALT−803(0.2mg/kg)+抗PD−L1及び抗CTLA4 Ab(各々、100μg/注射,i.p.で)を、MB49luc腫瘍細胞の点滴後、7、10、14及び17日目に投与した。マウスを、有効性エンドポイントとしての処置群間生存率を評価するために維持した。ALT−803での処置により、MB49luc担持マウスの生存期間がPBSと比べて有意に長くなった(図19A)。しかしながら、ALT−803と抗PD−L1及び抗CTLA4 Abとの併用では、単独療法の対照と比べて生存期間がさらに長くなった。この効果は、ALT−803+抗PD1及びALT−803+抗PD1/抗CTLA4 mAbの併用療法でもみられた(図19B)。
同系C57BL/6マウスの皮下B16F10黒色腫腫瘍モデルを使用し、固形腫瘍に対するALT−803+腫瘍抗原特異的治療用抗体の有効性をさらに評価した。また、このモデルは、確立された腫瘍及び再腫瘍負荷刺激に対するT細胞及び他の免疫細胞の活性も評価されるという利点を有する。標的療法のための重要な黒色腫特異的抗原の一例は、メラノソームにおけるメラニン合成に関与している75kDaのタンパク質であるgp75(TYRP−1,チロシナーゼ関連タンパク質−1)である(Kobayashi T,et al.1994.EMBO J.13:5818−25)。TA99(マウスIgG2a)は、ヒト及びマウスgp75に特異的なモノクローナル抗体(mAb)である(Thomson TM,et al.1985.J Invest Dermatol.85:169−74)。この抗体での処置により、同系マウスのマウス皮下B16F10黒色腫が、抗体依存性細胞傷害(ADCC)の活性化によって有効に排除される(Hara I,et al.1995.J Exp Med.182:1609−14)。
免疫細胞に対する処置の効果を、B16F10黒色腫腫瘍を担持しているマウスから投与治療の3日後に収集した脾細胞及び腫瘍浸潤白血球(TIL)において調べた。ALT−803投与後、PBS対照と比べて、CD8+ T細胞集団及びNK細胞集団の増加、並びにCD4+ T細胞集団、B細胞集団及びマクロファージ集団の減少がみられた(図22A及び図22B)。予測通り、TA99では、腫瘍関連マクロファージの少量の低減が引き起こされたこと以外、免疫細胞サブセットのパーセンテージは脾細胞又はTILのいずれにおいても変化しなかった。ALT−803/TA99併用では、免疫細胞集団においてALT−803単独と同様の変化が示された。ALT−803は、単独又はTA99との併用で、脾細胞とTILの両方のデータによって裏付けられるように、CD8+ T細胞の記憶表現型(CD44high)の有意な増加をもたらした(図22C及び図22D)。TILのCD8+CD44high T細胞集団のベースラインは脾臓のこの細胞集団よりも2倍多いため、記憶CD8+ T細胞のALT−803媒介性増殖は、TILではあまり目立たなかった(1.2倍,p<0.01に対して脾臓では2.5倍,p<0.001)。TA99では、TILにおける記憶CD8+ T細胞のパーセンテージがわずかに低下し(p<0.05)、おそらく、より多くのエフェクターCD8+ T細胞が、黒色腫に対する抗体依存性免疫に関与するよう推進されたためである。
ALT−803は、悪性腫瘍を有する患者において、以下のとおりに評価中である。
本発明を、その詳細説明に関して説明したが、前述の説明は、実例を示すことを意図したものであって、本発明の範囲を限定することを意図したものではなく、本発明は、添付の特許請求の範囲の範囲によって規定される。他の態様、利点及び変形例は以下の特許請求の範囲の範囲に含まれる。
Claims (24)
- 有効量の抗体又は抗体様分子と、有効量のIL−15N72D:IL−15RαSu/Fc複合体(ALT−803)とを組み合わせたことを特徴とし、
該抗体は、腫瘍特異的抗体であり、
該ALT−803は、ダイマー型IL−15RαSu/Fcと2分子のIL−15N72Dを含むものである、
被験体の新生物を治療するための医薬。 - IL−15N72D分子が、配列番号3で表されるアミノ酸配列を含むものである、請求項1に記載の医薬。
- IL−15RαSu/Fcが、配列番号6で表されるアミノ酸配列を含むものである、請求項1又は2に記載の医薬。
- 新生物が、膠芽腫、前立腺癌、造血器の癌、B細胞腫瘍、多発性骨髄腫、B細胞リンパ腫、ホジキンリンパ腫、慢性リンパ性白血病、急性骨髄性白血病、皮膚T細胞リンパ腫、T細胞リンパ腫、固形腫瘍、尿路上皮/膀胱癌、黒色腫、肺癌、腎細胞癌、乳癌、胃及び食道の癌、頭頸部癌、結腸直腸癌、卵巣癌、非小細胞肺癌、B細胞性非ホジキンリンパ腫、並びに頭頸部扁平上皮癌からなる群より選択される、請求項1〜3の何れか一項に記載の医薬。
- 有効量の前記ALT−803が、毎日投与されるように用いられることを特徴とする、請求項1〜4の何れか一項に記載の医薬。
- 前記ALT−803の有効量が、0.1μg/kg〜100mg/kgである、請求項5に記載の医薬。
- 有効量の前記ALT−803が、1週間に1回又は2回投与されるように用いられることを特徴とする、請求項1〜4の何れか一項に記載の医薬。
- 前記ALT−803の有効量が、0.1μg/kg〜1mg/kgである、請求項7に記載の医薬。
- 有効量の前記ALT−803が、全身、静脈内、皮下、筋肉内、膀胱内投与、又は点滴によって投与されるように用いられることを特徴とする、請求項1〜8の何れか一項に記載の医薬。
- 前記抗体が、抗CD20抗体、抗HER2抗体又は抗EGFR抗体を含む、請求項1〜9の何れか一項に記載の医薬。
- 腫瘍特異的抗体が、リツキシマブである、請求項1〜9の何れか一項に記載の医薬。
- 前記抗体によって媒介される前記被験体の腫瘍細胞に対する抗体依存性細胞媒介性細胞傷害(ADCC)又は抗体依存性細胞食作用(ADCP)が、少なくとも5%増大する、請求項10又は11に記載の医薬。
- 前記抗体と前記ALT−803が、血中のNK細胞、T細胞、好中球又は単球のカウント数又は活性のレベルを増大させる、請求項1〜11の何れか一項に記載の医薬。
- 前記抗体と前記ALT−803が、CD4+又はCD8+ T細胞を刺激して腫瘍細胞を死滅させる、請求項1〜11の何れか一項に記載の医薬。
- 前記抗体と前記ALT−803が、NK細胞を刺激して腫瘍細胞を死滅させる、請求項1〜11の何れか一項に記載の医薬。
- 前記抗体と前記ALT−803が、好中球又は単核球細胞を刺激して腫瘍細胞を死滅させる、請求項1〜11の何れか一項に記載の医薬。
- 前記抗体と前記ALT−803が、血中サイトカインレベルを増大する、請求項1〜11の何れか一項に記載の医薬。
- 前記サイトカインが、IFN−γ及び/又はIL−6を含む、請求項17に記載の医薬。
- 医薬が、腫瘍細胞の数の減少させる、請求項1〜11の何れか一項に記載の医薬。
- 医薬が、新生物の疾患進行の低減させる、請求項1〜11の何れか一項に記載の医薬。
- 医薬が、未処置の被験体と比べて前記被験体の生存期間の長期化させる、請求項1〜11の何れか一項に記載の医薬。
- 医薬が、前記新生物の将来の再発を予防する、請求項1〜11の何れか一項に記載の医薬。
- 前記被験体がヒトである、請求項1〜22の何れか一項に記載の医薬。
- 前記抗体と前記ALT−803が、同時又は逐次投与されるように用いられることを特徴とする、請求項1〜23の何れか一項に記載の医薬。
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