JP2022507606A - Il-7タンパク質と免疫チェックポイント阻害剤の組み合わせで腫瘍を治療する方法 - Google Patents
Il-7タンパク質と免疫チェックポイント阻害剤の組み合わせで腫瘍を治療する方法 Download PDFInfo
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Abstract
Description
このPCT出願は、2018年11月16日出願の米国仮出願第62/768,355号、2019年3月29日出願の同第62/826,734号、及び2019年9月5日出願の同第62/896,484号に基づく優先権の利益を主張するものであり、これらの仮出願の各々は、全体として参照により本明細書に組み込まれる。
本出願と共に提出された、ASCIIテキストファイルで電子提出された配列表(名称:4241_002PC03_SequenceListing_ST25.txt、サイズ:78,087バイト、作成日:2019年11月14日)の内容は、全体として参照により本明細書に組み込まれる。
このような進歩にもかかわらず、特定の悪性腫瘍(例えば、転移性または難治性の固形腫瘍)を有する患者は、依然として予後がきわめて不良である。そのような患者の中で実際にがんの長期寛解を経験するのはほんの一部であり、多くの患者は抗体に応答しないか、または最初は抗体に応答しても最終的には耐性を発現するかのいずれかである。Sharma,P.,et al.,Cell 168(4):707-723(2017)。さらに、利用可能な標準治療によるがん治療(例えば、化学療法及び放射線療法)の多くがリンパ球減少を引き起こすことが知られており、多くのがん患者はリンパ球減少性である。Grossman,S.A.,et al.,J Natl Compr Canc Netw 13(10):1225-31(2015)。抗PD-1抗体などのチェックポイント阻害剤は、そのようながん患者において限られた効能を有することが示されている。Yarchoan,M.,et al.,J Clin Oncol 35:e14512(2017)。したがって、リンパ球減少患者を含めたがん患者において、許容できる安全性プロファイル及び高い効能を有する新たな治療選択肢が依然として必要とされている。
本開示をより容易に理解することができるように、特定の用語をまず定義する。本出願で使用するとき、本明細書に別段に明記されない限り、次の用語の各々は、下記に示す意味を有するものとする。さらなる定義は本明細書の随所に示される。
本開示は、有効量のインターロイキン-7(IL-7)タンパク質を有効量の免疫チェックポイント阻害剤と組み合わせて対象に投与することを含む、それを必要とする対象の腫瘍(またはがん)を治療する方法に関する。本発明の方法で使用することのできる免疫チェックポイント阻害剤の非限定的な例としては、抗PD-1抗体、抗PD-L1抗体、抗CTLA-4抗体、及びそれらの組み合わせが挙げられる。
本明細書では、がん(または腫瘍)を治療するために免疫チェックポイント阻害剤と組み合わせて使用され得るIL-7タンパク質が開示される。いくつかの態様において、この使用に有用なIL-7タンパク質は、野生型IL-7または改変型IL-7(すなわち、野生型ではないIL-7タンパク質)(例えば、IL-7バリアント、IL-7機能性断片、IL-7誘導体、またはそれらの任意の組み合わせ、例えば、融合タンパク質、キメラタンパク質など)であり得るが、ただし、IL-7タンパク質が、IL-7の生物活性を1以上含む、例えば、IL-7Rに結合すること、例えば、初期T細胞の発達を誘導すること、T細胞恒常性を促進することができる場合に限る。ElKassar and Gress.J Immunotoxicol.2010 Mar;7(1):1-7を参照されたい。いくつかの態様において、本開示のIL-7タンパク質は、野生型IL-7タンパク質ではない(すなわち、1以上の改変を含む)。かかる改変の非限定的な例は、オリゴペプチド及び/または半減期延長部分を含み得る。全体として参照により本明細書に組み込まれるWO2016/200219を参照されたい。
N’はN末端を含み、
Z1は、配列番号7の90~98位のアミノ酸残基のうち、98位のアミノ酸残基からN末端に向かって5~9個の連続アミノ酸残基を有するアミノ酸配列を含み、
Yは、配列番号7の99~162位のアミノ酸残基のうち、162位のアミノ酸残基からN末端に向かって5~64個の連続アミノ酸残基を有するアミノ酸配列を含み、
Z2は、配列番号7の163~199位のアミノ酸残基のうち、163位のアミノ酸残基からC末端に向かって4~37個の連続アミノ酸残基を有するアミノ酸配列を含み、
Z3は、配列番号8の115~220位のアミノ酸残基のうち、220位のアミノ酸残基からN末端に向かって71~106個の連続アミノ酸残基を有するアミノ酸配列を含み、
Z4は、配列番号8の221~327位のアミノ酸残基のうち、221位のアミノ酸残基からC末端に向かって80~107個の連続アミノ酸残基を有するアミノ酸配列を含む。
いくつかの態様において、本開示は、有効量のIL-7タンパク質を有効量のPD-1経路アンタゴニスト(「PD-1アンタゴニスト」)と組み合わせて対象に投与することを含む、それを必要とする対象の腫瘍を治療する方法を提供する。本明細書で使用する場合、「PD-1アンタゴニスト」という用語は、「PD-1経路阻害剤」という用語と同義に使用される場合があり、限定するものではないが、PD-1結合剤、PD-L1結合剤、及びPD-L2結合剤を含む。PD-1結合剤は、PD-1に特異的に結合する抗体を含む。PD-L1結合剤及びPD-L2結合剤は、PD-L1及び/またはPD-L2に特異的に結合する抗体、ならびにPD-L1及び/またはPD-L2に結合する可溶性PD-1ポリペプチドを含む。
いくつかの態様において、本開示で使用することのできるPD-1アンタゴニストは、抗PD-1抗体である。PD-1に高い親和性で特異的に結合する抗体(例えば、ヒト抗体)は、米国特許第8,008,449号及び同第8,779,105号に開示されており、これらは各々、参照により本明細書に組み込まれる。他の抗PD-1 mAbは、例えば、米国特許第6,808,710号、同第7,488,802号、同第8,168,757号、及び同第8,354,509号、ならびにPCT公開第WO2012/145493号に記載されており、これらは各々、参照により本明細書に組み込まれる。米国特許第8,008,449号に開示されている抗PD-1 HuMAbの各々は、次の特徴のうちの1以上を呈することが示されている:(a)Biacoreバイオセンサシステムを使用して表面プラズモン共鳴により決定した場合に1×10-7M以下のKDでヒトPD-1に結合する;(b)ヒトCD28、CTLA-4またはICOSに実質的に結合しない;(c)混合リンパ球反応(MLR)アッセイにおいてT細胞増殖を増大させる;(d)MLRアッセイにおいてインターフェロン-γ産生を増大させる;(e)MLRアッセイにおいてIL-2分泌を増大させる;(f)ヒトPD-1及びカニクイザルPD-1に結合する;(g)PD-L1及び/またはPD-L2のPD-1に対する結合を阻害する;(h)抗原特異的メモリー応答を刺激する;(i)Ab応答を刺激する;ならびに(j)in vivoで腫瘍細胞成長を阻害する。本発明において有用な抗PD-1抗体には、ヒトPD-1に特異的に結合し、前述の特徴のうち少なくとも1つ、好ましくは少なくとも5つを呈するmAbが含まれる。
いくつかの態様において、本開示で使用することのできるPD-1アンタゴニストは、抗PD-L1抗体である。本発明での使用に好適な抗ヒトPD-L1抗体(またはそれに由来するVHドメイン及び/またはVLドメイン)は、当該技術分野で周知の方法を使用して生成することができる。あるいは、当該技術分野で認識されている抗PD-L1抗体を使用してもよい。例えば、内容が参照により本明細書に組み込まれる米国特許第7,943,743号に開示されているヒト抗PD-L1抗体を使用してもよい。かかる抗PD-L1抗体には、3G10、12A4(BMS-936559とも呼ばれる)、10A5、5F8、10H10、1B12、7H1、11E6、12B7、及び13G4が含まれる。使用することのできる、当該技術分野で認識されている他の抗PD-L1抗体としては、例えば、米国特許第7,635,757号及び同第8,217,149号、米国公開第2009/0317368号、ならびにPCT公開第WO2011/066389号及び同第WO2012/145493号に記載されているものが挙げられ、これらの教示内容もまた、参照により本明細書に組み込まれる。抗PD-L1抗体の他の例としては、アテゾリズマブ(TECENTRIQ(登録商標);RG7446)、またはデュルバルマブ(IMFINZI(登録商標);MEDI4736)が挙げられる。これらの当該技術分野で認識されている抗体または阻害剤のいずれかとPD-L1への結合について競合する抗体またはその抗原結合性断片を使用することもできる。いくつかの態様において、抗PD-L1抗体(例えば、アテゾリズマブ)は、3週間毎に約1200mgの用量で対象に(例えば、本明細書に開示されるIL-7タンパク質と組み合わせて)投与される。いくつかの態様において、抗PD-L1抗体(例えば、デュルバルマブ)は、2週間毎に約10mg/kgの用量で(例えば、本明細書に開示されるIL-7タンパク質と組み合わせて)投与される。
いくつかの態様において、本開示はまた、有効量のIL-7タンパク質を有効量のCTLA-4経路アンタゴニスト(「CTLA-4アンタゴニスト」)と組み合わせて対象に投与することを含む、それを必要とする対象の腫瘍を治療する方法を提供する。いくつかの態様において、CTLA-4アンタゴニストは、抗CTLA-4抗体である。
本明細書に記載されるさらなる態様は、本明細書に記載される治療剤(例えば、IL-7タンパク質)をコードする1以上の核酸分子に関する。核酸は、全細胞に、細胞溶解物に、または部分的に精製された形態もしくは実質的に純粋な形態で存在し得る。核酸は、他の細胞成分または他の夾雑物、例えば、他の細胞核酸(例えば、他の染色体DNA、例えば、天然に単離DNAに連結している染色体DNA)またはタンパク質から、アルカリ/SDS処理、CsClバンディング、カラムクロマトグラフィー、制限酵素、アガロースゲル電気泳動、及び当該技術分野で周知の他の技術を含む標準的技術によって精製されている場合、「単離されている」または「実質的に純粋になっている」。F.Ausubel,et al.,ed.(1987)Current Protocols in Molecular Biology,Greene Publishing and Wiley Interscience,New Yorkを参照されたい。本明細書に記載される核酸は、例えば、DNAまたはRNAであってもよく、イントロン配列を含んでも含まなくてもよい。特定の態様において、核酸はcDNA分子である。本明細書に記載される核酸は、当該技術分野で公知の標準的な分子生物学技術を使用して得ることができる。
さらに本明細書では、所望の純度で生理学的に許容できる担体、賦形剤、または安定剤(Remington’s Pharmaceutical Sciences(1990)Mack Publishing Co.,Easton,PA)を有する1以上の治療剤(例えば、IL-7タンパク質及び/または免疫チェックポイント阻害剤)を含む組成物が提供される。いくつかの態様において、本明細書に開示される組成物は、IL-7タンパク質または免疫チェックポイント阻害剤を含む。本明細書に開示されるように、かかる組成物は、組み合わせ(例えば、IL-7タンパク質を含む第1の組成物、及び免疫チェックポイント阻害剤を含む第2の組成物)で使用され得る。他の態様において、本明細書に開示される組成物は、IL-7タンパク質と免疫チェックポイント阻害剤の両方を含み得る。
IL-7タンパク質とPD-1経路阻害剤の組み合わせが腫瘍体積に及ぼす効果を評価するために、結腸腺癌動物モデルを使用した。簡潔に述べると、MC-38結腸腺癌腫瘍細胞(1×105、皮下)を各C57BL/6マウスに移植した。腫瘍播種後4日目に、動物にIL-7タンパク質(1.25mpkまたは25μg/マウス)またはIL-7配合バッファーを皮下投与した。図1Aを参照されたい。次いで、腫瘍播種後12日目、15日目、及び18日目に、抗PD-1抗体(5mpkまたは100μg/マウス)またはアイソタイプ対照抗体を動物に腹腔内投与した。腫瘍体積を腫瘍播種後8日目、11日目、13日目、15日目、18日、及び20日目に測定した。図1Aは、投薬スケジュールのグラフ表示であり、表1(下記)は、各処置群を提示する。
IL-7タンパク質とPD-1経路阻害剤の組み合わせの抗腫瘍効果をさらに評価するため、MC-38結腸腺癌腫瘍細胞(1×105、皮下)をやはりC57BL/6マウスに移植した。腫瘍播種後4日目に、動物をIL-7タンパク質(1.25mpkまたは25μg/マウス、皮下)またはIL-7配合バッファーの単回投与で処置した。図2Aを参照されたい。次いで、腫瘍播種後9日目及び12日目に、動物を抗PD-1抗体(5mpkまたは100μg/マウス、腹腔内)またはアイソタイプ対照抗体で処置した。動物を腫瘍播種後14日目に屠殺し、各動物の腫瘍浸潤リンパ球をフローサイトメトリーで解析した。
次に、IL-7タンパク質及びPD-1経路阻害剤と化学療法剤(例えばCPA)の併用治療による抗腫瘍効果を、結腸腺癌動物モデルで評価した。簡潔に述べると、MC-38結腸腺癌腫瘍細胞(1×105、皮下)をC57BL/6マウスに移植した。次いで、腫瘍播種10日後に、動物の腹腔内にCPA(100mpkまたは2mg/マウス)またはPBSを単回投与した。CPA投与後2日目に、動物にIL-7タンパク質(10mpkまたは200μg/マウス)またはIL-7配合バッファーを皮下投与した。CPA投与後6日目から開始して、抗PD-1抗体(5mpkまたは100μg/マウス)、抗PD-L1-抗体(5mpkまたは100μg/マウス)、またはアイソタイプ対照抗体を3日毎に合計5回(すなわち、CPA誘導後6日目、9日目、12日目、15日目、及び18日目に)動物に腹腔内投与した。図3Aを参照されたい。腫瘍体積をCPA誘導後0日目、1日目、4日目、6日目、8日目、11日目、13日目、15日目、18日目、及び20日目に測定した。
上述のように、多くの抗がん剤(例えば、化学療法または放射線療法)が、がん対象においてリンパ球減少を引き起こし得る。したがって、リンパ球減少性状態におけるIL-7タンパク質とPD-1経路阻害剤の組み合わせの抗腫瘍効果を評価するために、胸腺摘除マウスを使用した。簡潔に述べると、C57BL/6マウスを麻酔し、解剖板上に固定した。ゴムバンドを使用し、マウスの頭を後方に傾けることによって気道を開いた。丸めた組織パッドをマウスの両肩の下に置き、心臓及び胸腺を前方に押す助けとして、接触を容易にした。滅菌のために、マウスの頸部及び上胸部を70%エタノールで拭いた。頸切痕から胸部側へ、正中縦方向の皮膚を1.5~2cm切開した。はさみを胸骨下に挿入して第一胸骨を切断した。鉗子を広げて胸部を開いた。舌骨下筋を引き裂いた後、胸腺を注意深くつかみ、次いで胸部から取り出した。動物の皮膚縫合に使用されるアプライヤー及びクリップを使用し、正中縦方向の皮膚を素早く閉鎖した。第一胸骨切断から皮膚閉鎖までの時間は1分未満であった。動物をおよそ5週間にわたって手術から回復させた。次いで、動物にMC-38結腸腺癌腫瘍細胞(1×105、皮下)を播種した。図4Aを参照されたい。腫瘍播種後5日目に、動物にIL-7タンパク質(1.25mpkまたは25μg/マウス)またはIL-7配合バッファーを皮下投与した。抗PD-1抗体(5mpkまたは100μg/マウス)またはアイソタイプ対照抗体を、腫瘍播種後10日目、13日目、及び16日目の動物に投与した。腫瘍体積を腫瘍播種後10日目、13日目、16日目、19日目、21日、及び23日目に測定した。
IL-7タンパク質とPD-1経路阻害剤の組み合わせがリンパ球減少性環境でTILに影響を及ぼすかどうかを評価するために、実施例4に記載したようにC57BL/6マウスを胸腺摘除した。手術5週間後、MC-38結腸腺癌腫瘍細胞(1×105、皮下)を動物に移植した。腫瘍播種後4日目に、動物をIL-7タンパク質(1.25mpkまたは25μg/マウス、皮下)またはIL-7配合バッファーの単回投与で処置した。図5Aを参照されたい。次いで、腫瘍播種後9日目及び12日目に、動物を抗PD-1抗体(5mpkまたは100μg/マウス、腹腔内)またはアイソタイプ対照抗体で処置した。動物を腫瘍播種後14日目に屠殺し、各動物の腫瘍浸潤リンパ球をフローサイトメトリーで解析した。
本明細書に開示されるIL-7タンパク質の抗腫瘍効果をよりよく理解するために、IL-7タンパク質がT細胞の増殖及び活性化に及ぼす効果を、まず正常マウスにおいて評価した。簡潔に述べると、C57BL/6マウスを10mg/kgのIL-7タンパク質の皮下投与によって処置した。対照動物にはバッファーのみを与えた。投与後の様々な時点(すなわち、2日目、4日目、5日目、6日目、8日目、10日目、12日目、及び14日目)で動物の採血を行い、フローサイトメトリーを使用して様々なCD8+T細胞集団の割合を評価した。処置後5日目、一部の動物を屠殺し、脾臓のCD8+T細胞を様々な活性化マーカー(T-bet、Eomes、PD-1、グランザイムB(GzmB)、CXCR3)の発現及びサイトカイン産生(IFN-γ、TNF-α、及びIL-2)について評価した。ex vivoでのPMA/イオノマイシン刺激後に細胞内サイトカイン染色を使用し、サイトカイン産生を評価した。
本明細書に開示されるIL-7タンパク質の抗腫瘍効果をよりよく解析するために、C57BL/6マウスにMC-38結腸腺癌腫瘍細胞(1×105、皮下)を移植した。腫瘍播種後5日目に、次のうち1つの濃度のIL-7タンパク質でマウスを処置した:(i)0mg/kg(すなわち、バッファーのみ)、(ii)1.25mg/kg、(iii)2.5mg/kg、(iv)5mg/kg、及び(v)10mg/kg。腫瘍体積を投与後定期的に評価した。処置後7日目に動物の採血を行い、様々な免疫細胞(すなわち、CD8+T細胞、CD4+T細胞、Foxp3+CD4+制御性T細胞、B220+細胞)の割合を評価した。
IL-7タンパク質の抗腫瘍効果をさらに解析するために、先行実施例に記載したようにMC38結腸腺癌腫瘍細胞をC57BL/6マウスに移植した。次いで、腫瘍播種後5日目に、動物を10mg/kgのIL-7タンパク質またはバッファーの皮下投与によって処置した。処置後7日目に動物を屠殺し、腫瘍組織を様々な免疫細胞(すなわち、単球性骨髄系由来サプレッサー細胞(M-MDSC)、多形核骨髄系由来サプレッサー細胞(PMN-MDSC)、腫瘍関連マクロファージ(TAM)、腫瘍関連樹状細胞(TADC)、CD8+T細胞、CD4+T細胞、Foxp3+CD4+制御性T細胞(Treg)、NK細胞、及びB細胞)の存在について評価した。
他の抗がん剤と組み合わせるとIL-7タンパク質の抗腫瘍効果が向上し得るかどうかをさらに評価するために、先行実施例に記載したようにC57BL/6マウスにMC38結腸腺癌腫瘍細胞を播種した。次いで、マウスを次のうちの1つで処置した:(i)バッファーのみ、(ii)シクロホスファミド(CPA)(100mg/kg)と免疫チェックポイント阻害剤(10mg/kg)の組み合わせ、及び(iii)CPA、免疫チェックポイント阻害剤、及びIL-7タンパク質(10mg/kg)の三剤併用。使用した免疫チェックポイント阻害剤は、抗PD-1抗体、抗PD-L1抗体、または抗CTLA-4抗体を含んだ。腫瘍播種後10日目にCPAを動物に腹腔内投与した。免疫チェックポイント阻害剤はCPA処置後6日目から腹腔内投与した(3日毎で合計5用量)。IL-7タンパク質はCPA処置後2日目に皮下投与した。腫瘍体積と生存期間の両方を、処置後の様々な時点で評価した。
リンパ球減少性環境におけるIL-7タンパク質の抗腫瘍効果をよりよく解析するために、実施例4に記載したようにC57BL/6マウスを胸腺摘除した。図11Aに示すように、シャム対照(すなわち、胸腺を除去しなかったこと以外は同じ外科手技)と比較すると、胸腺摘除動物は、少ない数のCD8+T細胞を脾臓、血液、及びリンパ節で発現し、それらのリンパ球減少性状態が裏付けられた。手術から回復させた後、動物をPBSまたはIL-7タンパク質(1.25mg/kg、皮下)で処置した。次いで、動物を処置後第1週、第2週、及び第4週で屠殺し、脾臓内の様々なCD8+T細胞集団の数を評価した。
本明細書に開示されるIL-7タンパク質(すなわち、hyFcを含む;「IL-7-hyFc」)の進行固形癌患者における安全性及び効能を評価するために、フェーズ1b臨床試験を行った。この研究の主な目的は、患者における(i)IL-7-hyFcの安全性及び忍容性を評価すること、ならびに(ii)最大耐容用量(MTD)、フェーズ2推奨用量(RP2D)、及び用量制限毒性(DLT)を決定することであった。二次的な目的には、患者におけるIL-7-hyFcの(i)薬物動態及び薬力学特性、ならびに(ii)免疫原性を決定することが含まれた。探索的バイオマーカーについても評価した。
上記臨床試験(実施例11参照)は、グリア芽細胞腫の治療におけるIL7-hyFcの安全性及び効能も評価した。全体的な研究設計は実施例11のものと同じ(例えば、3+3の従来的な用量漸増及び同様の適格性要件)であったが、グリア芽細胞腫試験での用量は、(i)60μg/kg、(ii)360μg/kg、(iii)600μg/kg、(iv)840μg/kg、及び(v)1,440μg/kgとした。合計15名の患者が研究に登録した。
Claims (79)
- 有効量のインターロイキン-7(IL-7)タンパク質を有効量のProgrammed Death-1(PD-1)経路阻害剤と組み合わせてヒト対象に投与することを含む、腫瘍の治療を必要とする前記対象の前記腫瘍を治療する方法であって、腫瘍体積が、前記投与後の前記対象では、前記PD-1経路阻害剤単独またはIL-7タンパク質単独のいずれかの投与後の参照腫瘍体積と比較して減少する、前記方法。
- 前記腫瘍体積が、前記投与後に、少なくとも約5%、少なくとも約10%、少なくとも約20%、少なくとも約30%、少なくとも約40%、少なくとも約50%、少なくとも約60%、少なくとも約70%、少なくとも約80%、少なくとも約90%、または少なくとも約100%減少する、請求項1に記載の方法。
- 前記腫瘍中の腫瘍浸潤リンパ球(TIL)数が、前記投与後に、前記PD-1経路阻害剤単独または前記IL-7タンパク質単独のいずれかの投与後の腫瘍におけるTIL数と比較して増大する、請求項1または2に記載の方法。
- 前記TILがCD4+TILである、請求項3に記載の方法。
- 前記TILがCD8+TILである、請求項3に記載の方法。
- 前記TIL数が、前記投与後に、少なくとも約10%、少なくとも約20%、少なくとも約30%、少なくとも約40%、少なくとも約50%、少なくとも約60%、少なくとも約70%、少なくとも約80%、少なくとも約90%、少なくとも約100%、少なくとも約125%、少なくとも約150%、少なくとも約200%、少なくとも約250%、または少なくとも約300%増大する、請求項3~5のいずれか1項に記載の方法。
- 前記ヒト対象が、前記投与前にリンパ球減少を呈する、請求項1~6のいずれか1項に記載の方法。
- 有効量のインターロイキン-7(IL-7)タンパク質を有効量のProgrammed Death-1(PD-1)経路阻害剤と組み合わせて対象に投与することを含む、腫瘍の治療を必要とする前記対象の前記腫瘍を治療する方法であって、前記対象がリンパ球減少を呈する、前記方法。
- リンパ球減少を呈する前記ヒト対象が、Tリンパ球減少、Bリンパ球減少、及び/またはNKリンパ球減少を有する、請求項7または8に記載の方法。
- 前記リンパ球減少が、前記腫瘍に起因または関連する、請求項7~9のいずれか1項に記載の方法。
- 前記リンパ球減少が、前記腫瘍に対する過去の療法に起因または関連する、請求項7~10のいずれか1項に記載の方法。
- 前記リンパ球減少が、感染、慢性右心室不全、ホジキン病及びリンパ系のがん、白血病、胸管の漏出もしくは破裂、抗がん剤(例えば、化学療法)、抗ウイルス剤、及びグルココルチコイドを含む処方薬の副作用、低タンパク質の食事によって生じる栄養不良、放射線療法、尿毒症、自己免疫障害、免疫不全症候群、高ストレスレベル、外傷、胸腺摘除、またはそれらの組み合わせに起因する、請求項7~11のいずれか1項に記載の方法。
- 前記リンパ球減少が特発性である、請求項7~12のいずれか1項に記載の方法。
- 前記リンパ球減少が、特発性CD4陽性Tリンパ球減少症(ICL)、急性放射線症候群(ARS)、またはそれらの組み合わせを含む、請求項7~13のいずれか1項に記載の方法。
- 前記リンパ球減少が、リンパ球減少を呈さない対応する対象の循環血中総リンパ球数と比較して、少なくとも約5%、少なくとも約10%、少なくとも約20%、少なくとも約30%、少なくとも約40%、少なくとも約50%、少なくとも約60%、少なくとも約70%、少なくとも約80%、少なくとも約90%、または少なくとも約100%少ない循環血中総リンパ球数を特徴とする、請求項7~14のいずれか1項に記載の方法。
- 前記リンパ球減少が、1μL当たりリンパ球約1,500未満、1μL当たりリンパ球約1,000未満、1μL当たりリンパ球約800未満、1μL当たりリンパ球約500未満、または1μL当たりリンパ球約200未満の循環血中総リンパ球数を特徴とする、請求項7~15のいずれか1項に記載の方法。
- 前記腫瘍中の腫瘍浸潤リンパ球(TIL)数が、前記投与後に、前記PD-1経路阻害剤単独または前記IL-7タンパク質単独のいずれかの投与後の腫瘍におけるTIL数と比較して増大する、請求項8~16のいずれか1項に記載の方法。
- 前記TIL数が、前記投与後に、少なくとも約10%、少なくとも約20%、少なくとも約30%、少なくとも約40%、少なくとも約50%、少なくとも約60%、少なくとも約70%、少なくとも約80%、少なくとも約90%、少なくとも約100%、少なくとも約125%、少なくとも約150%、少なくとも約200%、少なくとも約250%、または少なくとも約300%増大する、請求項17に記載の方法。
- 前記TILがCD4+TILである、請求項17または18に記載の方法。
- 前記TILがCD8+TILである、請求項17または18に記載の方法。
- 前記IL-7タンパク質が、野生型IL-7ではない、請求項1~20のいずれか1項に記載の方法。
- 前記IL-7タンパク質が、1~10個のアミノ酸残基からなるオリゴペプチドを含む、請求項1~21のいずれか1項に記載の方法。
- 前記オリゴペプチドが、メチオニン、グリシン、メチオニン-メチオニン、グリシン-グリシン、メチオニン-グリシン、グリシン-メチオニン、メチオニン-メチオニン-メチオニン、メチオニン-メチオニン-グリシン、メチオニン-グリシン-メチオニン、グリシン-メチオニン-メチオニン、メチオニン-グリシン-グリシン、グリシン-メチオニン-グリシン、グリシン-グリシン-メチオニン、及びグリシン-グリシン-グリシンからなる群から選択される、請求項22に記載の方法。
- 前記オリゴペプチドがメチオニン-グリシン-メチオニンである、請求項23に記載の方法。
- 前記IL-7タンパク質が半減期延長部分を含む、請求項1~24のいずれか1項に記載の方法。
- 前記半減期延長部分が、Fc、アルブミン、アルブミン結合ポリペプチド、Pro/Ala/Ser(PAS)、ヒト絨毛性ゴナドトロピンのβサブユニットのC末端ペプチド(CTP)、ポリエチレングリコール(PEG)、長鎖非構造化親水性アミノ酸配列(XTEN)、ヒドロキシエチルデンプン(HES)、アルブミン結合低分子、またはそれらの組み合わせを含む、請求項25に記載の方法。
- 前記半減期延長部分がFcである、請求項26に記載の方法。
- 前記Fcが、ヒンジ領域、CH2ドメイン、及びCH3ドメインを含むハイブリッドFcであり、
前記ヒンジ領域が、ヒトIgDヒンジ領域を含み、
前記CH2ドメインが、ヒトIgD CH2ドメインの一部及びヒトIgG4 CH2ドメインの一部を含み、
前記CH3ドメインが、ヒトIgG4 CH3ドメインの一部を含む、請求項27に記載の方法。 - 前記IL-7タンパク質が、配列番号1~6及び15~25と少なくとも約70%、少なくとも約75%、少なくとも約80%、少なくとも約85%、少なくとも約90%、少なくとも約95%、少なくとも約96%、少なくとも約97%、少なくとも約98%、少なくとも約99%、または約100%の配列同一性を有するアミノ酸配列を含む、請求項1~28のいずれか1項に記載の方法。
- 前記PD-1経路阻害剤が、抗PD-1抗体または抗PD-L1抗体を含む、請求項1~29のいずれか1項に記載の方法。
- 前記抗PD-1抗体が、ニボルマブ、ペンブロリズマブ、MEDI0608、AMP-224、PDR001、BGB-A317、またはそれらの任意の組み合わせを含む、請求項30に記載の方法。
- 前記抗PD-L1抗体が、BMS-936559、MPDL3280A、MEDI4736、MSB0010718C、またはそれらの任意の組み合わせを含む、請求項31に記載の方法。
- 前記IL-7タンパク質及び前記PD-1経路阻害剤が同時に投与される、請求項1~32のいずれか1項に記載の方法。
- 前記IL-7タンパク質及び前記PD-1経路阻害剤が順次投与される、請求項1~32のいずれか1項に記載の方法。
- 前記IL-7タンパク質が、前記PD-1経路阻害剤を投与する前に前記対象に投与される、請求項34に記載の方法。
- 前記腫瘍が、乳癌、頭頸部癌、子宮癌、脳癌、皮膚癌、腎癌、肺癌、大腸癌、前立腺癌、肝臓癌、膀胱癌、腎臓癌、膵臓癌、甲状腺癌、食道癌、眼癌、胃の癌(胃癌)、胃腸癌、卵巣癌、癌腫、肉腫、白血病、リンパ腫、骨髄腫、またはそれらの組み合わせを含むがんに由来する、請求項1~35のいずれか1項に記載の方法。
- 前記乳癌が、トリプルネガティブ乳癌(TNBC)である、請求項36に記載の方法。
- 前記脳癌が、グリア芽細胞腫である、請求項36に記載の方法。
- 前記皮膚癌が、基底細胞癌(BCC)、皮膚扁平上皮癌(cSCC)、黒色腫、メルケル細胞癌(MCC)、またはそれらの組み合わせである、請求項36に記載の方法。
- 前記頭頸部癌が、頭頸部扁平上皮癌である、請求項36に記載の方法。
- 前記肺癌が、小細胞肺癌(SCLC)である、請求項36に記載の方法。
- 前記食道癌が、食道胃接合部癌である、請求項36に記載の方法。
- 前記腎臓癌が、腎細胞癌である、請求項36に記載の方法。
- 前記肝臓癌が、肝細胞癌である、請求項36に記載の方法。
- 前記IL-7タンパク質が、前記対象に補足的投与、筋肉内投与、皮下投与、点眼、静脈内投与、腹腔内投与、皮内投与、眼窩内投与、脳内投与、頭蓋内投与、脊髄内投与、心室内投与、髄腔内投与、大槽内投与、嚢内投与、または腫瘍内投与される、請求項1~44のいずれか1項に記載の方法。
- 前記PD-1経路阻害剤が、前記対象に補足的投与、筋肉内投与、皮下投与、静脈内投与、または腹腔内投与される、請求項1~45のいずれか1項に記載の方法。
- 有効量のインターロイキン-7(IL-7)タンパク質を有効量のCTLA-4経路阻害剤と組み合わせてヒト対象に投与することを含む、腫瘍の治療を必要とする前記対象の前記腫瘍を治療する方法。
- 腫瘍体積が、前記投与後に、少なくとも約5%、少なくとも約10%、少なくとも約20%、少なくとも約30%、少なくとも約40%、少なくとも約50%、少なくとも約60%、少なくとも約70%、少なくとも約80%、少なくとも約90%、または少なくとも約100%減少する、請求項47に記載の方法。
- 前記ヒト対象が、前記投与前にリンパ球減少を呈する、請求項47または48に記載の方法。
- 前記CTLA-4経路阻害剤が、抗CTLA-4抗体を含む、請求項47~49のいずれか1項に記載の方法。
- 前記抗CTLA-4抗体が、イピリムマブ、トレメリムマブ(チシリムマブ;CP-675,206)、AGEN-1884、またはそれらの組み合わせを含む、請求項50に記載の方法。
- 前記IL-7タンパク質及び前記CTLA-4経路阻害剤が同時に投与される、請求項47~51のいずれか1項に記載の方法。
- 前記IL-7タンパク質及び前記CTLA-4経路阻害剤が順次投与される、請求項47~51のいずれか1項に記載の方法。
- 前記IL-7タンパク質が、前記CTLA-4経路阻害剤を投与する前に前記対象に投与される、請求項53に記載の方法。
- 前記腫瘍が、乳癌、頭頸部癌、子宮癌、脳癌、皮膚癌、腎癌、肺癌、大腸癌、前立腺癌、肝臓癌、膀胱癌、腎臓癌、膵臓癌、甲状腺癌、食道癌、眼癌、胃の癌(胃癌)、胃腸癌、卵巣癌、癌腫、肉腫、白血病、リンパ腫、骨髄腫、またはそれらの組み合わせを含むがんに由来する、請求項47~54のいずれか1項に記載の方法。
- 前記IL-7タンパク質が、約600μg/kg超、約700μg/kg超、約800μg/kg超、約900μg/kg超、約1,000μg/kg超、約1,100μg/kg超、約1,200μg/kg超、約1,300μg/kg超、約1,400μg/kg超、約1,500μg/kg超、約1,600μg/kg超、約1,700μg/kg超、約1,800μg/kg超、約1,900μg/kg超、または約2,000μg/kg超の用量で投与される、請求項1~55のいずれか1項に記載の方法。
- 前記IL-7タンパク質が、約610μg/kg~約1,200μg/kg、約650μg/kg~約1,200μg/kg、約700μg/kg~約1,200μg/kg、約750μg/kg~約1,200μg/kg、約800μg/kg~約1,200μg/kg、約850μg/kg~約1,200μg/kg、約900μg/kg~約1,200μg/kg、約950μg/kg~約1,200μg/kg、約1,000μg/kg~約1,200μg/kg、約1,050μg/kg~約1,200μg/kg、約1,100μg/kg~約1,200μg/kg、約1,200μg/kg~約2,000μg/kg、約1,300μg/kg~約2,000μg/kg、約1,500μg/kg~約2,000μg/kg、約1,700μg/kg~約2,000μg/kg、約610μg/kg~約1,000μg/kg、約650μg/kg~約1,000μg/kg、約700μg/kg~約1,000μg/kg、約750μg/kg~約1,000μg/kg、約800μg/kg~約1,000μg/kg、約850μg/kg~約1,000μg/kg、約900μg/kg~約1,000μg/kg、または約950μg/kg~約1,000μg/kgの用量で投与される、請求項1~56のいずれか1項に記載の方法。
- 前記IL-7タンパク質が、約700μg/kg~約900μg/kg、約750μg/kg~約950μg/kg、約700μg/kg~約850μg/kg、約750μg/kg~約850μg/kg、約700μg/kg~約800μg/kg、約800μg/kg~約900μg/kg、約750μg/kg~約850μg/kg、または約850μg/kg~約950μg/kgの用量で投与される、請求項1~57のいずれか1項に記載の方法。
- 前記IL-7タンパク質が、約650μg/kg、約680μg/kg、約700μg/kg、約720μg/kg、約740μg/kg、約750μg/kg、約760μg/kg、約780μg/kg、約800μg/kg、約820μg/kg、約840μg/kg、約850μg/kg、約860μg/kg、約880μg/kg、約900μg/kg、約920μg/kg、約940μg/kg、約950μg/kg、約960μg/kg、約980μg/kg、約1,000μg/kg、約1,020μg/kg、約1,040μg/kg、約1,060μg/kg、約1,080μg/kg、約1,100μg/kg、約1,120μg/kg、約1,140μg/kg、約1,160μg/kg、約1,180μg/kg、約1,200μg/kg、約1,220μg/kg、約1,240μg/kg、約1,260μg/kg、約1,280μg/kg、約1,300μg/kg、約1,320μg/kg、約1,340μg/kg、約1,360μg/kg、約1,380μg/kg、約1,400μg/kg、約1,420μg/kg、約1,440μg/kg、約1,460μg/kg、約1,480μg/kg、約1,500μg/kg、約1,520μg/kg、約1,540μg/kg、約1,560μg/kg、約1,580μg/kg、約1,600μg/kg、約1,620μg/kg、約1,640μg/kg、約1,660μg/kg、約1,680μg/kg、約1,700μg/kg、約1,720μg/kg、約1,740μg/kg、約1,760μg/kg、約1,780μg/kg、約1,800μg/kg、約1,820μg/kg、約1,840μg/kg、約1,860μg/kg、約1,880μg/kg、約1,900μg/kg、約1,920μg/kg、約1,940μg/kg、約1,960μg/kg、約1,980μg/kg、または約2,000μg/kgの用量で投与される、請求項1~58のいずれか1項に記載の方法。
- 前記IL-7タンパク質が、1週間に1回、2週間に1回、3週間に1回、4週間に1回、5週間に1回、6週間に1回、7週間に1回、8週間に1回、9週間に1回、10週間に1回、11週間に1回、または12週間に1回の投薬頻度で投与される、請求項1~59のいずれか1項に記載の方法。
- 前記IL-7タンパク質が補足的に投与される、請求項1~60のいずれか1項に記載の方法。
- 前記IL-7タンパク質が静脈内投与される、請求項1~60のいずれか1項に記載の方法。
- 前記IL-7タンパク質、前記PD-1経路阻害剤、及び/または前記CTLA-4経路阻害剤が、増量剤、安定剤、界面活性剤、緩衝剤、またはそれらの組み合わせを含む組成物に配合される、請求項1~62のいずれか1項に記載の方法。
- 前記PD-1経路阻害剤がニボルマブであり、前記組成物が(a)マンニトール(例えば、約30mg)、(b)ペンテト酸(例えば、約0.008mg)、(c)ポリソルベート80(例えば、約0.2mg)、(d)塩化ナトリウム(例えば、約2.92mg)、及び(e)無水クエン酸ナトリウム(例えば、約5.88mg)を含む、請求項63に記載の方法。
- 前記PD-1経路阻害剤が、2週間毎に約240mgまたは4週間毎に約480mgの一定用量で前記対象に投与される、請求項64に記載の方法。
- 前記PD-1経路阻害剤が、2週間毎に約3mg/kgの重量基準用量で前記対象に投与される、請求項64に記載の方法。
- 前記PD-1経路阻害剤がペンブロリズマブであり、前記組成物が(a)L-ヒスチジン(例えば、約1.55mg)、(b)ポリソルベート80(例えば、約0.2mg)、及び(c)スクロース(例えば、約70mg)を含む、請求項63に記載の方法。
- 前記PD-1経路阻害剤が、3週間毎に約200mgの一定用量で前記対象に投与される、請求項67に記載の方法。
- 前記PD-1経路阻害剤が、3週間毎に約2mg/kgの重量基準用量で前記対象に投与される、請求項67に記載の方法。
- 前記PD-1経路阻害剤がアテゾリズマブであり、前記組成物が(a)氷酢酸(例えば、約16.5mg)、(b)L-ヒスチジン(例えば、約62mg)、(c)スクロース(例えば、約821.6mg)、及び(d)ポリソルベート20(例えば、約8mg)を含む、請求項63に記載の方法。
- 前記PD-1経路阻害剤が、3週間毎に約1200mgの一定用量で前記対象に投与される、請求項70に記載の方法。
- 前記PD-1経路阻害剤がデュルバルマブであり、前記組成物が(a)L-ヒスチジン(例えば、約2mg)、(b)L-ヒスチジン塩酸塩一水和物(例えば、約2.7mg)、(c)α,α-トレハロース二水和物(例えば、約104mg)、及び(d)ポリソルベート80(例えば、約0.2mg)を含む、請求項63に記載の方法。
- 前記PD-1経路阻害剤が、2週間毎に約10mg/kgの重量基準用量で前記対象に投与される、請求項72に記載の方法。
- 前記PD-1経路阻害剤がアベルマブであり、前記組成物が(a)D-マンニトール(例えば、約51mg)、(b)氷酢酸(例えば、約0.6mg)、(c)ポリソルベート20(例えば、約0.5mg)、及び(d)水酸化ナトリウム(例えば、約0.3mg)を含む、請求項63に記載の方法。
- 前記PD-1経路阻害剤が、2週間毎に約800mgの一定用量で前記対象に投与される、請求項74に記載の方法。
- 前記CTLA-4経路阻害剤がイピリムマブであり、前記組成物が(a)ジエチレントリアミンペンタ酢酸(DTPA)(例えば、約0.04mg)、(b)マンニトール(例えば、約10mg)、(c)ポリソルベート80(植物由来)(例えば、約0.1mg)、(d)塩化ナトリウム(例えば、約5.85mg)、及び(e)トリス塩酸塩(例えば、約3.15mg)を含む、請求項63に記載の方法。
- 前記CTLA-4経路阻害剤が、3週間毎に約3mg/kgの重量基準用量で前記対象に投与される、請求項76に記載の方法。
- 前記CTLA-4経路阻害剤が、3週間毎に約10mg/kgで4用量、続いて12週間毎に10mg/kgの重量基準用量で前記対象に投与される、請求項76に記載の方法。
- 前記IL-7タンパク質が、(a)クエン酸ナトリウム(例えば、約20mM)、(b)スクロース(例えば、約5%)、(c)ソルビトール(例えば、約1.5%)、及び(d)Tween80(例えば、約0.05%)を含む組成物に配合される、請求項63~78のいずれか1項に記載の方法。
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MX2022002277A (es) * | 2019-09-04 | 2022-06-08 | Genexine Inc | Metodo para incrementar el conteo de linfocitos mediante el uso de proteina de fusion de interleucina 7 (il-7) en tumores. |
WO2022013221A1 (en) * | 2020-07-13 | 2022-01-20 | Transgene | Treatment of immune depression |
WO2023172036A1 (ko) * | 2022-03-10 | 2023-09-14 | 주식회사 제넥신 | 두경부암 치료를 위한 삼중 복합약물 투여요법 |
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