JP2023159179A - 抗pd-1抗体を用いる腫瘍の治療方法 - Google Patents
抗pd-1抗体を用いる腫瘍の治療方法 Download PDFInfo
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Abstract
Description
E1.腫瘍に罹患している対象の治療方法であって、(i)前記対象におけるSTK11遺伝子の変異状態を決定し;次いで(ii)STK11遺伝子が野生型である場合、プログラム死-1(PD-1)受容体に特異的に結合し、PD-1活性を阻害する抗体またはその抗原結合部分(「抗PD-1抗体」)を前記対象に投与することを特徴とする方法。
(a)約4mg~約500mgの範囲の用量の抗PD-1抗体;および
(b)前記抗PD-1抗体をE1~E70のいずれか1つに記載の方法において使用するための説明書
を含む、キット。
本開示がより容易に理解されうるために、まず、一定の用語が定義される。本出願で用いられるように、本明細書で特に明確に供される場合を除き、下記用語の各々は、下記に記載される意味を有する。さらなる定義は本願を通して説明される。
本開示は、腫瘍に罹患している対象を治療するためのものであって、(i)前記対象におけるSTK11遺伝子の変異状態を決定し;次いで(ii)プログラム死-1(PD-1)受容体に特異的に結合し、PD-1活性を阻害する抗体またはその抗原結合部分(「抗PD-1抗体」)を前記対象に投与することを特徴とするものを提供する。ある態様において、前記腫瘍(例えば、NSCLC、例えば、非扁平上皮NSCLC)に罹患している対象は、STK11遺伝子が野生型である場合、抗PD-1抗体が投与される。ある態様において、本開示は、腫瘍(例えば、NSCLC、例えば、非扁平上皮NSCLC)に罹患している対象の治療方法であって、抗PD-1抗体を前記対象に投与することを特徴とし、前記対象が、野生型STK11遺伝子を有するとしてとして同定されているものである方法に関する。ある態様において、本開示は、抗PD-1抗体治療に適する腫瘍(例えば、NSCLC、例えば、非扁平上皮NSCLC)に罹患している対象を同定するための方法であって、(i)前記対象におけるSTK11遺伝子の変異状態を決定し;次いで(ii)STK11遺伝子が野生型である場合、抗PD-1抗体を前記対象に投与することを含む方法に関する。
ある実施態様において、前記対象は、PD-L1+である腫瘍細胞を有する。ある実施態様において、前記対象は、PD-L1-である癌細胞を有する。ある実施態様において、対象は、一切喫煙していないものである。1の実施態様において、前記対象は、以前喫煙していたものである。ある実施態様において、前記対象は、現在喫煙しているものである。ある実施態様において、前記対象は、扁平の癌細胞を有する。ある実施態様において、前記対象は、非扁平の癌細胞を有する。
本開示のある実施態様は、対象における1つまたはそれ以上のマーカー遺伝子(例えば、STK11)の変異状態を決定することに関する。当該技術分野で公知の方法は、対象がマーカー遺伝子の野生型または変異型を保有するかどうかを決定することに用いることができる。ある実施態様において、標的マーカー遺伝子は、当該技術分野で利用可能な手法を用いて配列決定され、前記マーカー遺伝子の配列は、当該技術分野における同一のマーカー遺伝子の既知の配列と比較される。ある実施態様において、前記マーカー遺伝子は、非同義変異を有する。ある実施態様において、前記マーカー遺伝子は、ナンセンス変異を有する。ある実施態様において、前記マーカー遺伝子は、フレームシフト変異を有する。ある実施態様において、前記マーカー遺伝子は、スプライシング変異を有する。ある実施態様において、変異型マーカー遺伝子が発現される。他の実施態様において、前記変異型マーカー遺伝子が発現されていない。
組織スコア=[(%腫瘍x1(低強度))+(%腫瘍x2(中間強度))+(%腫瘍x3(高強度)]。
本開示の他の態様は、対象から取得された腫瘍組織のTMBを測定することに関する。腫瘍が増殖するにつれ、生殖細胞系列DNAに存在しない体細胞変異が蓄積する。腫瘍変異量(TMB)は、(生殖細胞系列の変異DNAを考慮に入れた後の)腫瘍ゲノムにおける体細胞変異数および/または腫瘍ゲノムの1領域あたりの体細胞変異数を意味する。体細胞変異の獲得、すなわち、より高いTMBは、異なるメカニズム、例えば、外因性変異誘導源への暴露(例えば、喫煙またはUV光暴露)およびDNAミスマッチ修復突然変異(例えば、結腸直腸および食道癌におけるMSI)によって影響されうる。固形腫瘍において、突然変異の約95%は、一塩基置換である(Vogelstein et al., Science (2013) 339:1546-1558.)。本明細書における「非同義変異」は、タンパク質のアミノ酸配列を変化させるヌクレオチド変異を意味する。ミスセンス変異およびナンセンス変異は、両方とも非同義変異でありうる。本明細書における「ミスセンス変異」は、単一のヌクレオチド変化が、異なるアミノ酸をコードするコドンを生じる非同義の点変異を意味する。本明細書における「ナンセンス変異」は、コドンが、生成されたタンパク質の切断を生じる未成熟終止コドンに変化されている非同義の点変異を意味する。
FOUNDATIONONE(登録商標)アッセイは、下記に限定されないが、肺、結腸、および乳房の固形腫瘍、黒色腫、および卵巣癌を含む固形腫瘍のための網羅的ゲノムプロファイリングアッセイである。FOUNDATIONONE(登録商標)アッセイは、ゲノム変化(塩基置換、挿入および欠失、コピー数変化、および再配列)を同定し、ゲノム特性(例えば、TMBおよびマイクロサテライト不安定性)を選択するためのハイブリッドキャプチャー次世代シークエンシング法を使用する。前記アッセイは、322個の独特の遺伝子(315個の癌関連遺伝子の全コード領域、および28個の遺伝子に由来する選択されたイントロンを含む)を網羅する。FOUNDATIONONE(登録商標)アッセイ遺伝子の全リストは、表1および2で供される。2018年3月16日に最終訪問したFoundationMedicine.comで利用可能なFOUNDATIONONE:技術仕様書(Foundation Medicine,Inc.)(出典明示によりその全体が本明細書に取り込まれる)を参照のこと。
表1:全コード配列がFOUNDATIONONE(登録商標)アッセイでアッセイされる遺伝子リスト。
表2:選択されるイントロンがFOUNDATIONONE(登録商標)アッセイでアッセイされる遺伝子リスト。
FOUNDATIONONE(登録商標)Hemeアッセイは、血液学的悪性腫瘍および肉腫のための網羅的ゲノムプロファイリングアッセイである。前記FOUNDATIONONE(登録商標)Hemeアッセイは、ゲノム変化(塩基置換、挿入および欠失、コピー数変化、および再配列)を同定し、ゲノム特性(例えば、TMBおよびマイクロサテライト不安定性)を選択するためのハイブリッドキャプチャー次世代シークエンシング法を使用する。前記アッセイは、406個の遺伝子のコード領域、31個の遺伝子の選択されたイントロン、および癌で一般に再編成される265個の遺伝子のRNA配列を解析する。FOUNDATIONONE(登録商標)Hemeアッセイ遺伝子の全リストは、表3、4、および5で供される。2018年3月16日に最終訪問したFoundationMedicine.comで利用可能なFOUNDATIONONE(登録商標)HEME:技術仕様書(Foundation Medicine,Inc.)(出典明示によりその全体が本明細書に取り込まれる)を参照のこと。
表3:全コード配列がFOUNDATIONONE(登録商標)Hemeアッセイでアッセイされる遺伝子リスト。
表4:選択されたイントロンがFOUNDATIONONE(登録商標)Hemeアッセイでアッセイされる遺伝子リスト。
表5:RNA配列がFOUNDATIONONE(登録商標)Hemeアッセイでアッセイされる遺伝子リスト。
1の実施態様において、TMBは、EXODX(登録商標)固形腫瘍アッセイを用いて測定される。EXODX(登録商標)固形腫瘍アッセイは、癌経路における実用的な変異を検出するexoRNAおよびcfDNAに基づくアッセイである。前記EXODX(登録商標)固形腫瘍アッセイは、組織試料を必要としない血漿に基づくアッセイである。EXODX(登録商標)固形腫瘍アッセイは、26個の遺伝子および1000個の変異を網羅する。EXODX(登録商標)固形腫瘍アッセイで網羅される特定の遺伝子が表6に示される。2018年3月16日に最終訪問したexosomedx.comで利用可能な血漿に基づく固形腫瘍変異パネル液体生検(Exosome Diagnostics,Inc.)を参照のこと。
表6:EXODX(登録商標)固形腫瘍アッセイで網羅される遺伝子。
ある実施態様において、TMB状態は、Guardant360アッセイを用いて決定される。Guardant360アッセイは、少なくとも73個の遺伝子(表7)、23個のインデル(表8)、18個のCNV(表9)、および6個の融合遺伝子(表10)の変異を測定する。2018年3月16日に最終訪問したGuardantHealth.comを参照のこと。
表7:Guardant360アッセイ遺伝子。
ある実施態様において、TMBは、TruSight腫瘍170アッセイ(ILLUMINA(登録商標))を用いて決定される。前記TruSight腫瘍170アッセイは、DNAおよびRNAを同時に解析する一般的な固形腫瘍に関連する170個の遺伝子を網羅する次世代シークエンシングアッセイである。前記TruSight腫瘍170アッセイは、融合、スプライス変異体、挿入/欠失、一ヌクレオチド変異型(SNV)、および増幅を評価する。前記TruSight腫瘍170アッセイ遺伝子リストは、表11~13に示される。
表11:TruSight腫瘍170アッセイ遺伝子(増幅)。
FOUNDATIONONE(登録商標)CDXTM(「F1CDx」)は、ホルマリンで固定されたパラフィン包埋(FFPE)腫瘍組織試料から単離されたDNAを用いて、324個の遺伝子および選択された遺伝子再配列、ならびにゲノム特性(マイクロサテライト不安定性(MSI)および腫瘍変異量(TMB)を含む)における置換、挿入および欠失の変化(インデル)、およびコピー数変化(CNA)の検出のための次世代シークエンシングに基づくインビトロ診断装置である。F1CDxは、NSCLC、黒色腫、乳癌、結腸直腸癌、および卵巣癌を含むいくつかの腫瘍への適用について米国食品医薬品局(FDA)に認可されている。
表14:置換、挿入および欠失(インデル)、ならびにコピー数変化(CNA)の検出のためのFOUNDATIONONE(登録商標)CDX(登録商標)に含まれる全コーディングエクソン領域を有する遺伝子。
ある実施態様において、TMB状態は、MSK-IMPACT(登録商標)アッセイを用いてアッセイされる。前記MSK-IMPACT(登録商標)アッセイは、468個の遺伝子の変異状態を解析するために次世代シークエンシングを用いる。標的遺伝子は、ILLUMINA(登録商標)HISEQ(登録商標)装置で捕捉され、配列決定される。前記MSK-IMPACT(登録商標)アッセイは、固形悪性腫瘍の体細胞変異およびマイクロサテライト不安定性の検出について米国FDAに認可されている。MSK-IMPACT(登録商標)アッセイによって分析される468個の遺伝子の全リストは、表16に示される。accessdata.fda.govで2017年11月15日に利用可能なEvaluation of Automatic Class III Designation for MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets): Decision Summary(米国食品医薬品局)を参照のこと。
表16:MSK-IMPACT(登録商標)アッセイによって分析される遺伝子。
ある実施態様において、TMBは、NEOGENICS(登録商標)NEOTYOPE(登録商標)アッセイを用いて決定される。ある実施態様において、前記TMBは、NEOTYPE(登録商標)ディスカバリープロフィールを用いて決定される。ある実施態様において、前記TMBは、NEOTYPE(登録商標)固形腫瘍プロフィールを用いて決定される。NEOGENICS(登録商標)アッセイは、配列決定されたDNAの1メガベースあたりの非同義DNAコード配列の変化の数を測定する。
ある実施態様において、TMBは、THERMOFISHER SCIENTIFIC(登録商標)ONCOMINE(登録商標)腫瘍変異アッセイを用いて決定される。ある実施態様において、TMBは、THERMOFISHER SCIENTIFIC(登録商標)ION TORRENT(登録商標)ONCOMINE(登録商標)腫瘍変異アッセイを用いて決定される。ION TORRENT(登録商標)ONCOMINE(登録商標)腫瘍変異アッセイは、腫瘍変異量を決定するために体細胞変異を定量化する標的化NGSアッセイである。前記アッセイは、1.7MbのDNAを網羅する。
ある実施態様において、TMBは、NOVOGENE(登録商標)NOVOPM(登録商標)アッセイを用いて決定される。ある実施態様において、TMBは、NOVOGENE(登録商標)NOVOPM(登録商標)癌パネルアッセイを用いて決定される。NOVOGENE(登録商標)NOVOPM(登録商標)癌パネルアッセイは、548個の遺伝子の全コード領域および21個の遺伝子のイントロン(約1.5MbのDNAを表す)を解析し、全米総合癌情報ネットワーク(NCCN)ガイドラインおよび医学文献による固形腫瘍の診断および/または治療に適する網羅的NGS癌パネルである。前記アッセイは、SNV、インデル、融合、およびコピー数変異(CNV)のゲノム異常を検出する。
ある実施態様において、TMBは、CARIS(登録商標)ライフサイエンスから供されるTMBアッセイを用いて決定される。ある実施態様において、TMBは、PESONALIS(登録商標)ACEIMMUNOIDアッセイを用いて決定される。ある実施態様において、TMBは、PGDX(登録商標)CANCERXOME(登録商標)-Rアッセイを用いて決定される。
本方法は、いずれのステージの腫瘍も治療することができる。ある実施態様において、前記腫瘍は、いずれものステージにおけるNSCLCに由来する。NSCLCに用いられる少なくとも7つのステージ(潜在(隠れた)ステージ、ステージ0(生体で癌腫)、ステージI、ステージII、ステージIIIA、ステージIIIB、およびステージIV)が存在する。潜在ステージにおいて、前記癌は、画像化または気管支鏡検査によって観察することはできない。ステージ0において、癌細胞は、気道の被覆(lining)で見出される。
当該技術分野で公知の抗PD-1抗体は、本明細書に記載の組成物および方法において用いることができる。高い親和性でPD-1に特異的に結合する様々なヒトモノクローナル抗体は、米国特許第8,008,449号に記載されている。抗PD-1ヒト抗体は、1つまたは以上の下記の特徴を示すことが示されている米国特許第8,008,449号に記載されている:(a)Biacoreバイオセンサーシステムを用いる表面プラズモン共鳴によって調べられるように、1x10-7Mまたはそれ以下の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細胞の増殖を増加させる;(d)MLRアッセイにおいてインターフェロン-γの産生を増加させる;(e)MLRアッセイにおいてIL-2分泌を増加させる;(f)ヒトPD-1およびカニクイザルPD-1に結合する;(g)PD-1に対するPD-L1および/またはPD-L2の結合を阻害する;(h)抗原特異的記憶応答を活性化する;(i)抗体応答を活性化する;および(j)インビボでの腫瘍細胞の増殖を阻害する。本開示で用いることができる抗PD-1抗体には、ヒトPD-1に特異的に結合し、前記特徴のうちの少なくとも1つ、ある実施態様において、少なくとも5つを示すモノクローナル抗体が含まれる。
ある実施態様において、本方法に用いられる抗PD-1抗体は、別のPD-1または抗PD-L1アンタゴニストと置き換えることができる。例えば、抗PD-L1抗体は、PD-1およびPD-L1の相互作用を阻害し、それによりPD-1シグナル伝達経路に対して同様の効果を示すことから、抗PD-L1抗体は、本明細書に記載の方法における抗PD-1抗体の使用に置き換えることができる。当該技術分野で公知の抗PD-L1抗体は、本開示の組成物および方法で使用することができる。本開示の組成物および方法において有用な抗PD-L1抗体の例として、米国特許第9,580,507号に記載の抗体が含まれる。抗PD-L1ヒトモノクローナル抗体は、下記の特性のうちの1つまたはそれ以上を示すことが示されている米国特許第9,580,507号に記載されている:(a)Biacoreバイオセンサーシステムを用いて表面プラズモン共鳴によって調べられるように、1x10-7Mまたはそれ以下のKDでヒトPD-L1に結合する;(b)混合リンパ球反応(MLR)アッセイにおいてT細胞の増殖を増加させる;(c)MLRアッセイにおいてインターフェロン-γ産生を増加させる;(d)MLRアッセイにおいてIL-2分泌を増加させる;(e)抗体応答を活性化する;および(f)T細胞エフェクター細胞および/または樹状細胞におけるT調節性細胞の効果を逆転させる。本開示で用いることができる抗PD-L1抗体には、ヒトPD-L1に特異的に結合し、前記特徴のうちの少なくとも1つ、ある実施態様において、少なくとも5つを示すモノクローナル抗体が含まれる。
異なるタイプの癌の標準治療は、当業者に周知である。例えば、全米総合癌情報ネットワーク(NCCN)(米国における21個の主要な癌センターの連合)は、多種多様の癌の標準治療における詳細な最新情報を提供する腫瘍学におけるNCCN標準治療ガイドライン(NCCN GUIDELINES(登録商標))を公表している(NCCN GUIDELINES(登録商標)(2014)(2014年5月14日に最近アクセスした:www.nccn.org/professionals/physician_gls/pdf/nscl.pdfにて利用可能)を参照のこと)。
複数の標的療法に対して進行してしまった患者、ならびに現在の標準治療を超えたより長期間の生存率を延長させる治療のために有効な薬剤の必要性が明確に存在している。免疫療法、とりわけ、免疫チェックポイントの遮断(CTLA-4、PD-1、およびPD-L1阻害経路を含む)に関する最近のアプローチは有望性が示されている(Creelan et al. (2014) Cancer Control 21(1):80-89)。しかしながら、免疫療法に対してより応答性を示しうる患者を同定すること、特に、抗PD-1または抗PD-L1抗体治療に対してより応答性を示す可能性のある患者を同定する必要性が残っている。
本開示の治療剤は、組成物、例えば、1つまたはそれ以上の抗体および医薬的に許容される担体を含む医薬組成物中で構成されうる。本明細書で用いられる「医薬的に許容される担体」には、生理学的に適合性を有するいずれか全ての溶媒、分散媒体、コーティング剤、抗菌および抗真菌剤、等張および吸収遅延剤などが含まれる。1の実施態様において、抗体を含有する組成物のための担体は、(例えば、注射または注入による)静脈内、筋肉内、皮下、非経口、脊髄、または上皮投与に適する。本開示の医薬組成物は、1つまたはそれ以上の医薬的に許容される塩、酸化防止剤、水性および非水性担体、および/またはアジュバント(例えば、防腐剤、湿潤剤、乳化剤および分散剤)を含みうる。
抗PD-1抗体または抗PD-L1抗体を含むキットもまた本発明の範囲内である。キットには、一般に、キットの内容物の目的とする使用を示す表示および使用説明書が含まれる。用語「表示」には、キット中またはキットとともに供され、またはキットに付属する物質の記載または記録が含まれる。よって、本開示は、腫瘍に罹患している対象を治療するためのキットであって、(a)約4mg~約500mgの範囲の用量の抗PD-1抗体;および(b)本明細書に記載の方法における抗PD-1抗体の使用説明書を含むキットを提供する。ヒト患者を治療するためのある実施態様において、前記キットには、本明細書に記載の抗ヒトPD-1抗体、例えば、ニボルマブまたはペムブロリズマブが含まれる。ある実施態様において、前記キットには、抗PD-L1抗体がさらに含まれる。ある実施態様において、前記キットには、腫瘍試料におけるSTK11の変異状態を検出するための説明書がさらに含まれる。他の実施態様において、前記キットには、腫瘍試料におけるPD-L1の発現を検出するための説明書がさらに含まれる。
PD-L1は、異なる発現パターンによりNSCLC腫瘍(例えば、市販のNSCLC腫瘍)で発現される(図1)。これらのパターンを、散在、不均一、腫瘍間質接合面、および陰性と表した。PD-L1発現パターンは、メカニズム仮説に関連しうる。例えば、散在パターンの腫瘍では、前記PD-L1の発現は、突然変異によって駆動されるのではなく、発癌シグナル伝達経路における9p24増幅により駆動される。腫瘍間質接合面パターンの腫瘍では、上皮間葉転換(EMT)ではなく適応耐性が存在する。
非盲検無作為化第3相臨床試験は、PD-L1陽性NSCLCを有する患者における第一選択の抗PD-1モノクローナル抗体(ニボルマブ)治療の効果を試験するために行った。未治療のステージIVまたは再発性NSCLCに罹患し、1%またはそれ以上のPD-L1腫瘍発現レベルの患者は、ニボルマブ(体重の3mg/kgの用量で2週間ごとに1回静脈内投与)または白金を用いた化学療法(3週間ごとに1回投与)を6サイクルまで受ける。
非盲検無作為化第3相臨床試験は、白金を用いた二剤化学療法中またはその後に進行した非扁平上皮NSCLCを有する患者における第二選択の抗PD-1モノクローナル抗体(ニボルマブ)治療の効果を試験するために行った。患者にニボルマブ(体重の3mg/kgの用量で2週間ごとに1回静脈内投与)またはドセタキセル(75mg/m2の用量で3週間ごとに1回投与)を投与した。
非盲検無作為化第3相臨床試験は、白金を用いた二剤化学療法中またはその後に進行した扁平上皮NSCLCを有する患者における第二選択の抗PD-1モノクローナル抗体(ニボルマブ)治療の効果を試験するために行った。患者にニボルマブ(体重の3mg/kgの用量で2週間ごとに1回静脈内投与)またはドセタキセル(75mg/m2の用量で3週間ごとに1回投与)を投与した。
Claims (15)
- 腫瘍に罹患している対象を治療するための、プログラム死-1(PD-1)受容体に特異的に結合し、PD-1活性を阻害する抗体またはその抗原結合部分(「抗PD-1抗体」)であって、前記対象が、野生型STK11遺伝子を有すると同定されているものである、前記抗体。
- 前記対象が、KRAS、TP53、CDKN2A、PTPND、CUBN、HERC1、およびこれらのいずれかの組み合わせからなる群から選択される変異型マーカー遺伝子を有すると同定されているものである、請求項1に記載の抗PD-1抗体。
- 腫瘍に罹患している対象を治療するための、プログラム死-1(PD-1)受容体に特異的に結合し、PD-1活性を阻害する抗体またはその抗原結合部分(「抗PD-1抗体」)であって、前記対象が、変異型マーカー遺伝子を有すると同定され、前記マーカー遺伝子が、TP53、CDKN2A、PTPND、CUBN、HERC1、およびこれらのいずれかの組み合わせからなる群から選択されるものである、前記抗体。
- 前記マーカー遺伝子が、非同義変異、ナンセンス、フレームシフト、またはスプライシング変異を含むものである、請求項2または3に記載の抗PD-1抗体。
- 前記腫瘍が、肺癌に由来する、請求項1~4のいずれかに記載の抗PD-1抗体。
- 前記腫瘍が、小細胞肺癌(SCLC)または非小細胞性肺癌(NSCLC)に由来する、請求項5に記載の抗PD-1抗体。
- PD-L1発現が、前記抗PD-1抗体の投与前に腫瘍で検出される、請求項1~6のいずれかに記載の抗PD-1抗体。
- 前記腫瘍が、PD-L1を散在パターンまたは不均一パターンで発現する、請求項7に記載の抗PD-1抗体。
- 前記腫瘍が、高TMBである腫瘍変異量(TMB)状態を有する、請求項1~8のいずれかに記載の抗PD-1抗体。
- 前記腫瘍TMB状態が、前記腫瘍における核酸を配列決定し、次いで配列決定された核酸におけるゲノム変化を同定することによって決定されるものであって、前記ゲノム変化が、体細胞変異、非同義変異、ミスセンス変異、塩基対置換、塩基対挿入、塩基対欠失、コピー数変化(CNA)、遺伝子再配列、およびこれらのいずれかの組み合わせからなる群から選択される1つまたはそれ以上の変化を含むものである。請求項9に記載の抗PD-1抗体。
- 前記腫瘍が、高い炎症を示す。請求項1~10のいずれかに記載の抗PD-1抗体。
- 前記抗PD-1抗体が、ニボルマブまたはペムブロリズマブである、請求項1~11のいずれかに記載の抗PD-1抗体。
- 前記抗PD-1抗体が、少なくとも約0.1mg/kg~少なくとも約10.0mg/kg体重の範囲の用量で約1、2、または3週間ごとに1回投与される、請求項1~12のいずれかに記載の抗PD-1抗体。
- 前記抗PD-1抗体またはその抗原結合部分が、約240mgまたは約480mgのフラット用量で約1、2、3、または4週間ごとに1回投与される。請求項1~13のいずれかに記載の抗PD-1抗体。
- 腫瘍に罹患している対象を治療するためのキットであって、
(a)約4mg~約500mgの範囲の用量の抗PD-1抗体;および
(b)前記抗PD-1抗体を、野生型STK11遺伝子を有すると同定されている対象に投与するための説明書を含む、キット。
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