JP2022513700A - 放射性免疫複合体とチェックポイント阻害剤の併用療法 - Google Patents
放射性免疫複合体とチェックポイント阻害剤の併用療法 Download PDFInfo
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Abstract
Description
本願は、2018年12月3日付で出願された米国特許仮出願第62/774,847号に対する優先権を主張し、その全内容はあらゆる目的において参照により本明細書に組み込まれる。
(iii)哺乳動物に放射性免疫複合体を投与するのと同時に哺乳動物に1またはそれを超えるチェックポイント阻害剤を投与するステップを含む。
化学用語:
本明細書において使用される「アシル」という用語は、本明細書において定義されるようにカルボニル基を通じて親分子基に結合されている、本明細書において定義される水素またはアルキル基(例えば、ハロアルキル基)を表し、ホルミル(すなわち、カルボキシアルデヒド基)、アセチル、トリフルオロアセチル、プロピオニル、ブタノイルなどに例示される。例示的な非置換アシル基は、1~7、1~11、または1~21個の炭素を含む。一部の実施形態では、アルキル基は、本明細書に記載される1、2、3または4つの置換基でさらに置換される。
E’は、-N-および-CH-からなる群より選択され;F’は、-N=CH-、-NH-CH2-、-NH-C(O)-、-NH-、-CH=N-、-CH2-NH-、-C(O)-NH-、-CH=CH-、-CH2-、-CH2CH2-、-CH2O-、-OCH2-、-O-、および-S-からなる群より選択される;G’は、-CH-および-N-からなる群より選択される。本明細書で言及されるヘテロシクリル基はいずれも、必要に応じて、以下からなる群より独立に選択される1、2、3、4、または5個の置換基で置換されていてもよい:(1)C1-7アシル(例えば、カルボキシアルデヒド);(2)C1-20アルキル(例えば、C1-6アルキル、C1-6アルコキシ-C1-6アルキル、C1-6アルキルスルフィニル-C1-6アルキル、アミノ-C1-6アルキル、アジド-C1-6アルキル、(カルボキシアルデヒド)-C1-6アルキル、ハロ-C1-6アルキル(例えば、パーフルオロアルキル)、ヒドロキシ-C1-6アルキル、ニトロ-C1-6アルキル、またはC1-6チオアルコキシ-C1-6アルキル);(3)C1-20アルコキシ(例えば、C1-6アルコキシ、例えばパーフルオロアルコキシなど);(4)C1-6アルキルスルフィニル;(5)C6-10アリール;(6)アミノ;(7)C1-6 alk-C6-10アリール;(8)アジド;(9)C3-8シクロアルキル;(10)C1-6 alk-C3-8シクロアルキル;(11)ハロ;(12)C1-12ヘテロシクリル(例えば、C2-12ヘテロアリール);(13)(C1-12ヘテロシクリル)オキシ;(14)ヒドロキシ;(15)ニトロ;(16)C1-20チオアルコキシ(例えば、C1-6チオアルコキシ);(17)-(CH2)qCO2RA’(ここでqは0~4の整数であり、RA’は、(a)C1-6アルキル、(b)C6-10アリール、(c)水素、および(d)C1-6 alk-C6-10アリールからなる群より選択される);(18)-(CH2)qCONRB’RC’(ここで、qは0~4の整数であり、RB’およびRC’は独立に、(a)水素、(b)C1-6アルキル、(c)C6-10アリール、および(d)C1-6 alk-C6-10アリールからなる群より選択される);(19)-(CH2)qSO2RD’(ここで、qは0~4の整数であり、RD’は、(a)C1-6アルキル、(b)C6-10アリール、および(c)C1-6 alk-C6-10アリールからなる群より選択される);(20)-(CH2)qSO2NRE’RF’(ここで、qは0~4の整数であり、RE’とRF’の各々は、独立に、(a)水素、(b)C1-6アルキル、(c)C6-10アリール、および(d)C1-6 alk-C6-10アリールからなる群より選択される);(21)チオール;(22)C6-10アリールオキシ;(23)C3-8シクロアルコキシ;(24)アリールアルコキシ;(25)C1-6 alk-C1-12ヘテロシクリル(例えば、C1-6 alk-C1-12ヘテロアリール);(26)オキソ;(27)(C1-12ヘテロシクリル)イミノ;(28)C2-20アルケニル;および(29)C2-20アルキニル。一部の実施形態では、これらの基の各々は、本明細書に記載されるようにさらに置換することができる。例えば、C1-アルカリルまたはC1-アルクヘテロシクリルのアルキレン基は、さらにオキソ基で置換されて、それぞれのアリーロイルおよび(ヘテロシクリル)オイル置換基を得ることができる。
本明細書で使用される、「組合せ投与」、「併用投与」または「同時投与」という用語は、2またはそれを超える薬剤が同時に、または患者に対する各薬剤の効果が重複する可能性があるような間隔で被験体に投与されることを意味する。したがって、組合せて投与される2またはそれを超える薬剤は一緒に投与する必要はない。一部の実施形態では、これらは互いに90日以内(例えば、80、70、60、50、40、30、20、10、5、4、3、2、または1日以内)に投与される、28日以内(例えば、14、7、6、5、4、3、2、または1日以内)、24時間以内(例えば、12、6、5、4、3、2、または1時間以内)、または約60、30、15、10、5、または1分以内に投与される。一部の実施形態では、薬剤の投与は、組合せの効果が達成されるように十分に接近した間隔で行われる。
本開示に従う使用に適した放射性免疫複合体は、一般に、式I-aの構造を有する:
A-L-B
式I-a
式中、Aはキレート部分またはその金属錯体であり)、
式中、Bは標的化部分であり、
式中、Lはリンカーである。
標的化部分には、所与標識に結合できる分子または分子の任意の部分が含まれる。一部の実施形態では、標的化部分は、タンパク質またはポリペプチドを含む。一部の実施形態では、標的化部分は、抗体またはその抗原結合フラグメント、ナノボディ、アフィボディ、およびフィブロネクチンIII型ドメイン(例えば、センチリンまたはアドネクチン)のコンセンサス配列からなる群より選択される。一部の実施形態では、部分は、標的化部分と治療部分の両方である。すなわち、部分は、所与標的に結合でき、治療上の利益も与える。
抗体は一般にジスルフィド結合によって互いに連結された2つの同一のポリペプチド軽鎖と2つの同一のポリペプチド重鎖を含む。各鎖のアミノ末端に位置する第1のドメインはアミノ酸配列が可変であり、個々の抗体の抗体結合特異性を提供する。これらは、可変重鎖(VH)領域および可変軽鎖(VL)領域として公知である。各鎖の他のドメインは、アミノ酸配列が比較的不変であり、定常重(CH)領域および定常軽(CL)領域として公知である。軽鎖は一般に、1つの可変領域(VL)と1つの定常領域(CL)を含む。IgG重鎖には、可変領域(VH)、第1定常領域(CH1)、ヒンジ領域、第2定常領域(CH2)、および第3定常領域(CH3)が含まれる。IgEおよびIgM抗体では、重鎖には、さらなる定常領域(CH4)が含まれる。
インスリン様成長因子1受容体は、インスリン様成長因子1(IGF-1)および2(IGF-2)によって活性化されたヒト細胞の表面に見出される膜貫通タンパク質である。一部の実施形態では、放射性免疫複合体は、インスリン様成長因子-1受容体(IGF-1R)に対する抗体を含む。典型的ながん遺伝子ではないが、IGF-1Rは、がんの開始および進行を促進し、***促進性の形質転換および形質転換された表現型の維持において重要な役割を果たす。IGF-1Rは、乳がん、肺がん(例えば、非小肺がん)、肝臓がん、前立腺がん、膵臓がん、卵巣がん、結腸がん、黒色腫、副腎皮質癌、およびさまざまな種類の肉腫を含む、複数の一般的ながんの発症に関連している。IGF-1Rシグナル伝達は、腫瘍細胞の増殖と代謝を刺激し、血管新生を支援し、アポトーシスからの保護を付与する。それは、転移因子(例えば、HIF-1依存性低酸素シグナル伝達)、足場非依存性増殖、ならびに血管外漏出後の腫瘍転移の増殖および生存に影響を与える。IGF-1Rは、治療抵抗性のがん幹細胞集団の発生、維持、および濃縮にも関与している。
配列番号1(CDR-L1)RSSQSIVHSNVNTYLE
配列番号2(CDR-L2)KVSNRFS
配列番号3(CDR-L3)FQGSHVPPT
AVE1642の軽鎖可変領域は、次の配列を有する:
配列番号4
DVVMTQTPLSLPVSLGDPASISCRSSQSIVHSNVNTYLEWYLQKPGQSPRLLIYKVSNRF
SGVPDRFSGSGAGTDFTLRISRVEAEDLGIYYCFQGSHVPPTFGGGTKLEIKRTVAAPSV
FIFPPSDEQLKSGTASVVCLLNNFYPREAK
AVE1642の重鎖可変領域のCDRは、次の配列を有する:
配列番号5(CDR-H1)SYWMH
配列番号6(CDR-H2)GEINPSNGRTNY NQKFQG
配列番号7(CDR-H3)GRPDYYGSSKWY FDV
AVE1642の重鎖可変領域は、次の配列を有する:
配列番号8
QVQLVQSGAEVVKPGASVKLSCKASGYTFTSYWMHWVKQRPGQGLEWIGEINPSNGRTNY
NQKFQGKATLTVDKSSSTAYMQLSSLTSEDSAVYYFARGRPDYYGSSKWYFDVWGQGTTV
TVSSASTKGPSVFPLAPSSKSTSGGTAALG
TEM-1またはCD-248としても公知であるエンドシアリンは、腫瘍関連内皮細胞、間質細胞、および周皮細胞によって発現される抗原である。
CDR-H1:GYGVN(配列番号10)またはGFSLTGYGVN(配列番号11)
CDR-H2:MIWVDGSTDYNSALKS(配列番号12)
CDR-H3:GGYGAMDY(配列番号13)
CDR-L1:HASQNINVWLT(配列番号14)
CDR-L2:KASNLHT(配列番号15)
CDR-L3:QQGQSYPWT(配列番号16)
ヒト化VH1:
QVQLQESGPGLVKPSETLSLTCTVSGFSLTGYGVNWIRQPPGKGLEWIGMIWVDGSTDYN
SALKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGYGAMDYWGQGTLVTVSS
(配列番号17)
ヒト化VH2:
QVQLQESGPGLVKPSETLSLTCTVSGFSLTGYGVNWIRQPPEKGLEWIGMIWVDGSTDYN
SALKSRVNISVDTSKNQFSLKLSSVTAADTAVYYCARGGYGAMDYWGQGTLVTVSS
(配列番号18)
ヒト化VH3:
QLQLQESGPGLVKPSETLSLTCTVSGFSLTGYGVNWIRQPPGKGLEWIGMIWVDGSTDYN
SALKSRVTISVDKSKNQFSLKLSSVTAADTAVYYCARGGYGAMDYWGQGTLVTVSS
(配列番号19)
ヒト化VH4:
QLQLQESGPGLVKPSETLSLTCTVSGFSLTGYGVNWIRQPPEKGLEWIGMIWVDGSTDYN
SALKSRVNISVDKSKNQFSLKLSSVTAADTAVYYCARGGYGAMDYWGQGTLVTVSS
(配列番号20)
ヒト化VL1:
DIQMTQSPSSVSASVGDRVTITCHASQNINVWLTWYQQKPGKAPKLLIYKASNLHTGVPS
RFSGSGSGTDFTLTISSLQPEDFATYYCQQGQSYPWTFGGGTKLEIK
(配列番号21)
ヒト化VL2:
DIQMTQSPSTLSASVGDRVTITCHASQNINVWLTWYQQKPGKAPKLLIYKASNLHTGVPS
RFSGSGSGTEFTLTISSLQPDDFATYYCQQGQSYPWTFGGGTKLEIK
(配列番号22)
ヒト化VL3:
DIQMTQSPSSLSASVGDRVTITCHASQNINVWLTWYQQKPGKAPKLLIYKASNLHTGVPS
RFSGSGSGTDFTFTISSLQPEDIATYYCQQGQSYPWTFGGGTKLEIK
(配列番号23)
ヒト化VL4:
DIQMTQSPSSLSASVGDRVTITCHASQNINVWLTWYQQKPEKAPKSLIYKASNLHTGVPS
RFSGSGSGTDFTLTISSLQPEDFATYYCQQGQSYPWTFGGGTKLEIK
(配列番号24)
ナノボディは、単一の単量体可変抗体ドメインからなる抗体フラグメントである。ナノボディは、単一ドメイン抗体と呼ばれることもある。抗体と同様に、ナノボディは特定の抗原に選択的に結合する。ナノボディは、重鎖可変ドメインまたは軽鎖ドメインであり得る。ナノボディは、天然に存在するものであってもよいし、生物工学による産物であってもよい。ナノボディは、部位特異的変異誘発または変異原性スクリーニング(例えば、ファージディスプレイ、酵母ディスプレイ、細菌ディスプレイ、mRNAディスプレイ、リボソームディスプレイ)によって生物学的に操作される場合がある。
アフィボディは、特定の抗原に結合するように操作されたポリペプチドまたはタンパク質である。したがって、アフィボディは抗体のある機能を模倣していると考えられ得る。アフィボディは、ブドウ球菌プロテインAの免疫グロブリン結合領域内のBドメインの操作された改変体であってよい。アフィボディは、Fab領域に対する親和性が低いBドメインであるZドメインの操作された改変体であってよい。アフィボディは、部位特異的変異誘発または変異原性スクリーニング(例えば、ファージディスプレイ、酵母ディスプレイ、細菌ディスプレイ、mRNAディスプレイ、リボソームディスプレイ)によって生物学的に操作される場合がある。
フィブロネクチンIII型ドメインは、多様な細胞外タンパク質に見られる進化的に保存されたタンパク質ドメインである。フィブロネクチンIII型ドメインは、特定の抗原に選択的に結合できる分子を生成するための分子足場として使用されてきた。選択的結合のために操作されたフィブロネクチンIII型ドメイン(FN3)の改変体は、モノボディと呼ばれることもある。FN3ドメインは、部位特異的変異誘発または変異原性スクリーニング(例えば、CIS-ディスプレイ、ファージディスプレイ、酵母ディスプレイ、細菌ディスプレイ、mRNAディスプレイ、リボソームディスプレイ)によって生物学的に操作される場合がある。
本開示に従って使用されるポリペプチドは、修飾されたアミノ酸配列を有し得る。修飾されたポリペプチドは、対応する参照ポリペプチドと実質的に同一であり得る(例えば、修飾されたポリペプチドのアミノ酸配列は、参照ポリペプチドのアミノ酸配列と少なくとも50%、60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%、または100%の同一性を有し得る)。特定の実施形態では、修飾は、望ましい生物活性(例えば、IGF-1Rまたはエンドシアリンとの結合)を著しく破壊しない。修飾は、元のポリペプチドの生物活性を(例えば、少なくとも5%、10%、20%、25%、35%、50%、60%、70%、75%、80%、90%、または95%)低下させることもあり、影響がないこともあり、(例えば、少なくとも5%、10%、25%、50%、100%、200%、500%、または1000%)増加させることもある。修飾されたポリペプチドは、インビボ安定性、生物学的利用能、毒性、免疫学的活性、免疫学的同一性、およびコンジュゲーション特性などのポリペプチドの特徴を有するかまたは最適化することがある。
キレート部分
適したキレート部分の例としては、限定されるものではないが、DOTA(1,4,7,10-テトラアザシクロドデカン-1,4,7,10-四酢酸)、DOTMA(1R,4R,7R,10R)-α、α’、α’’、α’’’-テトラメチル-1,4,7,10-テトラアザシクロドデカン-1,4,7,10-四酢酸、DOTAM(1,4,7,10-テトラキス(カルバモイルメチル)-1,4,7,10-テトラアザシクロドデカン)、DOTPA(1,4,7,10-テトラアザシクロドデカン-1,4,7,10-テトラプロピオン酸)、DO3AM-酢酸(2-(4,7,10-トリス(2-アミノ-2-オキソエチル)-1,4,7,10-テトラアザシクロドデカン-1-イル)酢酸)、DOTA-GA無水物(2,2’,2”-(10-(2,6-ジオキソテトラヒドロ-2H-ピラン-3-イル)-1,4,7,10-テトラアザシクロドデカン-1,4,7-トリイル)三酢酸、DOTP(1,4,7,10-テトラアザシクロドデカン-1,4,7,10-テトラ(メチレンホスホン酸))、DOTMP(1,4,6,10-テトラアザシクロデカン-1,4,7,10-テトラメチレンホスホン酸、DOTA-4AMP(1,4,7,10-テトラアザシクロドデカン-1,4,7,10-テトラキス(アセトアミド-メチレンホスホン酸)、CB-TE2A(1,4,8,11-テトラアザビシクロ[6.6.2]ヘキサデカン-4,11-二酢酸)、NOTA(1,4,7-トリアザシクロノナン-1,4,7-三酢酸)、NOTP(1,4,7-トリアザシクロノナン-1,4,7-トリ(メチレンホスホン酸)、TETPA(1,4,8,11-テトラアザシクロテトラデカン-1,4,8,11-テトラプロピオン酸)、TETA(1,4,8,11-テトラアザシクロテトラデカン-1,4,8,11-四酢酸)、HEHA(1,4,7,10,13,16-ヘキサアザシクロヘキサデカン-1,4,7,10,13,16-六酢酸)、PEPA(1,4,7,10,13-ペンタアザシクロペンタデカン-N,N’,N’’,N’’’,N’’’’-五酢酸)、H4オクタパ(H4octapa)(N,N’-ビス(6-カルボキシ-2-ピリジルメチル)-エチレンジアミン-N,N’-二酢酸)、H2デドパ(H2dedpa)(1,2-[[6-(カルボキシ)-ピリジン-2-イル]-メチルアミノ]エタン)、H6ホスパ(H6phospa)(N,N’-(メチレンホスホネート)-N,N’-[6-(メトキシカルボニル)ピリジン-2-イル]-メチル-1,2-ジアミノエタン)、TTHA(トリエチレンテトラミン-N,N,N’,N’’,N’’’,N’’’’-六酢酸)、DO2P(テトラアザシクロドデカンジメタンホスホン酸)、HP-DO3A(ヒドロキシプロピルテトラアザシクロドデカン三酢酸)、EDTA(エチレンジアミン四酢酸)、デフェロキサミン、DTPA(ジエチレントリアミン五酢酸)、DTPA-BMA(ジエチレントリアミン五酢酸-ビスメチルアミド)、HOPO(八座ヒドロキシピリジノン)、またはポルフィリンが挙げられる。
一部の実施形態では、金属錯体は、放射性核種を含む。適した放射性同位元素および放射性核種の例としては、限定されるものではないが、3H、14C、15N、18F、35S、47Sc、55Co、60Cu、61Cu、62Cu、64Cu、66Ga、67Ga、67Cu、68Ga、75Br、76Br、77Br、82Rb、89Zr、86Y、87Y、90Y、97Ru、99Tc、99mTc、105Rh、109Pd、111In、123I、124I、125I、131I、149Pm、149Tb、153Sm、166Ho、177Lu、117mSn、186Re、188Re、198Au、199Au、201Tl、203Pb、211At、212Pb、212Bi、213Bi、223Ra、225Ac、227Th、および229Thが挙げられる。
一部の実施形態では、リンカーは、式I-bの構造内に示されるように、式I-bのAおよびBを含まない部分である:
A-L1-(L2)n-B
式I-b
(AおよびBは、式I-aに定義される通りである)。
したがって、一部の実施形態では、リンカーは、-L1-(L2)n-であり、
式中、L1は、必要に応じて置換されたC1-C6アルキル、置換されたC1-C6ヘテロアルキル、置換されたアリールまたはヘテロアリールであり;
nは、1~5であり;
各L2は、独立に、次の構造を有する:
(-X1-L3-Z1-)
式II
式中、X1は、C=O(NR1)、C=S(NR1)、OC=O(NR1)、NR1C=O(O)、NR1C=O(NR1)、-CH2PhC=O(NR1)、-CH2Ph(NH)C=S(NR1)、O、またはNR1であり;各R1は、独立に、Hまたは必要に応じて置換されたC1-C6アルキルまたは必要に応じて置換されたC1-C6ヘテロアルキル、置換されたアリールまたはヘテロアリールであり、ここで、C1-C6アルキルは、オキソ(=O)、ヘテロアリール、またはそれらの組合せで置換されていてよい;
L3は、必要に応じて置換されたC1-C50アルキルまたは必要に応じて置換されたC1-C50ヘテロアルキルまたはC5-C20ポリエチレングリコールであり;Z1は、CH2、C=O、C=S、OC=O、NR1C=O、NR1であり、R1は、水素または必要に応じて置換されたC1-C6アルキル、ピロリジン-2,5-ジオンである。
一部の実施形態では、放射性免疫複合体は、標的化部分または治療部分の代わりに、またはそれらに加えて、架橋基を含む(例えば、式IのBは、架橋基を含む)。
一部の実施形態では、チェックポイント阻害剤は放射性免疫複合体と同時投与される。一般に、適したチェックポイント阻害剤は、免疫抑制チェックポイントタンパク質を阻害する。一部の実施形態では、チェックポイント阻害剤は、細胞傷害性Tリンパ球関連抗原4(CTLA-4)、プログラム細胞死1(PD-1)、プログラム細胞死リガンド-1(PD-L1)、LAG-3、T細胞免疫グロブリンムチン3(TIM-3)、およびキラー免疫グロブリン様受容体(KIR)からなる群より選択されるタンパク質を阻害する。
一部の開示される方法では、治療(例えば、治療剤を含む)が被験体に投与される。一部の実施形態では、被験体は哺乳動物、例えば、ヒトである。
有効用量およびより低い有効用量
本開示は、各治療薬の量がそれ自体で治療上有効であってもなくてもよい併用療法を提供する。例えば、第1の治療および第2の治療を、障害、例えば、がんを処置するかまたは好転させるのに有効な量で一緒に投与することを含む方法が提供される。一部の実施形態では、第1および第2の治療の少なくとも1つは、より低い有効用量で被験体に投与される。一部の実施形態では、第1および第2の治療は両方とも、より低い有効用量で投与される。
薬学的組成物は、予防的および/または治療的処置のために、非経口、鼻腔内、局所、経口、または経皮的手段などによる局所投与のために製剤化され得る。薬学的組成物は、非経口的に(例えば、静脈内、筋肉内、または皮下注射によって)、あるいは経口摂取によって、あるいは、血管またはがんの状態によって影響を受ける領域への局所適用または関節内注射によって投与することができる。さらなる投与経路の例としては、血管内、動脈内、腫瘍内、腹腔内、脳室内、上皮内、ならびに鼻、眼、強膜内、眼窩内、直腸、局所、またはエアロゾル吸入投与が挙げられる。また、デポー注射または侵食性のインプラントまたは成分などの手段による持続放出投与も特に企図されている。適した組成物には、例えば非経口投与用の、許容され得る担体、好ましくは水性担体、例えば、数ある中でも、水、緩衝化水、食塩水、またはPBSなどに溶解または懸濁させた薬剤(例えば、本明細書に開示される化合物)を含む組成物が含まれる。組成物は、生理学的条件を近似させるために、薬学的に許容され得る補助物質、例えば、数ある中でも、pH調整剤および緩衝化剤、張度調整剤、湿潤剤、または洗剤などを含んでいてよい。一部の実施形態では、組成物は経口送達用に製剤化される;例えば、組成物は、錠剤またはカプセル剤などの単位剤形の製剤のための結合剤またはフィラーなどの不活性成分を含んでよい。一部の実施形態では、組成物は、局所投与用に製剤化される;例えば、組成物は、クリーム、軟膏、ゲル、ペースト、または点眼薬の製剤のための溶媒または乳化剤などの不活性成分を含んでよい。
一部の実施形態では、本開示の方法は、治療効果をもたらす。一部の実施形態では、治療効果は免疫応答を含み、例えば、免疫応答はT細胞、例えばCD8+(例えば、IFNγ産生CD8+細胞)および/またはCD4+細胞の増加を含む。一部の実施形態では、T細胞は、処置または改善されているがんに発現する腫瘍関連抗原または腫瘍特異的抗原に特異的なT細胞を含む。一部の実施形態では、T細胞の増加は、脾臓と比較して腫瘍で観察される。
その他の薬剤
2つのチェックポイント阻害剤(PD-1およびCTLA-4)の単剤有効性試験を、マウス結腸癌モデルであるCT-26モデルで実施した。これらの癌腫は、α-PD-1mAbに部分的に感受性があり、α-CTLA-4mAbに感受性があることが知られている。マウスに、α-PD-1mAbまたはα-CTLA-4mAbのいずれかの5または15mg/kgのいずれかを腹腔内注射した。α-PD-1mAb群は、週2回4週間投与された。α-CTLA-4mAb群は、3日の間隔で1日3回だけ投与された。このモデルで予想されるように、CTLA-4処置のほうがPD-1処置よりも有効であった。両方の処置群では、5mg/kgが、腫瘍の増殖を最も有効に損なう用量であると思われた。図1を参照されたい。異なる処置の後のCD8+/CD4+T細胞の動員も、免疫組織化学およびフローサイトメトリー技術を用いて測定される。
IGF-1Rに対するネズミモノクローナル抗体であるMAB391を、FPI-1397(二官能性キレート)とコンジュゲ―ションさせ、当技術分野で周知の方法を使用してLu-177で放射性標識して、[177Lu]-FPI-1755を形成した。インビボで抗原を発現するマウスIGF-1R過剰発現腫瘍を標的とする[177Lu]-FPI-1755の能力を、CT-26同系モデルを使用して実証した。腫瘍の取り込みは、15~17%の注射用量/g(ID/g)で、注射後24~96時間安定していた。図2を参照されたい。
IGF-1Rに対するネズミモノクローナル抗体であるMAB391を、FPI-1397(二官能性キレート)とコンジュゲ―ションさせ、標準的な技法を使用して[225Ac]で放射性標識して、[225Ac]-FPI-1792を形成した。免疫適格マウスおよび免疫不全マウスにおける[225Ac]-FPI-1792の有効性試験は、400nCi線量の[225Ac]-FPI-1792を使用して実施された。[225Ac]-FPI-1792は、免疫系のないマウスと比較して、免疫系が無傷のマウスの腫瘍体積を減少させる効果が高いことがわかった。図3を参照されたい。
インビボ相乗効果試験を実施して、CT26マウスモデルの相対的腫瘍体積に対する[225Ac]-FPI-1792(実施例3に記載)およびチェックポイント阻害剤、α-CTLA-4およびα-PD-1抗体の効果を試験した。CTLA-4阻害剤のみ、またはPD-1阻害剤のみのいずれかで処置したマウスは、ビヒクル対照群と比較した場合に、相対的腫瘍体積の中程度の減少を示した。[225Ac]-FPI-1792で処置したマウスは、ビヒクル対照群あるいはCTLA-4阻害剤またはPD-1阻害剤のみを投与された群と比較して、腫瘍体積の大きな減少を示した。しかし、[225Ac]-FPI-1792を、CTLA-4またはPD-1のどちらかあるいはその両方と同時投与した場合には、相乗作用が見られた。同時投与により、[225Ac]-FPI-1792による処置と比較した場合、またはCTLA-4阻害剤またはPD-1阻害剤のみによる処置と比較した場合に、有意に小さい腫瘍体積をもたらした。図4を参照されたい。
再負荷実験を実施して、CT26再負荷時の[225Ac]-FPI-1792処置マウスにおける防御免疫の発生を試験した。マウスは以前に[225Ac]-FPI-1792単独で、またはα-CTLA-4またはα-PD-1抗体と組み合わせて処置されていた。ナイーブマウスを対照として使用した。以前に[225Ac]-FPI-1792+/-抗CTLA-4または抗PD-1抗体で処置したマウスはすべて、腫瘍負荷から保護され、防御T細胞免疫の発生を示唆している。図5を参照されたい。
[225Ac]-FPI-1792処置後のサイトカイン応答およびT細胞動員を測定する。マウスに1×106個のCT26細胞を接種した。次に、マウスを、[225Ac]-FPI-1792、コンジュゲ―ションされていないMAB391抗体またはビヒクルのいずれかで処置した。24、48、または72時間後に腫瘍、脾臓、および血漿の試料をサイトカインの存在について分析する。72時間、5日および8日での免疫組織化学用に追加の試料を腫瘍および脾臓から採取して、さまざまなT細胞型の存在を評価する。最後に、8日目に、腫瘍浸潤リンパ球を抽出し、分離し、フローサイトメトリーを用いて定量化する。図6を参照されたい。
Ac-TAB-199は、225-アクチニウムで標識したヒトモノクローナルIGF-1R抗体を含む放射性免疫複合体である。Ac-TAB-199とチェックポイント阻害剤(α-PD-1、α-CTLA-4、またはα-PD-1とα-CTLA-4の両方)との組合せを、CT26同系マウスモデルで試験した。最初の腫瘍接種から28日目に、マウスにCT26細胞を再負荷した。再負荷後、CD8+およびCD4+のT細胞集団を、脾臓と腫瘍の両方で評価した。Ac-TAB-199とチェックポイント阻害剤で処置したマウスは、脾臓と腫瘍の両方でCD8+T細胞の存在を示した。重要なことに、対照と比較して、腫瘍におけるCD8+T細胞の頻度の増加が観察された。これらの結果は、これらの併用処置が治療上有効なCD8+T細胞のレベルの向上につながることを示唆している。
当業者は、本明細書に記載される特定の実施形態に対する多くの均等物を認識するか、または日常的な実験のみを使用して確認できるであろう。そのような均等物は、以下の特許請求の範囲に含まれることが意図される。
Claims (44)
- 哺乳動物の腫瘍に対する免疫応答を誘導する方法であって、前記方法は、
(i)前記哺乳動物に放射性免疫複合体を投与するステップであって、前記哺乳動物は1またはそれを超えるチェックポイント阻害剤を投与済みであるかまたは投与中である、ステップ;
(ii)前記哺乳動物に1またはそれを超えるチェックポイント阻害剤を投与するステップであって、前記哺乳動物は放射性免疫複合体を投与済みであるかまたは投与中である、ステップ;あるいは
(iii)前記哺乳動物に放射性免疫複合体を投与するのと同時に前記哺乳動物に1またはそれを超えるチェックポイント阻害剤を投与するステップ
を含む、方法。 - 前記方法が、哺乳動物に1またはそれを超えるチェックポイント阻害剤を投与するステップを含み、前記哺乳動物が放射性免疫複合体を投与済みであるかまたは投与中である、請求項1に記載の方法。
- 前記1またはそれを超えるチェックポイント阻害剤が、より低い有効用量で投与される、請求項1または2に記載の方法。
- 前記放射性免疫複合体が、より低い有効用量で投与される、請求項1から3のいずれか一項に記載の方法。
- 前記放射性免疫複合体が、(i)標的化部分、(ii)リンカー、および(iii)キレート部分またはキレート部分の金属錯体を含む、請求項1に記載の方法。
- 前記標的化部分が腫瘍関連抗原に結合できる、請求項5に記載の方法。
- 前記腫瘍関連抗原が腫瘍特異的抗原である、請求項6に記載の方法。
- 前記標的化部分が、抗体またはその抗原結合フラグメントである、請求項6または7に記載の方法。
- 前記抗体またはその抗原結合フラグメントが、IGF-1R抗体またはその抗原結合フラグメントである、請求項8に記載の方法。
- 前記抗体またはその抗原結合フラグメントが、エンドシアリン(TEM-1)抗体またはその抗原結合フラグメントである、請求項8に記載の方法。
- 前記放射性免疫複合体がキレート部分の金属錯体を含む、請求項5から10のいずれか一項に記載の方法。
- 前記金属錯体が放射性核種を含む、請求項11に記載の方法。
- 前記放射性核種がα放射体である、請求項12に記載の方法。
- 前記放射性核種が、アスタチン-211(211At)、ビスマス-212(212Bi)、ビスマス-213(213Bi)、アクチニウム-225(225Ac)、ラジウム-223(223Ra)、鉛-212(212Pb)、トリウム-227(227Th)、およびテルビウム-149(149Tb)からなる群より選択されるα放射体である、請求項13に記載の方法。
- 前記放射性核種が225Acである請求項14に記載の方法。
- 前記1またはそれを超えるチェックポイント阻害剤がPD-1阻害剤を含む、請求項1から16のいずれか一項に記載の方法。
- 前記PD-1阻害剤が抗体である、請求項17に記載の方法。
- 前記1またはそれを超えるチェックポイント阻害剤がCTLA-4阻害剤を含む、請求項1から18のいずれか一項に記載の方法。
- 前記CTLA-4阻害剤が抗体である、請求項19に記載の方法。
- 前記1またはそれを超えるチェックポイント阻害剤が、PD-1阻害剤とCTLA-4阻害剤の両方を含む、請求項1から16のいずれか一項に記載の方法。
- 前記哺乳動物がヒトである、請求項1から21のいずれか一項に記載の方法。
- 前記哺乳動物ががんと診断されている、請求項1から22のいずれか一項に記載の方法。
- 前記がんが、乳がん、非小細胞肺がん、小細胞肺がん、膵臓がん、頭頸部がん、前立腺がん、結腸直腸がん、肉腫、副腎皮質癌、神経内分泌がん、ユーイング肉腫、多発性骨髄腫、または急性骨髄性白血病からなる群より選択される、請求項23に記載の方法。
- 哺乳動物が、少なくとも1つの固形腫瘍を有する、請求項1から24のいずれか一項に記載の方法。
- 前記投与により治療効果がもたらされる、請求項1から25のいずれか一項に記載の方法。
- 前記標的化部分は腫瘍関連抗原に結合でき、前記治療効果が、前記腫瘍関連抗原に特異的なT細胞の増加を含む、請求項26に記載の方法。
- T細胞の前記増加が前記腫瘍で起こる、請求項27に記載の方法。
- 前記腫瘍におけるT細胞の前記増加が、前記脾臓におけるT細胞と比べてのものである、請求項27または28に記載の方法。
- 前記投与により、前記哺乳動物由来の試料における全T細胞集団のうち少なくとも15%が、前記腫瘍関連抗原に特異的となる、請求項27、28、または29に記載の方法。
- 前記投与により、前記哺乳動物由来の試料における全T細胞集団のうち少なくとも20%が、前記腫瘍関連抗原に特異的となる、請求項30に記載の方法。
- 前記投与により、前記哺乳動物由来の試料における全T細胞集団のうち少なくとも25%が、前記腫瘍関連抗原に特異的となる、請求項31に記載の方法。
- 前記投与により、前記哺乳動物由来の試料における全T細胞集団のうち少なくとも30%が、前記腫瘍関連抗原に特異的となる、請求項32に記載の方法。
- 前記投与により、前記哺乳動物由来の試料における全T細胞集団のうち少なくとも35%が、前記腫瘍関連抗原に特異的となる、請求項33に記載の方法。
- 前記投与により、前記哺乳動物由来の試料における全T細胞集団のうち少なくとも40%が、前記腫瘍関連抗原に特異的となる、請求項34に記載の方法。
- 前記投与により、前記哺乳動物由来の試料における全T細胞集団のうち少なくとも45%が、前記腫瘍関連抗原に特異的となる、請求項35に記載の方法。
- 前記投与により、前記哺乳動物由来の試料における全T細胞集団のうち少なくとも50%が、前記腫瘍関連抗原に特異的となる、請求項36に記載の方法。
- 前記投与により、前記哺乳動物由来の試料における全T細胞集団のうち少なくとも55%が、前記腫瘍関連抗原に特異的となる、請求項37に記載の方法。
- 前記投与により、前記哺乳動物由来の試料における全T細胞集団のうち少なくとも60%が、前記腫瘍関連抗原に特異的となる、請求項38に記載の方法。
- 前記投与により、前記哺乳動物由来の試料における全T細胞集団のうち少なくとも65%が、前記腫瘍関連抗原に特異的となる、請求項40に記載の方法。
- 前記投与により、前記哺乳動物由来の試料における全T細胞集団のうち少なくとも70%が、前記腫瘍関連抗原に特異的となる、請求項41に記載の方法。
- 前記試料が腫瘍試料である、請求項30から41のいずれか一項に記載の方法。
- 前記治療効果が、腫瘍体積の減少、安定した腫瘍体積、または腫瘍体積の増大速度の低下を含む、請求項26から42のいずれか一項に記載の方法。
- 前記治療効果が、再発または転移の発生率の低下を含む、請求項26から43のいずれか一項に記載の方法。
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