JP2019511552A - Cd47遮断療法におけるマクロファージの刺激 - Google Patents
Cd47遮断療法におけるマクロファージの刺激 Download PDFInfo
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Abstract
Description
RPαは、ヒトに存在するSIRPαの形態の約80%を構成し、両方とも「ヒトSIRPα」という用語によって本明細書に包含される。また、「ヒトSIRPα」という用語に包含されるのは、ヒトに内在性であり、CD47との結合の際にCD47を介したシグナル伝達を誘発するのと同じ特性を有するその少数派の形態である。本発明は、最も詳細には、バリアント2形態またはV2を含む薬剤の組み合わせに関する。
EELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGA(配列番号1)
EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPS(配列番号5)
DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVE
WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK*(配列番号2)
ESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNS
TYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号6)
ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号7)
EELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVV
VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK*(配列番号28)
EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号3)
EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号8)
もしくは10個のアミノ酸などの遺伝的にコードされたアミノ酸、または5〜50、5〜30もしくは5〜20個のアミノ酸などの5〜100個のアミノ酸、から構成されたリンカーを介して間接的であってもよい。リンカーは、BamHI、ClaI、EcoRI、HindIII、PstI、SalI及びXhoI部位などの制限部位を構成するDNAによってコードされるペプチドを含んでもよい。
ある。
領域に結合する受容体として種々のタイプの免疫細胞に機能する。このことは、これらのタンパク質のクリアランスの原因となる。当該タンパク質のヒト形態では、CD64は、既知のアミノ酸配列を有する75kDaのI型膜貫通タンパク質である。CD64は、IgGに対する高親和性受容体であり、食作用、抗体依存性細胞媒介性細胞毒性、及びサイトカイン産生に関与する。単球及びマクロファージはCD64を恒常的に発現する。成熟顆粒球及びリンパ球は陰性であるが、多形核白血球をIFNγ及びG−CSFのようなサイトカインで処理すると、これらの細胞上でCD64発現を同様に誘導することができる。
1)インターフェロンガンマ(IFN−γ、Actimmune(登録商標))及びインターフェロン−アルファ2a(IFNα−2a、Pegasys(登録商標))などのインターフェロン−アルファから選択されるインターフェロン、
2)単独または先の1)の下にある作用剤とともにあるリポ多糖(LPS)、
3)インターロイキン1β、インターロイキン4、及びインターロイキン10などのインターロイキン、
4)M−CSF及びGM−CSFなどのコロニー刺激因子、形質転換成長因子ベータ(TGFβ)、腫瘍壊死因子アルファ(TNFα)、ならびに熱凝集ヒトガンマグロブリン(HAGG)などのタンパク質、
5)TLR3リガンド、TLR4リガンド、TLR7リガンドまたはTLR8リガンドなどのトール様受容体(TLR)リガンド、及びこれらのいずれか2つ以上の混合物。
ンアルファ、またはIFN−α1、IFN−α8、IFN−α10、IFN−α14及びIFN−α21のうちの1つであり得る。
たものに由来する必要な他の成分とを含有する滅菌済みビヒクルへと組み込むことによって調製される。調製のための滅菌粉末の場合、あらかじめ濾過滅菌した溶液から有効成分及び何らかの追加の所望の成分の粉末を生じる真空乾燥及び凍結乾燥(freeze−drying)(凍結乾燥(lyophilization))である。
膜投与経路による、例えば、鼻内、経口、膣内、直腸内もしくは舌下でなどの非経口経路を介して投与することができる。
療的用途において、相対的に短い間隔で相対的に高い投与量が時には必要となり、疾患の進行が低下または終了するまで、好ましくは患者が疾患の症状の部分的または完全な寛解を示すまで、時々必要とされる。その後、予防的投与計画を用いて患者を治療することができる。
パ腫(小細胞及び大細胞)、多発性骨髄腫(MM)、巨細胞性骨髄腫、重鎖骨髄腫、及び軽鎖またはベンス・ジョーンズ骨髄腫ならびに骨髄肉腫から選択されるCD47+リンパ腫または骨髄腫である。
正常な健常ヒトドナーからヘパリン化全血を得(Biological Specialty Corporation)、すべてのドナーからインフォームドコンセントを得た。末梢血単核細胞(PBMC)をFicoll−Paque Plus密度勾配(GE
Healthcare)で単離し、CD14抗体でコーティングしたMicroBeadの分離(Miltenyi Biotec)を用いた陽性選択によってPBMCからCD14+単球を単離した。20ng/mLのM−CSF(PeproTech)を補充したX−Vivo−15培地(Lonza)中で少なくとも10日間培養することにより、単球をマクロファージへ分化させた。食作用アッセイの前日に、単球由来マクロファージをM−CSF培地中で未処理のままにしておく(M0)か、またはM1として20ng/mLのM−CSF及び300ng/mLのインターフェロンガンマ(IFN−γ)(PeproTech)、M1+LPSとして50ng/mL IFN−γ及び50ng/mL
LPS(MD Biosciences)、M2aとして20ng/mLのIL−4(PeproTech)、M2bとして20ng/mLのIL−1β(PeproTech)及び50ug/mLの熱凝集ヒトIgG(HAGG)、またはM2cとして20ng/mLのIL−10(PeproTech)及び20ng/mLのTGFβ(PeproTech)を用いて一晩処理した。翌日、酵素非含有細胞解離緩衝液(ThermoFisher)を用いてマクロファージを収集した。ヒトB細胞リンパ腫細胞株トレド(Toledo)を、バイオレット増殖色素450(BD Biosciences)で標識し、丸底非組織培養物で処理した96ウェルプレート中のこれらの6サブセットは1:5のエフェクター:標的比で標識した。マクロファージ及び腫瘍細胞を、SIRPaFcまたは対照Fcタンパク質の存在下、37℃、5%CO2で2時間共培養した。その後、細胞をヒトFc受容体結合阻害剤(ebioscience)でブロッキングし、次に近赤外生存/死滅固定可能な死細胞染色(Invitrogen)、APC結合抗ヒトCD14(61D3,eBioscience)及びPE結合抗ヒトCD11b(ICRF44,eBioscience)を用いた染色を行った。細胞を洗浄し、安定化固定液(BD Biosciences)中に再懸濁した。細胞をFACSVerseフローサイトメーターで取得し、データを、FlowJoソフトウェア(Treestar Inc.)を用いて分析した。マクロファージを、単一のCD14+CD11b+生細胞と同定した。二重線はSSC−W及びSSC−H差別によって除外した。食作用%を、VPD450+であるマクロファージの%として評価した。統計的有意性は、GraphPad Prismソフトウェアを用いて対形成されていないt検定とアイソタイプ対照とによって計算し
た(p***<0.001)。
極性化したMDMの食作用能力を駆動するものをさらに理解するために、本発明者らは6つの明確に極性化したマクロファージ上でのFcγR発現を分析した。
正常な健常ヒトドナーからヘパリン化全血を得(Biological Specialty Corporation)、すべてのドナーからインフォームドコンセントを得た。末梢血単核細胞(PBMC)をFicoll−Paque Plus密度勾配(GE
Healthcare)にわたって単離し、CD14抗体でコーティングしたMicroBead分離(Miltenyi Biotec)を用いて陽性選択によりPBMCからCD14+単球を単離した。20ng/mLのM−CSF(PeproTech)を補充したX−Vivo−15培地(Lonza)中で少なくとも10日間培養することにより、単球をマクロファージへ分化させた。マクロファージを洗浄し、20ng/mLのM−CSF、20ng/mLのIL−4(PeproTech)または50ug/mLの熱凝集ヒトガンマグロブリン(HAGG)及び20ng/mLのIL−1β(PeproTech)でそれぞれ1日培養することにより、M0、M2a、M2bへと極性化した。極性化の翌日、極性化培地を洗い流し、細胞を20ng/mLのIFN−γ(PeproTech)、1000U/mLのIFNα2a(PBL Assay Science)、20ng/mLのIL−10(PeproTech)、10ug/mLのポリ(I:C)(InvivoGen)、1ug/mLのLPS(MDBiosciences)、1ug/mLのR848(InvivoGen)または10ug/mLのODN2395 CpG(InvivoGen)を用いて一晩処理した。翌日、マクロファージをフローベー
スの食作用アッセイのために無酵素細胞解離緩衝液(ThermoFisher)を用いて収集した。ヒトB細胞リンパ腫細胞株トレド(Toledo)をバイオレット増殖色素450(BD Biosciences)で標識し、1:5のエフェクター:標的比で、丸底非組織培養物で処理した96ウェルプレート中で再極性化したマクロファージへ添加した。マクロファージ及び腫瘍細胞を、SIRPaFcまたはTTI−402、対照Fcタンパク質の存在下で37℃、5%CO2で2時間共培養した後、ヒトFc受容体結合阻害剤(ebioscience)で遮断し、近赤外生存/死滅固定可能な死細胞染色(Invitrogen)、APC結合抗ヒトCD14(61D3、eBioscience)及びPE結合抗ヒトCD11b(ICRF44,eBioscience)で染色し、洗浄し、安定化固定液(BD Biosciences)中で再懸濁した。細胞をFACSVerseフローサイトメーターで取得し、データを、FlowJoソフトウェア(Treestar Inc.)を用いて分析した。マクロファージは、単一のCD14+CD11b+生細胞と同定した。二重線はSSC−W及びSSC−H差別によって除外した。食作用は、VPD450+であるマクロファージの%として評価した。統計的有意性は、GraphPad Prismソフトウェアを用いて、対形成していないt検定対アイソタイプ対照によって計算した。
正常な健常ヒトドナーからヘパリン化全血を得(Biological Specialty Corporation)、すべてのドナーからインフォームドコンセントを得た。末梢血単核細胞(PBMC)をFicoll−Paque Plus密度勾配(GE
Healthcare)上で単離し、CD14抗体でコーティングしたMicroBead分離(Miltenyi Biotec)を用いて陽性選択によりPBMCからCD14+単球を単離した。20ng/mLのM−CSF(PeproTech)を補充したX−VIVO−15培地(Lonza)中で少なくとも10日間培養することにより、単球をマクロファージへと分化させた。20ng/mLのM−CSF、20ng/mLのIL−4(PeproTech)または50ug/mLの熱凝集ヒトガンマグロブリン(HAGG)及び20ng/mLのIL−1β(PeproTech)をそれぞれ用いて1日培養することにより、マクロファージを洗浄し、M0、M2a及びM2bへと極性化した。極性化の翌日、極性化培地を洗い流し、20ng/mLのIFN−γ(Peprotech)、1000U/mLのIFNa2a(PBL Assay Science)、20ng/mLのIL−10(PeproTech)、10ug/mLのポリ(I:C)(InvivoGen)、1ug/mLのLPS(MDBiosciences)、1ug/mLのR848(InvivoGen)、または10ug/mLのODN2395 CpG(InvivoGen)を用いて一晩処理した。翌日、CD16、CD32及びCD64発現の分析のために、無酵素細胞解離緩衝液(ThermoFisher)を用いてマクロファージを収集した。マクロファージをヒトFc受容体結合阻害剤(ebioscience)でブロッキングし、3つの独立したカクテルの中の近赤外生存/死滅固定可能な死細胞染色(Invitrogen)、FITC結合抗CD16(クローンCB16
)、FITC結合抗CD32(クローンFL18.26)及びV450結合抗CD64(クローン10.1)を用いて染色した。細胞を洗浄し、安定化固定剤(BD Biosciences)中に再懸濁し、データをFACSVerseフローサイトメトリー機で取得し、データを、FlowJoソフトウェア(Treestar Inc.)を用いて分析した。マクロファージは、単一生細胞と同定した。二重線は、SSC−W及びSSC−H差別によって除外した。
Claims (30)
- CD47+疾患細胞を枯渇させることを必要とする対象においてCD47+疾患細胞を枯渇させるための方法であって、前記対象に、SIRPαFc薬及びマクロファージ刺激剤を投与することを含む、方法。
- 前記マクロファージ刺激剤が、M1またはM2cであるマクロファージの形成を促進する、請求項1に記載の方法。
- 前記マクロファージ刺激剤が、TLRアゴニストである、請求項1に記載の方法。
- 前記TLRアゴニストが、リポ多糖(LPS)、レシキモド、及びポリ(I:C)から選択される、請求項3に記載の方法。
- 前記TLRアゴニストが、ポリ(I:C)である、請求項3に記載の方法。
- 前記マクロファージ刺激剤が、マクロファージコロニー刺激因子(M−CSF)、顆粒球マクロファージコロニー刺激因子(GM−CSF)、熱凝集ガンマグロブリン(HAGG)、腫瘍壊死因子アルファ(TNFα)、及び形質転換成長因子β(TGFβ)から選択される少なくとも1つのタンパク質を含む、請求項1に記載の方法。
- 前記マクロファージ刺激剤が、インターフェロンガンマ及びインターフェロンアルファから選択されるインターフェロンを含む、請求項1に記載の方法。
- 前記マクロファージ刺激剤が、IL−1β、IL−4、及びIL−10、ならびにこれらの混合物から選択されるインターロイキンを含む、請求項1に記載の方法。
- 前記マクロファージ刺激剤は、前記SIRPαFc薬が投与される前に投与され、それにより内在性マクロファージが前記SIRPαFc薬へ曝露されたときに活性化されるか、または極性化される、請求項1に記載の方法。
- 前記SIRPαFc薬が、IgG1に基づくFcを含む、請求項1〜9に記載の方法。
- 前記SIRPαFc薬が、IgG4に基づくFcを含む、請求項1〜9に記載の方法。
- 前記SIRPαFc薬が、配列番号3のアミノ酸配列を含む、請求項10に記載の方法。
- 前記SIRPαFc薬が、配列番号8のアミノ酸配列を含む、請求項11に記載の方法。
- 前記SIRPαFc薬が、L4V/I、V6I/L、A21V、V27I/L、131T/S/F、E47V/L、K53R、E54Q、H56P/R、S66T/G、K68R、V92I、F94V/L、V63I、及びF103Vから選択される1つ以上のアミノ酸置換を含むSIRPαのCD47結合領域を含む、請求項1〜9に記載の方法。
- CD47+疾患細胞を枯渇させるのに有効なSIRPαFc薬、及びCD47+疾患細胞の前記枯渇を増強するのに有効なマクロファージ刺激剤、ならびに請求項1〜14のいずれか1項に記載の治療方法を教示する説明書の組み合わせ。
- CD47+疾患細胞を提示する対象の治療のための、請求項15に記載の組み合わせの使用。
- 前記CD47+疾患細胞が、CD47+癌細胞である、請求項16に記載の使用。
- 前記CD47+癌細胞が、CD47+血液癌である、請求項17に記載の使用。
- 前記CD47+癌細胞が、急性リンパ性白血病(ALL)、急性骨髄性白血病(myeloid leukemia)(AML)、慢性リンパ性白血病(CLL)、慢性骨髄性白血病(myelogenous leukemia)(CML)、骨髄増殖性疾患/腫瘍(MPDS)、菌状息肉症、及び骨髄異形成症候群から選択される癌タイプの細胞である、請求項18に記載の使用。
- 前記癌が、ホジキンリンパ腫、無痛性でも侵襲性でもある非ホジキンリンパ腫、バーキットリンパ腫、小細胞濾胞性リンパ腫及び大細胞濾胞性リンパ腫から選択されるリンパ腫である、請求項19に記載の使用。
- 前記癌が、多発性骨髄腫(MM)、巨細胞骨髄腫、重鎖骨髄腫、及び軽鎖またはベンス・ジョーンズ骨髄腫から選択される骨髄腫である、請求項20に記載の使用。
- インターフェロンガンマ1b、インターフェロンアルファ2a、インターロイキン1β、インターロイキン4、インターロイキン−10、マクロファージコロニー刺激因子、及び形質転換成長因子ベータから選択される作用剤との組み合わせにおけるSIRPaFcの、CD47+癌の治療のための、使用。
- リポ多糖(LPS)、レシキモド、及びポリ(I:C)から選択されるトール様受容体アゴニストとの組み合わせにおけるSIRPaFcの、CD47+癌の治療のための、使用。
- 前記SIRPaFc薬が、配列番号3を含む、請求項16〜23のいずれか1項に記載の使用。
- 前記SIRPaFc薬が、配列番号3を含む、請求項15に記載の組み合わせ。
- 前記SIRPaFc薬が、配列番号8を含む、請求項16〜23のいずれか1項に記載の使用。
- 前記SIRPaFc薬が、配列番号8を含む、請求項15に記載の組み合わせ。
- SIRPαFc薬を用いて治療中である対象においてCD47+癌を治療するための、マクロファージ刺激剤の使用。
- マクロファージ刺激剤を用いて治療中である対象においてCD47+癌を治療するための、SIRPαFc薬の使用。
- SIRPαFc薬の抗癌作用を増強する方法であって、前記SIRPαFc薬を投与されている対象に、マクロファージ刺激剤を投与することを含む、方法。
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