JP2009521685A - 可溶性ヒトm−csf受容体およびその使用 - Google Patents
可溶性ヒトm−csf受容体およびその使用 Download PDFInfo
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Abstract
Description
毎年およそ140万の癌の新規症例が生じ、毎年およそ60万人が癌で死亡する。検出と治療方法の改善によって、これらの患者の多くは、かなりの長期間に亙って生存する。2002年1月1日現在で、人口の約3.4%に相当するおよそ1010万人の癌生存者が存在していた。これらの癌生存者のうちで、乳房(22%)、前立腺(18%)、結腸直腸(10%)および婦人科(10%)に関すものが、最も一般的な癌の部位である。
Kacinski、Ann.Med.(1995年)27巻:79〜85頁 Smithら、Clin.Cancer Res.(1995年)1巻:313〜25頁 Schollら、J.Natl.Cancer Inst.(1994年)86巻:120〜6頁 Linら、J.Exp.Med.(2001年)93巻:727〜39頁 Hamilton J.A.、J Leukoc Biol(1997年)62巻(2号):145〜55頁 Hamilton J,A.、Immuno Today.(1997年)18巻(7号):313〜7頁 FixeとPraloran、Cytokine(1998年)10巻:32〜37頁
本発明の材料および方法は、当技術分野における前述の必要性および他の関連する必要性を満たす。本発明の一態様では、ヒトM−CSF(CSF−1)受容体(膜貫通ドメインを欠く)の天然に存在する可溶性フラグメント(複数可)の発見が、M−CSF活性の中和が望まれる治療的使用のためにそのような天然に存在するフラグメントの組み換え型の産生を可能にする。
本発明は、通常は膜結合型の受容体であるヒトM−CSF受容体の天然に存在する可溶性形態の発見に基づく。受容体のこの可溶性形態(shM−CSFR)の濃度は、癌、破骨細胞分化および月経周期と相関していることが示されている。shM−CSFRの濃度増加は、癌の重篤度および細胞の増殖状態と相関していることが示されている。
哺乳動物はヒトであるのが好ましい。
モノクローナルまたはポリクローナル抗体を本発明の検出方法で使用することができるが、一貫性および特異性を有するのでモノクローナル抗体が好都合に使用される。マウスのモノクローナル抗体などのげっ歯類の抗体は、診断法に使用するのに好都合である。修飾語「モノクローナル」は、抗体の実質的に均質な集団から得られる抗体の特徴を示し、任意の特定の方法による抗体産生を必要とするものとして解釈されない。
本発明は、生物試料中のshM−CSFRを検出する方法であって、試料を、shM−CSFRに特異的に結合する抗体と接触させること、およびshM−CSFRに結合した抗体または結合していない抗体のいずれかを検出することを含む方法を提供する。どちらの相対的な量も、試料中のshM−CSFRの量に相関する。抗体は、検出可能な標識で直接的にまたは間接的に標識される。
1つの典型的な実施形態では、アッセイ装置はラテラルフロー試験ストリップであり、場合によってハウジング内に入れられている。shM−CSFRに対する第1標識抗体は溶液の中にあるが、shM−CSFRに対する第2抗体は試験ストリップ上に固定化されている。shM−CSFRを含む患者試料が両方の抗体と接触する場合、抗体−標的−抗体サンドイッチ複合体が形成され、固体支持体上に固定化されているこの生じた複合体は標識により検出可能である。次いで試験ストリップを読取機に挿入し、ここで複合体の標識からのシグナルを測定する。結果は、陽性もしくは陰性の結果のいずれであるか、または疾患もしくは障害のリスクもしくは存在を示す結果と相関する試料中のshM−CSFRの濃度の定量であり得る。この全工程は、自動化および/またはコンピュータ制御することもできる。あるいは、試験ストリップは、適切な色の視覚的な基準と比較することにより、目視で読出しを行い得る。この試験はshM−CSFR ELISAと同様であるが、非常に短時間に治療の時点で臨床的な関連情報を提供する。
2つ以上のM−CSFアンタゴニスト(たとえば、shM−CSFRおよび抗M−CSF抗体)を混合して、M−CSFを伴う疾患または障害(たとえば、癌、癌転移および/または骨変性)に対してさらに改善された有効性を提供することは有利であり得る。1つまたは複数のM−CSFアンタゴニストを含む組成物を、癌転移および/または癌転移を伴う骨量減少に罹患しているか、または患う素因を有するヒトまたは哺乳動物に投与され得る。2つの治療剤の同時投与は、薬剤がその治療薬効果を発揮している期間に重複部分がある限り、同時にまたは同経路によって薬剤が投与されることを必要としない。同時または連続投与は、異なる日または異なる週の投与が意図されている。またshM−CSFR治療法を化学療法または放射線療法と組み合わせることも実施され得る。
本発明の方法の実行において使用されるshM−CSFRは、所望の送達方法に適切な担体を含む医薬組成物に調製することができる。適切な担体はshM−CSFRと組み合わせた場合、shM−CSFRの抗腫瘍機能を保持し、被験体の免疫系に対して非反応性である任意の物質を含む。例として、これらに限定するものではないが、多くの標準の製剤学上の担体のいずれか、たとえば滅菌リン酸緩衝食塩水溶液、静菌水などが含まれる。種々の水性担体、たとえば水、緩衝水、0.4%の生理食塩水、0.3%のグリシンなどを使用することができ、安定性を向上するために他のタンパク質、たとえば軽度の化学的修飾などを付したアルブミン、リポタンパク質、グロブリンなどを含み得る。
本発明のshM−CSFRは、M−CSFに対する親和性精製薬剤として、またはたとえば、特異的な細胞、組織もしくは血清におけるその発現を検出する、M−CSFタンパク質用の診断アッセイにおいて使用することもできる。shM−CSFRは、in vivoにおける診断アッセイに使用することもできる。一般にこれらの目的のために、shM−CSFRは、腫瘍がイムノシンチオグラフィーを用いて局所化できるように、放射性核種(たとえば111In、99Tc、14C、131I、125I、3H、32Pまたは35S)で標識される。
この実施例は、ヒトM−CSFに対する可溶性受容体の同定を記載し、この可溶性受容体はM−CSFを結合できることを示す。
A.材料および方法
マイクロタイタープレート(R&D systems、カタログ番号CP0011)を、PBS中100ng/ml作用希釈の100μl/ウェル捕捉抗体(Duo Set Elisa development system hM−CSF R(R&D systems、カタログ番号DY329))でコートした。プレートをシールし、一夜室温でインキュベートした。マニホルドディスペンサ/ワッシャ(manifold dispenser/washer)を用いて洗浄緩衝液(PBS中、0.05%Tween、pH7.2〜7.4)で3回ウェルを洗浄後、プレートを300μl/ウェルのブロッキング緩衝液(1%BSA、PBS中5%スクロース、pH7.2〜7.4)を用いて、室温で少なくとも1時間ブロックした。
ELISAアッセイを血清試料中の可溶性ヒトM−CSF受容体の存在を測定するために使用した場合、強い陽性シグナルがヒト血清試料で検出された。このELISAアッセイで用いた捕捉抗体および検出抗体は、ヒトM−CSF受容体の細胞外ドメインに特異的であった。図2に示すように、強い陽性シグナルがヒト血清試料で検出された。このシグナルは、ヒト血清の濃度に依存している。捕捉抗体が使用されなかった場合にはシグナルは存在しない。
A.材料および方法
マイクロタイタープレート(R&D systems、カタログ番号CP0011)を、PBS中100ng/ml作用希釈の100μl/ウェル捕捉抗体(Duo Set Elisa development system hM−CSF R(R&D systems、カタログ番号DY329))でコートした。プレートをシールして一夜室温でインキュベートした。マニホルドディスペンサ/ワッシャを用いて、洗浄緩衝液(PBS中0.05%Tween、pH7.2〜7.4)で3回ウェルを洗浄後、プレートを300μl/ウェルのブロッキング緩衝液(1%BSA、PBS中5%シュークロース、pH7.2〜7.4)を用いて、室温で少なくとも1時間ブロックした。
ヒト血清中に存在する可溶性受容体は、M−CSFを結合することができる。図3に示すように、ヒト血清試料の階段希釈を、マウスモノクローナル抗ヒトc−fms抗体でコートしたELISAプレートにアプライした。アルカリホスファターゼ結合ポリクローナル抗ヒトM−CSF抗体によるヒトM−CSFの検出前に、1μg/mlの外来性ヒトM−CSF(四角)またはPBS(ひし形)のいずれかを添加した。明白なM−CSFの結合が約5%のヒト血清に見出された。しかしヒト血清中の可溶性受容体は、組み換え型のc−fms Fc融合タンパク質と比べて低い結合親和性を有することが見出された(図4)[組み換え型c−fms Fc融合タンパク質の結合親和性は、リガンド誘導二量体化のため天然の膜結合型c−fmsの結合親和性に近いと考えられる]。可溶性受容体の低親和性に対する1つの解釈は、この受容体はリガンドに対する1つの結合部位のみを有するが、組み換え型c−fms Fc融合タンパク質は、結合活性効果に関して2つの結合部位を有することである。
A.材料および方法
500μlのストレプトアビジンビーズ(#20347、Pierce)を、15mlファルコンチューブ中の10mlの20%ヒト血清(Sigma カタログ番号 S 7023、あらかじめ凍結されている)に添加し、穏やかに振盪して4℃で1時間インキュベートした。試料を400rpmで5分間遠心して上清を新たなチューブに移した。10μgの抗hMCSFR抗体(R&D # BAF 329)を上清に添加し、穏やかに振盪して4℃で1時間インキュベートした。500μlのストレプトアビジンビーズを添加後、試料を4℃で一夜振盪してインキュベートした。試料を400rpmで5分間遠心し、上清を新しいチューブへ移し、そして同時に上清を保存した。ビーズをエッペンドルフチューブへ移し、洗浄緩衝液#1(0.5M LiCL2)、#2(0.5M LiCL2/0.5%Triton)および#3(10mM TRIS pH7.4)のそれぞれ1mlで1回洗浄した。最後の遠心後、大部分の洗浄緩衝液を除去した(ビーズがほぼ乾燥でするまで)。次いでビーズを500μlのPBSに再懸濁した。ゲル(10%Novex)泳動前に、DTTを有する5×SDS試料緩衝液を添加し、試料を100℃で2分間煮沸した。
可溶性ヒトM−CSF受容体は、分子量97KDを有するグリコシル化タンパク質であることが分かった(図5)。脱グリコシル化後、可溶性ヒトM−CSF受容体の分子量は約60KDである(図6)。
この実施例は、可溶性M−CSF受容体がヒト尿試料中に認められたことを示す。この実施例は、さらにこの受容体が正常被験体および乳癌患者両方の血清中に存在し、M−CSFレベルと相関した可溶性M−CSF受容体レベルであることを示している。最後にこの実施例は、可溶性M−CSF受容体は霊長類にも認められることを示している。
可溶性ヒトM−CSF受容体濃度を、以下のように乳癌血清試料で分析した。ヒト血清試料の階段希釈を、上記のように可溶性ヒトM−CSF受容体の存在に関してELISAでアッセイした。ヒト血清をこのELISA構成(「標準」と呼ぶ)でアッセイした場合、強い陽性シグナルが検出された。対照としての、捕捉抗体または検出抗体のいずれかの除去はシグナルを消去し、このシグナルはこれら抗ヒトc−fms抗体に対して特異的であることを示した。基準として組み換え型c−fmsヒトFc融合タンパク質を用いる可溶性ヒトM−CSF受容体濃度の定量は、0.5μg/mlであると測定された。
ヒトM−CSF可溶性受容体に関する上記のELISAアッセイはまた、他の動物種からの血清試料を調べるために使用される(図13)。カニクイザルおよびアカゲザルの血清試料は強い陽性シグナルを示し、可溶性受容体の存在を示す。カニクイザルおよびアカゲザルに関する膜結合M−CSF受容体タンパク質配列は入手不可能である。しかしこれらの配列は、そのヒト対応物と高いレベルのタンパク質相同性を共有すると考えられる。したがって、ヒト膜結合型M−CSF受容体の細胞外ドメインを認識するELISAアッセイで用いた抗体はまた、カニクイザルおよびアカゲザルのこの細胞外ドメインを認識する。
この実施例は、可溶性ヒトM−CSF受容体の発現を、破骨細胞分化と密接に関連していることを示している。この実施例は、さらに分化した破骨細胞のみが可溶性ヒトM−CSF受容体を発現し、そのレベルがM−CSFの除去により増加することを示している。
M−CSF可溶性受容体の発現を、膜結合M−CSF受容体の発現が見出されたヒト破骨細胞を用いたin vitro系で研究した。特に可溶性受容体の発現を、破骨細胞分化に関連して調べた。初代のヒト破骨細胞前駆体(Cambrex Bio Science Walkersville、Inc.カタログ番号2T−110)を、30ng/mlのヒトM−CSFおよび100ng/mlのRANKLを含む細胞培養培地中、0.2ml/ウェルの10,000細胞/ウェルで接種した。細胞のプレーティングと同日に、試験抗体を1μg/mLでウェルに添加した。細胞を37℃、5%CO2の加湿雰囲気下でインキュベートした。7日目に、破骨細胞を異常に大きな多核細胞として位相差顕微鏡で同定した。フィーディングして培養をさらに1週間続けることができ、その間に破骨細胞は大きさが増し続ける。培養の最後に、細胞を酒石酸塩耐性酸性ホスファターゼで染色し、この陽性の染色は破骨細胞の存在を示す。各ウェル中の破骨細胞数を光学顕微鏡下で計数し、顕微鏡の視野下の破骨細胞の平均としてグラフに示した。
図14で示すように、M−CSF可溶性受容体は破骨細胞で発現した。分化した破骨細胞の馴化培地における可溶性受容体の濃度を測定した。可溶性受容体の発現は破骨細胞に特異的であった。このケースではM−CSF中和抗体であるChir−RX1による破骨細胞分化の阻害は、可溶性受容体の抑制を生じた。
Claims (17)
- 癌を診断する方法であって、
(a)患者由来の流体試料を可溶性M−CSF受容体のレベルに関して分析する工程を含み、閾値を上回る可溶性M−CSF受容体のレベルは癌の存在と相関し、該閾値未満のレベルは該患者が癌を有する可能性が低いことを示す、方法。 - 前記流体試料が、尿、血漿または血清から成る群から選択される、請求項1に記載の方法。
- 癌に罹患した被験体の予後を判定する方法であって、
(a)患者由来の流体試料を可溶性M−CSF受容体のレベルに関して分析する工程を含み、閾値を上回る可溶性M−CSF受容体のレベルは該患者が予後不良である可能性が高いことを示し、該閾値未満のレベルは該患者が予後良好である可能性が高いことを示す方法。 - 前記流体試料が、尿、血漿または血清から成る群から選択される、請求項3に記載の方法。
- 癌に罹患した被験体において癌治療をモニタリングする方法であって、
(a)癌治療薬による治療の開始前に、患者由来の流体試料を可溶性M−CSF受容体のレベルに関して分析する工程と;
(b)該癌治療薬による治療の開始後に、該流体試料を分析する工程とを含み、
該癌治療薬による治療の開始後での可溶性M−CSF受容体レベルの減少は、該患者が治療有効量の該癌治療薬を受容していることを示す、方法。 - 前記流体試料が、尿、血漿または血清から成る群から選択される、請求項5に記載の方法。
- 前記癌が、乳癌、肺癌、腎臓癌、多発性骨髄腫、甲状腺癌、前立腺癌、腺癌、白血病およびリンパ腫を含む血球悪性疾患;頭頚部癌;食道癌、胃癌、大腸癌、腸癌、結腸直腸癌、直腸癌、膵臓癌、肝臓癌、胆管癌または胆嚢癌を含む消化管癌;卵巣癌腫、子宮内膜癌、膣癌、および子宮頸癌を含む女性生殖管の悪性疾患;膀胱癌;神経芽細胞腫を含む脳癌;肉腫、骨肉腫;ならびに悪性黒色腫または扁平上皮癌を含む皮膚癌から成る群から選択される、請求項1、3または5に記載の方法。
- 前記癌が乳癌である、請求項7に記載の方法。
- 女性における月経周期をモニタリングする方法であって、
(a)女性患者由来の流体試料を可溶性M−CSF受容体のレベルに関して分析する工程を含み、閾値を上回る可溶性M−CSF受容体のレベルは該患者が妊娠している可能性が高いことを示し、該閾値未満のレベルは該患者が妊娠している可能性が低いことを示す方法。 - 前記流体試料が、尿、血漿または血清から成る群から選択される、請求項9に記載の方法。
- (a)shM−CSFRに特異的に結合する第1抗体と、
(b)既知量のM−CSFRを含むM−CSFR標準物質と
を含むキット。 - 前記第1抗体が検出可能な標識に結合している、請求項11に記載のキット。
- 前記標識が酵素である、請求項12に記載のキット。
- 前記酵素が検出可能なシグナルを放出する基質をさらに含む、請求項13に記載のキット。
- shM−CSFRに結合する第2抗体をさらに含む、請求項11に記載のキット。
- 前記第1抗体に結合する第2抗体をさらに含む、請求項11に記載のキット。
- shM−CSFRに結合する第2抗体をさらに含む、請求項11に記載のキット。
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WO2010062401A2 (en) | 2008-11-26 | 2010-06-03 | Five Prime Therapeutics, Inc. | Treatment of osteolytic disorders and cancer using csf1r extracellular domain fusion molecules |
WO2010062399A2 (en) | 2008-11-26 | 2010-06-03 | Five Prime Therapeutics, Inc. | Csf1r extracellular domain fusion molecules and treatments using same |
US9796761B2 (en) | 2009-07-14 | 2017-10-24 | National Institute Of Advanced Industrial Science And Technology | Glycan markers as measure of disease state of hepatic diseases |
ES2706412T3 (es) | 2010-05-04 | 2019-03-28 | Five Prime Therapeutics Inc | Anticuerpos que se unen a CSF1R |
US20130302322A1 (en) | 2012-05-11 | 2013-11-14 | Five Prime Therapeutics, Inc. | Methods of treating conditions with antibodies that bind colony stimulating factor 1 receptor (csf1r) |
ES2442991B1 (es) * | 2012-08-14 | 2014-11-25 | Fundación Md Anderson International España | Método para el diagnóstico y/o pronóstico de linfomas |
CA2882804A1 (en) | 2012-08-31 | 2014-03-06 | Brian Wong | Methods of treating conditions with antibodies that bind colony stimulating factor 1 receptor (csf1r) |
KR20230086809A (ko) | 2014-06-23 | 2023-06-15 | 파이브 프라임 테라퓨틱스, 인크. | 콜로니 자극 인자 1 수용체 (csf1r)에 결합하는 항체를 이용하여 병태를 치료하는 방법 |
BR112017008914A2 (pt) | 2014-10-29 | 2018-01-16 | Five Prime Therapeutics, Inc. | método para tratar câncer, composição e uso da composição |
CA2969341C (en) | 2014-12-22 | 2023-07-04 | Five Prime Therapeutics, Inc. | Anti-csf1r antibodies for treating pvns |
MX2017013178A (es) | 2015-04-13 | 2018-03-01 | Five Prime Therapeutics Inc | Terapia de combinacion para cancer. |
EP3681535A1 (en) | 2017-09-13 | 2020-07-22 | Five Prime Therapeutics, Inc. | Combination anti-csf1r and anti-pd-1 antibody combination therapy for pancreatic cancer |
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AU2006342119A1 (en) | 2007-10-25 |
KR101358600B1 (ko) | 2014-02-06 |
JP2012108155A (ja) | 2012-06-07 |
WO2007120252A2 (en) | 2007-10-25 |
CA2634945A1 (en) | 2007-10-25 |
EP1977238B1 (en) | 2016-09-28 |
AU2006342119B8 (en) | 2013-05-09 |
US20140030738A1 (en) | 2014-01-30 |
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US20100099123A1 (en) | 2010-04-22 |
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