JP2009155335A - 抗癌療法のためのマクロファージマイグレーション阻害因子アンタゴニストの使用 - Google Patents
抗癌療法のためのマクロファージマイグレーション阻害因子アンタゴニストの使用 Download PDFInfo
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- JP2009155335A JP2009155335A JP2009006088A JP2009006088A JP2009155335A JP 2009155335 A JP2009155335 A JP 2009155335A JP 2009006088 A JP2009006088 A JP 2009006088A JP 2009006088 A JP2009006088 A JP 2009006088A JP 2009155335 A JP2009155335 A JP 2009155335A
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Abstract
【解決手段】ヒトマクロファージマイグレーション阻害因子(MIF) mRNAに相補的であり、そして以下のヌクレオチド配列:5'-ATG-AAC-ATC-GGC-ATG-ATG-GC-3'(配列番号2)を含んでなる、アンチセンス分子。
【選択図】なし
Description
本発明は、MIF の生産又は活性を中和することにより細胞の過剰増殖の疾患を治療するための方法を供する。本発明は、腫瘍関連の疾患の治療のためのMIF の活性を阻害する治療組成物の使用を供する。本発明の特定の実施形態において、中和性MIF モノクローナル抗体又はMIF アンチセンスRNA 分子を含む治療組成物は、充実性腫瘍;最も好ましくはB及びT細胞リンパ腫を治療するのに用いられる。本発明は、MIF アンチセンスRNA 分子及びMIF モノクローナル抗体並びにそれらの誘導体及びアナログを含む治療組成物を包含する。
ヒトMIF ネズミMIF IgGサブタイプ
VII G3 − + IgG2b
IXD11 − + IgG2a
XB2 − + IgG3
XID5 − + IgG2b
XIG2 − + IgG3
VD8 − + IgG2b
IID9 + + IgG1
III D9 + + IgG1
XIF7 + + IgG2b
I31 + + IgG1
IV2.2 + + IgG1
XI7 + + n.d.
XII15.6 + + IgG1
XIV15.4 + + IgG1
悪性腫瘍及び関連する疾患
白血病
急性白血病
急性リンパ球白血病
急性骨髄球白血病
骨髄芽球
プロ骨髄芽球
骨髄単球
単球
赤白血病
慢性白血病
慢性骨髄球白血病
慢性リンパ球白血病
リンパ腫
ホジキン病
非ホジキン病
多発性骨髄腫
充実性腫瘍
肉腫及び癌腫
繊維肉腫
粘液肉腫
脂肪肉腫
軟骨肉腫
骨原性肉腫
骨肉腫
脊索腫
血管肉腫
内皮肉腫
ユーイング肉腫
直腸癌
結腸直腸癌
膵臓癌
乳癌
卵巣癌
前立腺癌
扁平上皮癌
腺癌
汗腺癌
脂腺癌
乳頭癌
ウィルムス腫瘍
子宮頸癌
肺癌
小細胞肺癌
上皮癌
黒色腫
神経芽腫
血管腫
糖尿病性網膜症
治療化合物、例えば治療用モノクローナル抗体は、それ自体により又は細胞の過剰発現に関する種々の病状を治療又は緩和するための投与量で適切な担体もしくは賦形剤と混合された医薬組成物においてヒト患者に投与することができる。治療に友好な量は、腫瘍成長を阻害するのに十分な化合物の量をいう。治療に有効な投与量は、単独で又は腫瘍成長もしくは関連する病気のための他の治療と組み合わせて補助的療法として投与することができる。本願の製剤のための技術及び化合物の投与は、“Remington's Pharmaceutical Sciences ”Mark Publishing Co., Easton, PA, Iatest edditionに見い出すことができる。
治療に有効な量は、治療される患者において癌又は過剰増殖性疾患の発達又は進行を防ぎ又は阻害するのに有効な量を意味する。有効量の決定は、特に本明細書に供される詳細な開示の範囲内で、十分に当業者の能力の範囲内である。本発明の方法に用いられるいずれかの化合物のために、治療に有効な投与量は、細胞培養アッセイから最初に評価することができる。このような情報は、ヒトにおいて役立つ投与量をより正確に決定するのに用いることができる。
この例は、抗MIF モノクローナル抗体での腫瘍を有するマウスの処置を示す。これらの実験のために、種々の抗MIF mAbsでのC3H-HeN マウスの処置を腫瘍移植と同日に始めた。この手順は、抗MIF mAbsが最初の腫瘍増殖を阻害する能力を検査し、転移性及び転移性癌を治療するための治療剤のための予想されるモデルであると考えられる。種々の抗MIF mAbsをこのモデルにおいて抗腫瘍効能について検査した。38C13 B細胞リンパ腫モデルは、1977年に最初に開示されてから、癌に対して新規な治療を評価するために用いられている十分に確立された充実性腫瘍モデルである(Kempら、Cancer Research 55 : 3817-3824, 1995)。そのモデルを、ネズミBリンパ腫細胞を、それらが最初に得られたマウスの株 (C3H-HeN)に皮内(i.d.)注入することにより行った。10日以内に、これらのマウスは容易に測定できる充実性リンパ腫を発達させた。
この例は、MIF アンタゴニスト治療が、予測される生体内モデルにおいて確立された腫瘍に対して有効であることを証明する。腫瘍細胞を接腫したマウスを、腫瘍が確立される期間の後に処理した。これらの実験において、固体腫瘍を6日間、約6mmの平均直径まで発達及び増殖させたことを除いて実施例1に記載されるのと同数の腫瘍細胞を同様に注入した。6日後に、動物の処理及び腫瘍の測定を上述と同じスキームで行った。この手順は、確立された腫瘍への抗MIF mAbsの治療活性を強調する。
この例は、MIF アンタゴニストが腫瘍脈管化を阻害することにより腫瘍成長を阻害することを証明する。増殖中のヒト微小血管内皮細胞(第4継代)(Clonetics ; San Diego, CA) (96ウェルプレート中 5,000/ウェル)を、1%胎児ウシ血清を含む内皮細胞成長培地(ECG−1;Clonetics)中の10〜 200μg/mlのIgG 、対照(Sigma ; St. Louis, MO)又は抗MIF 中和性モノクローナル抗体XIV. 15.5(Dr. C. Metz, Department of Medycal Biochemistry, The Picower Institute For Medical Research : Manhassert, NYのご好意)と共に3時間、インキュベートした。これらの培養物の増殖活性を、次の16時間、[3H] チミジン(4μCi/ml)(DuPont ; Boston, MA)の、DNA への組込み(液体シンチレーションカウンターで測定)により測定した(図3)。 ECG−1(96ウェルプレート中 5,000/ウェル)中で培養した増殖中のヒト微小血管内皮細胞(第4継代;Clonetics)に、製造元のプロトコル(Gibco ; Gaithersburg,MD)に従ってLipotectin試薬を用いて、以下のホスホロチオネートオリゴヌクレオチド(10μg/ml;Oligo's etc. ; Wilsonville,OR)をトランスフェクトした:S-MIF : 5'-GCC-ATC-ATG-CCG-ATG-TTC-AT-3'(センス、ヒトMIF ;配列番号:1)、AS−MIF ;5'-ATG-AAC-ATC-GGC-ATG-ATG-GC-3'(アンチセンス、ヒトMIF 、配列番号:2)。16時間後、これらの培養物の増殖活性を次の8時間にわたり、液体シンチレーションカウンティングにより測定して[3H] チミジン(4μCi/ml;DuPont)のDNA への組込みにより測定した(図5)。抗MIF 抗体は、ヒト微小血管内皮細胞について抗増殖性であることを示し(図4)、これは、抗MIF 抗体が生体内で抗血管形成活性を発揮することを示す。
この例は、試験管内での白血病細胞の増殖の阻害を証明する。これらの研究は、抗MIF 治療方法及び剤が腫瘍細胞への直接の抗増殖効果を有し得るか否かを検査するために行った。この例において、K562 細胞(慢性ヒト骨髄性白血病細胞)をアンチセンスMIF 構成物に露出した。log 期の増殖中のK562 慢性骨髄性白血病細胞培養物(96ウェルプレート中 5,000細胞/ウェル;ATCC;Rockville, MD から得たもの)に、製造元のプロトコル(Gibco)に従って、Lipofectin試薬を用いて、以下のホスホロチオネートオリゴヌクレオチド(10μg/ml;Oligo's etc)をトランスフェクトした:S−MIF: 5'-GCC-ATC-ATG-CCG-ATG-TTC-AT-3'(センス、ヒトMIF ;配列番号:1);AS−MIF : 5'-ATG-AAC-ATC-GGC-ATG-ATG-GC-3'(アンチセンス、ヒトMIF ;配列番号:2)。標準細胞培養条件(37℃、加湿大気中5% CO)下での16時間のインキュベーションの後、これらの培養物の増殖活性を、次の8時間にわたり、液体シンチレーションカウンティングにより測定して、[3H] チミジン(4μCi/ml;DuPont)のDNA への組込みにより測定した。
この例は、抗MIF 中和性抗体での処理による生体内リンパ腫脈管形成の阻害を証明する。腫瘍新血管形成を、構成的に発現される内皮細胞表面マーカー(CD31、血小板内皮細胞接着分子又はPE(AM−1としても知られる)についての免疫組織化学的染色により評価した。腫瘍増殖は、共通遺伝子のリンパ腫細胞の移植により正常なマウスにおいて始まった。腫瘍細胞を接種したマウスを腫瘍細胞転移の時から、抗MIF 又は対照抗体のいずれかで処理し、CD31について特異的な免疫組織化学的染色により収集された腫瘍の組織学的試料において視覚化した腫瘍脈管形成を、抗MIF 対対照抗体処理腫瘍を有するマウスからのセクション間で比較した。
この例は、抗MIF モノクローナル抗体を用いての、分泌されたMIF の枯渇を示す。モノクローナル抗体を確立されたプロトコルに従って作った。RIBIアジュバント(RIBI Immuno Chem Research Inc., Hamilton, MT) を伴う精製したネズミ組換えMIF を、雌BALB/cマウスを免疫化するために用いた。pET116 IPTG 誘導プラスミド(Novagen, Madison, WI) から大腸菌内で発現されたネズミ組換えMIF 10μgをFPLC及びC8 Sep Pak (Waters Co., Milford, MA)により精製し、 100μl RIBI アジュバントと混合し、i.p.注入した。抗体タイターを直接ELISA によりアッセイした。タイターが5倍超になった後、非免疫血清脾臓細胞を50%ポリエチレングリコールを用いてP3−X63Ag 8細胞に融合した。単一クローンをELISA 及びウェスタン・ブロットによりスクリーニングし、次に陽性物をBALB/cマウスにi.p.注入し、プリスチンプライミングし(pristine primed)、IgG 含有腹水を収集した。抗MIF 及び非免疫IgG を、製造元の説明(Pharmacia LKB, Piscataway, NJ)に従ってプロテイン−Gアフィニティークロマトグラフィーにより腹水から精製した。ほとんどの実験について、10μg/mlの非免疫又は抗MIF IgG をNIH 3T3細胞に加え(5×105細胞/ml)、[3H] チミジン(5μCi/ml;1Ci=3Gbq) (DuPont NEN, Boston, MA) の存在下で一晩、増殖させた。
ネズミハイブリドーマ株III .D.9及びXIV.15.5は、特許手続上の微生物の寄託の国際的承認に関するブダペスト条約の規定の下で、American Type Culture Collection, 120, Parklawn Drive, Rockville, Maryland 20852に、1996年10月29日に寄託し、寄託番号ATCC HB-12220 が割り当てられた。
Claims (5)
- ヒトマクロファージマイグレーション阻害因子(MIF) mRNA に相補的であり、そして以下のヌクレオチド配列:
5'-ATG-AAC-ATC-GGC-ATG-ATG-GC-3'(配列番号2)
を含んでなる、アンチセンス分子。 - 請求項1に記載のアンチセンス分子及び医薬として許容される担体又は賦形剤を含んでなる医薬組成物。
- ヒトマクロファージマイグレーション阻害因子(MIF)に免疫特異的に結合し、そして中和する、抗MIFモノクローナル抗体。
- 単離された形態又は精製された形態における、請求項3に記載の抗MIFモノクローナル抗体。
- 抗MIFモノクローナル抗体を分泌するハイブリドーマであって、該抗体がヒトマクロファージマイグレーション阻害因子(MIF)に免疫特異的に結合し、そして中和することを特徴とする、ハイブリドーマ。
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WO1998017314A1 (en) | 1998-04-30 |
CA2267069A1 (en) | 1998-04-30 |
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JP2001502698A (ja) | 2001-02-27 |
DK0954334T3 (da) | 2007-06-11 |
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US20080317759A1 (en) | 2008-12-25 |
AU5101498A (en) | 1998-05-15 |
DE69737397D1 (de) | 2007-04-05 |
PT954334E (pt) | 2007-05-31 |
ATE354372T1 (de) | 2007-03-15 |
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