JP2008546699A - 抗igf1r抗体処方物 - Google Patents
抗igf1r抗体処方物 Download PDFInfo
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- JP2008546699A JP2008546699A JP2008517021A JP2008517021A JP2008546699A JP 2008546699 A JP2008546699 A JP 2008546699A JP 2008517021 A JP2008517021 A JP 2008517021A JP 2008517021 A JP2008517021 A JP 2008517021A JP 2008546699 A JP2008546699 A JP 2008546699A
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- 210000002700 urine Anatomy 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
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Abstract
Description
本発明はとりわけ、高い安定性を示す抗体を含む薬学的処方物を提供する。
抗体は、ほとんどのタンパク質と同様、その活性を維持するためにその高次構造を維持しなければならない。抗体(治療抗体を含む)を販売している会社が直面している1つの問題は、抗体が変性する(つまり、生物学的活性を失う)ことなく長時間存在し得る状態の同定である。一般的に、市場にある治療抗体は、比較的不安定であり、注意深い操作および低温での貯蔵を必要とする。例えば、治療抗体であるAvastinTM、Herceptin(登録商標)およびErbituxTMは、2℃〜8℃での貯蔵を必要とする。この産業の様々な会社(例えば、Pfizer、Imclone、Pierre Fabre、RocheおよびImmunogen)によって所有されている抗IGF1R抗体は、同様に不安定性を示すようである。
本発明は、優れた安定性を示し、ゆえに、室温で貯蔵され得る、単離された抗IGF1R抗体(例えば、モノクローナル抗体)もしくはその抗原結合フラグメントを含む薬学的処方物を提供することによって、当該分野における上記で参照された必要性に取り組んでいる。
本発明の処方物中の抗体は、優れた安定性を示す。本発明の処方物は、その中に含まれる抗体を、数ヶ月の室温(例えば、25℃)での貯蔵の後でもインタクトな状態に保つことを許容する。このような高い安定性は、例えば、この処方物が、この処方物を所有する臨床医、患者もしくは薬局が室温もしくは冷蔵下で保存することを便宜的に選択することを許容するので、本発明の処方物を特に有用にする。さらに、高い安定性は、抗体がそれらの生物学的活性を時間がたっても保持することを確実にし、その有用性を保持することをも確実にする(例えば、癌のような状態を処置するために使用される場合)。本発明の処方物の特有の利点は、室温での保存なし(例えば、4℃での冷蔵下)でさえも実現され得る。4℃で貯蔵された場合、この処方物は、いくぶんより高い安定性を示す。
本発明の一実施形態において、本発明の処方物は、以下に述べるとおりである:
本発明は、抗IGF1R抗体もしくはその抗原結合フラグメントを含む薬学的組成物を含む。用語「抗IGF1R」抗体は、例えば、15H12/19D12 HC(重鎖)、HCAもしくはHCBおよび/または15H12/19D12 LC(軽鎖)、LCA、LCB、LCC、LCD、LCEもしくはLCF(もしくはそれらの任意の成熟フラグメント)(例えば、LCFおよびHCA)を含むあらゆる抗体を包含する。本発明の一実施形態において、抗IGF1R抗体もしくはその抗原結合フラグメントとしては、IGF1Rもしくはその任意のフラグメント(例えば、sIGF1R)に特異的に結合する抗体およびフラグメントが挙げられる。本発明の一実施形態において、抗体としては、モノクローナル抗体、ポリクローナル抗体、ヒト化された抗体、キメラ抗体、抗イディオタイプ抗体および二重特異性抗体が挙げられ、そしてフラグメントとしては、Fab抗体フラグメント、F(ab)2抗体フラグメント、Fv抗体フラグメント(例えば、VHもしくはVL)、単鎖Fv抗体フラグメントおよびdsFv抗体フラグメントが挙げられる。さらに、本発明の一実施形態において、本発明の抗IGF1R抗体は、完全にヒト抗体である。本発明の一実施形態において、抗IGF1R抗体はモノクローナルで、完全なヒト抗体である。本発明の一実施形態において、抗IGF1R抗体は、アミノ酸およびヌクレオチドの配列を本明細書中に述べる、可変領域および/もしくはCDRのうちの1つ以上を含む
(a)IGF1Rに約86×10−11もしくはそれより低い数値のKdで結合する;
(b)IGF1Rに対して約6.50×10−5もしくはそれより低い数値の解離速度(off rate)(Koff)を有する;
(c)IGF1Rに対して約0.7×105もしくはそれより高い数値の結合速度(on rate)(Kon)を有する;
(d)IGF1Rへの結合について、IGF1と競合する;
(e)IGF1Rの自己リン酸化を阻害する;および
(f)IGF1Rを発現する細胞の足場非依存性増殖を阻害する。
本発明の一実施形態において、さらなる化学治療剤が、本発明の抗IGF1R処方物と組み合わせて提供および/もしくは投与される。一実施形態において、さらなる化学治療剤は、白金ベースの化合物、シグナル伝達インヒビター、細胞周期インヒビター、IGF/IGF1R系調節因子(例えば、インヒビターもしくは活性化剤)、ファルネシルタンパク質トランスフェラーゼ(FPT)インヒビター、上皮増殖因子レセプター(EGFR)インヒビター、HER2インヒビター、脈管上皮増殖因子(VEGF)レセプターインヒビター、マイトジェン活性化タンパク質(MAP)キナーゼインヒビター、MEKインヒビター、AKTインヒビター、mTORインヒビター、pI3キナーゼインヒビター、Rafインヒビター、サイクリン依存性キナーゼ(CDK)インヒビター、微小管安定剤(microtubule stabilizer)、微小管インヒビター、SERM/抗エストロゲン、アロマターゼインヒビター、アントラサイクリン、プロテアソームインヒビター、もしくはインスリン様増殖因子(IGF)産生を阻害する因子である。
ここで、R20、R21およびR46はそれぞれ以下からなる群より独立して選択される:
(1)H;
(2)qが1〜3である、−(CH2)qSC(O)CH3;
(3)qが1〜3である、−(CH2)qOSO2CH3;
(4)−OH;
(5)−CS(CH2)w(置換フェニル)(ここで、wは1〜3であり、この置換フェニル基上の置換基は、この置換フェニルに関して以下で述べた置換基と同じ置換基である);
(6)−NH2;
(7)−NHCBZ;
(8)−NHC(O)OR22(ここで、R22は、1〜5個の炭素原子を有するアルキル基であるか、もしくはR22は、1〜3個のアルキル基で置換されたフェニルを表す);
(9)アルキル;
(10)kが1〜6である、−(CH2)kフェニル;
(11)フェニル;
(12)置換フェニル(ここで、置換基は、ハロ、NO2、−OH、−OCH3、−NH2、−NHR22、−N(R22)2、アルキル、−O(CH2)tフェニル(ここで、tは1〜3である)および−O(CH2)t置換フェニル(ここで、tは1〜3である)からなる群より選択される);
(13)ナフチル;
(14)置換基が上記の置換フェニルで定義したとおりである、置換ナフチル;
(15)5〜10個の炭素原子を有する架橋多環式炭化水素;
(16)5〜7個の炭素原子を有するシクロアルキル;
(17)ヘテロアリール;
(18)ヒドロキシアルキル;
(19)置換ピリジルもしくは置換ピリジルN−酸化物(ここで、置換基は、メチルピリジル、モルホリニル、イミダゾリル、1−ピペリジニル、1−(4−メチルピペラジニル)、−S(O)tR11、もしくは上記の置換フェニルに関して上記で示された置換基のうちの任意のものから選択され、そしてこの置換基は、前述の炭素に結合している水素を置き換えることによって環炭素に結合する);
またはR20、R21およびR46のうちの2つが一緒になって、ピペリジン環V
R54は、前述のN酸化物複素環式基(i)、(ii)、(iii)、(iv)、(ia)、(iia)、(iiia)もしくは(iva)のうちの1個で置換されたアルキル基を表し;Zは、Rが、上記で定義したようなR5、R6、R7もしくはR8と組み合わされ得るようにOもしくはSを表すか、またはRは、R40、R42、R44もしくはR54を表す。上記の式のR20、R21およびR46の例としては、
ここで、R1は、水素原子、または6個までの炭素原子を含む直鎖状もしくは分枝鎖状のアルキル基(例えば、−CH3)、アルケニル基もしくはアルキニル基を表し、このような基のそれぞれは、非置換であるか、もしくはハロゲン(すなわち、臭素、ヨウ素または好ましくは、塩素もしくはフッ素)原子、4個までの炭素原子を含む直鎖状もしくは分枝鎖状のアルコキシ基(例えば、メトキシ)、アルキルチオ基、アルキルスルフィニル(alkylsullihinyl)基およびアルキルスルホニル基、ならびに必要に応じて置換されたフェニル基から選択される1〜3個の置換基によって置換されるか、またはR1は、シクロアルキル基を表し、そしてR2は、窒素原子上に、直鎖状および分枝鎖状のアルキル基およびアルケニル基(それぞれは、4個までの炭素原子を含む)ならびにシクロアルキル基から選択される1個もしくは2個の基を有し得るカルバモイル基(例えば、メチルカルバモイル基もしくはジメチルカルバモイル基)を表す。
8−カルバモイル−3−n−プロピル−[3H]−イミダゾ[5,1−d]−1,2,3,5−テトラジン−4−オン;
8−カルバモイル−3−(2−クロロエチル)−[3H]−イミダゾ−[5,1−d]−1,2,3,5−テトラジン−4−オン;
3−(2−クロロエチル)−8−メチルカルバモイル−[3H]−イミダゾ[5,1−d]−1,2,3,5−テトラジン−4−オン;
8−カルバモイル−3−(3−クロロプロピル)−[3H]−イミダゾ−[5,1−d]−1,2,3,5−テトラジン−4−オン;
8−カルバモイル−3−(2,3−ジクロロプロピル)−[3H]−イミダゾ[5,1−d]−1,2,3,5−テトラジン−4−オン;
3−アリル−8−カルバモイル−[3H]−イミダゾ[5,1−d]−1,2,3,5−テトラジン−4−オン;
3−(2−クロロエチル)−8−ジメチルカルバモイル−[3H]−イミダゾ[5,1−dl−1,2,3,5−テトラジン−4−オン;3−(2−ブロモエチル)−8−カルバモイル−[3H]−イミダゾ−5,1−d]−1,2,3,5−テトラジン−4−オン;3−ベンジル−8−カルバモイル−[3H]−イミダゾ[5,1−d]−1,2,3,5−テトラジン−4−オン;
8−カルバモイル−3−(2−メトキシエチル)−[3H]−イミダゾ[5,1−d]−1,2,3,5−テトラジン−4−オン;
8−カルバモイル−3−シクロヘキシル−[3H]−イミダゾ[5,1−d]−1,2,3,5−テトラジン−4−オン;
もしくは8−カルバモイル−3−(Wメトキシベンジル)−[3H]イミダゾ[5,1−d]−1,2,3,5−テトラジン−4−オンは、本発明の一実施形態において、本発明の抗IGF1R処方物と組み合わせて投与および/もしくは提供される。
本発明の方法は、癌またはIGF1R、IGF−1および/もしくはIGF−2によって媒介される任意の医学的障害を処置もしくは予防するための、(必要に応じて、さらなる治療剤と組み合わせた)本明細書中に述べる薬学的処方物中のIGF1R抗体もしくはその薬学的組成物の提供および/もしくは投与を含む。通常、このようなさらなる薬剤の投与および投薬は、可能であれば、承認された薬剤の製品の情報シート、Physicians’Desk Reference 2003(Physicians’Desk Reference、第57版);Medical Economics Company;ISBN:1563634457;第57版(2002年11月)ならびに当該分野において周知である治療プロトコールに記載されているスケジュールにしたがって実施される。
本発明のキットはまた、本発明の抗IGF1R抗体処方物を、(例えば、パッケージ挿入物の形態の)情報(キット内の薬学的組成物および投薬形態に関する情報を含む)と一緒に含む。一般的に、このような情報は、患者および医師が同封されている薬学的組成物および投薬形態を効果的かつ安全に使用することを促進する。例えば、処方物に関する以下の情報が挿入物中に供給され得る:薬物動態学、薬力学、臨床研究、効能パラメーター、適応症および用法、禁忌、警告、注意事項、有害反応、過用量、適切な用量および投与、どのように供給されるか、適切な保存条件、参考文献ならびに特許の情報。処方物が乾燥/凍結乾燥された形態で提供される本発明の一実施形態において、キットは、処方物を液体形態に再構築するために無菌の水もしくは食塩水を含む。
本実施例において、成熟軽鎖LCF(配列番号14のアミノ酸20〜128)、成熟重鎖HCA(配列番号16のアミノ酸20〜137)および定常領域(重鎖γ1、軽鎖κ)を含む抗体を記載のように処方し、そして優れた安定性の特性を示す(例えば、室温で数ヶ月間にわたって安定性を示す)ことが決定された。
(材料)
1.酢酸ナトリウム三水和物 USP:1Lのバッチあたり2.30g
2.氷酢酸 USP/Ph.Eur:1Lのバッチあたり0.18g
3.スクロース エクストラピュア NF,Ph.Eur,BP:1Lのバッチあたり70.0g
4.抗体:1Lのバッチあたり20.0g
5.注射用水 USP/Ph.Eur:1Lの体積に充分な量
注意:抗IGF1R抗体は、発泡および振とうによって凝集し得る。製造、ろ過および充填中の過剰な発泡は避けられたい。
(調合)
バッチ体積のおおよそ70%の注射用水中の、酢酸ナトリウム三水和物、酢酸およびスクロースを、攪拌器を備えたステンレス鋼のタンク内に室温でいれ、溶解させた。この溶液に対して、必要な量の薬剤物質(抗体)をステンレス鋼の容器に入れ、そして少なくとも20分攪拌した。20分間攪拌した後、このバッチを注射用水で最終体積にして、そしてさらに20分攪拌した。この溶液のpHをチェックした。この溶液を滅菌フィルタ(0.22μm)にとおして無菌ろ過し、滅菌されたステンレス鋼の容器中に入れた。洗浄および滅菌されたバイアル中に無菌充填した。バイアルをアルミニウム封で封をしてそしてクリンプ(crimp)した。
調合の節に記載されているプロセスにしたがって2つのバッチを製造した。
pHは、5.3と5.4との範囲であった。
得られた最初のUV濃度は、22.34mg/mLであった。UVアッセイによって決定された他の時点での濃度は、最初の値の90〜110%以内で一定のままだった。観察された差異は、本アッセイの標準的な変動性の内にある。
HPSECアッセイによって評価された純度は、基本形の処方物に関しては、4℃および25℃で12週間まではモノマー含量の百分率が99%より高いことを示唆した。40℃では、モノマー含量の百分率は、2週間後および4週間後では、それぞれ98.93および98.47まで減少した。
SDS PAGEの結果は、非還元条件下で典型的な非還元抗体のプロフィールと一致する典型的なバンドのパターンを示唆し、全ての時点に関して、還元条件下で重鎖および軽鎖の検出が報告された。
バイオアッセイは、4週間の結果と12週間の結果との間に有意な変動性を示した。本アッセイで得られた濃度は、21.4mg/mLという最初の濃度に比べると、4℃で2週間後に14.0mg/mLまで減少した。他方で、4℃で12週間後では、基本形の処方物1について得られた濃度は23.3mg/mLであった。観察された差異は、本アッセイの標準的な変動性の内にある。
全てのサンプルに関して、粒子のデータは、USP<788>の仕様を満たした(光遮蔽型粒子計数(Light obscuration test particle count):≧10μm−容器あたり6000個、≧25μm−容器あたり600個)。
全てのサンプルに関して、サンプルの粒子サイズは、11.05nm〜14.92nmの範囲であった。粒子サイズについて観察された差異は、本アッセイの標準的な変動性の内にある。
記述:
記述は、最初の透明な溶液が粒子を含む、から、その後のサンプルについての、乳白色の溶液が粒子を含むまで変動した。
pHは、5.3と5.5との範囲であった。
得られた最初のUV濃度は、19.72mg/mLであった。UVアッセイによって決定された他の時点での濃度は、最初の値の90〜110%以内で一定のままだった。観察された差異は、本アッセイの標準的な変動性の内にある。
HPSECアッセイによって評価された純度は、基本形の処方物に関しては、4℃および25℃で6ヶ月間まではモノマー含量の百分率が98%より高いことを示唆した。40℃では、モノマー含量の百分率は、6ヶ月後では、95%まで減少した。
還元条件および非還元条件の両方の定量SDS PAGEの結果は、4℃および25℃で6ヶ月間まで、比較的一定のままの(本アッセイの変動内の)総不純物のレベルを示し、40℃で6ヶ月にわたって、レベルの上昇を示した。
バイオアッセイは、3ヶ月にわたって示した有意な変動性を温度もしくは時間のいずれについても明白な傾向を有さなかった。観察された差異は、本アッセイの標準的な変動内にある。
全てのサンプルに関して、粒子のデータは、USP<788>の仕様を満たした(光遮蔽型粒子計数:≧10μm−容器あたり6000個、≧25μm−容器あたり600個)。
等電点電気泳動は、抗体分子内の電荷の変動を測定する。最初および1ヶ月目に報告されたバンドのパターンの記述が3ヶ月目および6ヶ月目に報告された記述と等しいので、全ての温度において6ヶ月の間ずっと結果は一定のままである。
これらの研究で使用された抗IGF1R抗体は、実施例1で使用されたものと同じであった。これらの研究を基にして、以下が決定された:
・抗IGF1R抗体は、テストされた全ての緩衝液中で主にβシートの二次構造を示した。
・抗IGF1R抗体は、5および6のpH範囲で高いT開始温度を示した。
・抗IGF1R抗体は、pH5.5の酢酸緩衝液中で、最も高い開始温度を示した。
・塩化ナトリウムの添加は、テストされた全ての緩衝液に関して熱変性の開始を低減した。
・スクロースの添加は、テストされた全ての緩衝液に関して熱変性の開始を増進した。
・抗IGF1R抗体は、7%w/vスクロースを有する20mM酢酸緩衝液(pH5.5)の処方では、4℃および25℃で28日間安定していた。
5mM酢酸緩衝液(pH5.2)中の抗IGF1R抗体(28.36mg/ml)のストック溶液を使用して、pH4〜9の種々の緩衝液の希釈液を調製した。
サンプルを一定の速度で熱した際に、示差走査熱分析(DSC)、遠紫外円偏光二色分光法(FUV CD)、近紫外円偏光二色分光法(NUV CD)、トリプトファン蛍光分光法(TRP FL)、および光散乱による粒子サイズ(PS)を使用してタンパク質の構造変化をモニタリングした。
抗体のリアルタイム安定性を、スクロースを有する20mM酢酸緩衝液(pH5.5)中で研究した。使用した安定性の条件は、4℃、25℃および40℃であり、サンプルを1ヶ月間維持した。モノマー含量の百分率を、HPSECアッセイを使用して分析した。
pH5の酢酸緩衝液中での遠紫外(FUV)円偏光二色法のスキャン。217nmの最小値および235nmでの肩は、βシートの2次構造の主な存在を示す。202nmでの最大値は、βターンの2次構造の存在によるものである(図1(a)を参照されたい)。
250〜270nm:フェニルアラニン残基、
270〜290nm:チロシン残基、
280〜300nm:トリプトファン残基(図1(b)を参照されたい)。
Claims (33)
- IGF1Rに特異的に結合する単離された抗体もしくはその抗原結合フラグメント、緩衝剤およびスクロースを含む、薬学的処方物。
- 前記緩衝剤が、リン酸緩衝剤、クエン酸緩衝剤、ヒスチジン緩衝剤、グリシン緩衝剤もしくは酢酸緩衝剤である、請求項1に記載の処方物。
- IGF1Rに特異的に結合する抗体もしくはその抗原結合フラグメント、緩衝剤およびスクロースをpH約5.5〜約6.0で含む、請求項1に記載の薬学的処方物。
- 前記緩衝剤が、リン酸緩衝剤、クエン酸緩衝剤、ヒスチジン緩衝剤、グリシン緩衝剤もしくは酢酸緩衝剤である、請求項1に記載の処方物。
- 前記抗体もしくはフラグメントが、配列番号1〜配列番号3からなる群より選択される1つ以上の軽鎖相補性決定領域;および/もしくは配列番号4〜配列番号7からなる群より選択される1つ以上の重鎖相補性決定領域を含む、請求項1に記載の処方物。
- 配列番号8〜配列番号14のアミノ酸20〜128からなる群より選択される軽鎖可変領域:および/もしくは配列番号15〜配列番号17のアミノ酸20〜137からなる群より選択される重鎖可変領域を含む、抗体もしくはその抗原結合フラグメント;緩衝剤ならびにスクロースをpH約5.5〜約6.0で含む、請求項1に記載の薬学的処方物。
- 凍結乾燥された、請求項1に記載の処方物。
- 無菌である、請求項1に記載の処方物。
- 前記抗体もしくはフラグメントが、γ1、γ2、γ3およびγ4からなる群より選択される重鎖定常領域もしくはκ軽鎖定常領域を含む、請求項1に記載の処方物。
- 水溶液状である、請求項1に記載の処方物。
- 前記抗体もしくはフラグメントの濃度が、約20mg/mlである、請求項1に記載の処方物。
- 緩衝剤の濃度が、約1mM〜約20mMである、請求項1に記載の処方物。
- スクロースの濃度が、約5mg/ml〜約70mg/mlである、請求項1に記載の処方物。
- さらなる治療剤と組み合わせた、請求項1に記載の処方物。
- 配列番号8〜配列番号14のアミノ酸20〜128からなる群より選択される軽鎖可変領域および/もしくは配列番号15〜配列番号17のアミノ酸20〜137からなる群より選択される重鎖可変領域を含む、前記抗体もしくはフラグメント;酢酸塩;酢酸ならびにスクロースをpH約5.5で、さらなる治療剤と組み合わせて単一の組成物中に含む、請求項1に記載の処方物。
- (a)配列番号8〜配列番号14のアミノ酸20〜128からなる群より選択される軽鎖可変領域および/もしくは配列番号15〜配列番号17のアミノ酸20〜137からなる群より選択される重鎖可変領域を含む、20mg/mlの抗体もしくはその抗原結合フラグメント;
(b)2.3mg/mlの酢酸ナトリウム三水和物;
(c)0.18mg/mlの氷酢酸;
(d)70mg/mlのスクロース;ならびに
(e)水
を含む、pH5.5の、請求項1に記載の薬学的処方物。 - pH5.5の凍結乾燥された薬学的処方物であって、再構築された場合、該薬学的処方物は:
(a)アミノ酸20〜128からなる群より選択される軽鎖可変領域および/もしくは配列番号15〜配列番号17のアミノ酸20〜137からなる群より選択される重鎖可変領域を含む、20mg/mlの治療上有効な量の抗体もしくはその抗原結合フラグメント;
(b)2.3mg/mlの酢酸ナトリウム三水和物;
(c)0.18mg/mlの氷酢酸;および
(d)70mg/mlのスクロース;ならびに
(e)水
を含む、薬学的処方物。 - 請求項1に記載の処方物を含む、容器。
- ガラス製のバイアルである、請求項19に記載の容器。
- 請求項1に記載の処方物を含む、注入デバイス。
- 皮下針および注射器である、請求項21に記載の注入デバイス。
- (a)容器もしくは注入デバイス中の請求項1に記載の処方物;ならびに
(b)薬物動態、薬力学、臨床研究、効能パラメーター、適応症および用法、禁忌、警告、注意事項、有害反応、過用量、適切な用量および投与、どのように供給されるか、適切な保存条件、参考文献ならびに特許の情報からなる群より選択される該処方物に関連する1つ以上の情報項目を含むパッケージ挿入物を備える、キット。 - IGF1R、IGF−1および/もしくはIGF−2によって媒介される医学的障害を被験体において処置もしくは予防するための方法であって、該方法は、治療上有効な量の請求項1に記載の処方物を該被験体に投与する工程を包含する、方法。
- 前記医学的障害が、神経芽細胞腫、横紋筋肉腫、骨肉腫、小児癌、先端巨大症、卵巣癌、膵臓癌、良性前立腺肥大症、乳癌、前立腺癌、骨癌、肺癌、結腸直腸癌、頚部癌、滑膜肉腫、膀胱癌、胃癌、ウィルムス癌、卵巣癌、良性前立腺肥大症(BPH)、転移性カルチノイドおよび血管作動性腸管ペプチド分泌腫瘍に関連する下痢、ビポーマ、ウェルナー−モリソン症候群、腎臓癌、腎細胞癌、移行上皮癌、ユーイング肉腫、白血病、急性リンパ芽球性白血病、脳の癌、膠芽腫、非膠芽腫の脳の癌、髄膜腫、下垂体腺腫、前庭神経鞘腫、未分化神経外胚葉性腫瘍、髄芽腫、星状細胞腫、乏突起膠腫、脳室上衣腫、脈絡叢乳頭腫、巨人症、乾癬、アテローム性動脈硬化症、血管の平滑筋再狭窄、不適切な微小血管増殖、先端巨大症、巨人症、乾癬、アテローム性動脈硬化症、血管の平滑筋再狭窄もしくは不適切な微小血管増殖、グレーヴズ病、多発性硬化症、全身性エリテマトーデス、橋本甲状腺炎、重症筋無力症、自己免疫性甲状腺炎ならびにベーチェット病からなる群より選択される、請求項24に記載の方法。
- 前記被験体が、前記処方物と組み合わせてさらなる治療剤を投与される、請求項24に記載の方法。
- 前記被験体がヒトである、請求項24に記載の方法。
- 前記処方物が、前記被験体に非経口で投与される、請求項24に記載の方法。
- 前記処方物が、pH約5.5であり、そして:
(a)配列番号8〜配列番号14のアミノ酸20〜128からなる群より選択される軽鎖可変領域および/もしくは配列番号15〜配列番号17のアミノ酸20〜137からなる群より選択される重鎖可変領域を含む、20mg/mlの治療上有効な量の抗体もしくはその抗原結合フラグメント;
(b)2.3mg/mlの酢酸ナトリウム三水和物;
(c)0.18mg/mlの氷酢酸;
(d)70mg/mlのスクロース;ならびに
(e)水
を含む、請求項24に記載の方法。 - 配列番号20〜配列番号128のアミノ酸20〜128からなる群より選択される軽鎖可変領域および/もしくは配列番号15〜配列番号17のアミノ酸20〜137からなる群より選択される重鎖可変領域を含む抗体もしくはその抗原結合フラグメントを安定化させるための方法であって;該方法は、該抗体もしくはフラグメントと酢酸塩;酢酸およびスクロースを、必要に応じてpH約5.5で合わせる工程を包含する、方法。
- 前記抗体もしくはフラグメントの濃度が約20mg/mlである、請求項31に記載の方法。
- 酢酸塩の濃度が約2.3mg/mlであり、酢酸の濃度が約0.18mg/mlであり、そしてスクロースの濃度が約70mg/mlである、請求項31に記載の方法。
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- 2006-06-13 MX MX2007016306A patent/MX2007016306A/es not_active Application Discontinuation
- 2006-06-13 WO PCT/US2006/022995 patent/WO2006138315A2/en active Application Filing
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- 2006-06-13 EP EP06773043A patent/EP1896505A2/en not_active Withdrawn
- 2006-06-13 BR BRPI0611800-3A patent/BRPI0611800A2/pt not_active IP Right Cessation
- 2006-06-13 KR KR1020077030486A patent/KR20080019249A/ko not_active Application Discontinuation
- 2006-06-13 CA CA002611149A patent/CA2611149A1/en not_active Abandoned
- 2006-06-13 JP JP2008517021A patent/JP2008546699A/ja not_active Ceased
- 2006-06-13 US US11/452,167 patent/US20060286103A1/en not_active Abandoned
- 2006-06-14 AR ARP060102524A patent/AR054474A1/es not_active Application Discontinuation
- 2006-06-14 PE PE2009001322A patent/PE20100096A1/es not_active Application Discontinuation
- 2006-06-14 PE PE2006000669A patent/PE20070116A1/es not_active Application Discontinuation
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2007
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AR054474A1 (es) | 2007-06-27 |
EP1896505A2 (en) | 2008-03-12 |
JP2011148841A (ja) | 2011-08-04 |
US20060286103A1 (en) | 2006-12-21 |
ZA200710855B (en) | 2008-12-31 |
CA2611149A1 (en) | 2006-12-28 |
WO2006138315A2 (en) | 2006-12-28 |
KR20080019249A (ko) | 2008-03-03 |
PE20100096A1 (es) | 2010-02-17 |
AU2006259536A1 (en) | 2006-12-28 |
NO20080246L (no) | 2008-03-17 |
NZ564098A (en) | 2010-04-30 |
BRPI0611800A2 (pt) | 2008-12-09 |
TW200745161A (en) | 2007-12-16 |
WO2006138315A3 (en) | 2007-06-07 |
MX2007016306A (es) | 2008-03-07 |
CN101287761A (zh) | 2008-10-15 |
PE20070116A1 (es) | 2007-02-09 |
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