JP5608619B2 - Tnf−アルファ関連疾患の治療用ヒト抗体の製剤 - Google Patents
Tnf−アルファ関連疾患の治療用ヒト抗体の製剤 Download PDFInfo
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- JP5608619B2 JP5608619B2 JP2011204759A JP2011204759A JP5608619B2 JP 5608619 B2 JP5608619 B2 JP 5608619B2 JP 2011204759 A JP2011204759 A JP 2011204759A JP 2011204759 A JP2011204759 A JP 2011204759A JP 5608619 B2 JP5608619 B2 JP 5608619B2
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Description
a)表面プラズモン共鳴により測定した場合に1×10−3s−1以下のKoff速度定数でヒトTNFαから解離し;
b)配列番号3のアミノ酸配列を含むか、あるいは1、4、5、7もしくは8位の単一アラニン置換又は1、3、4、6、7、8及び/又は9位の1〜5カ所の保存アミノ酸置換により配列番号3から変異したアミノ酸配列を含む軽鎖CDR3ドメインをもち;
c)配列番号4のアミノ酸配列を含むか、あるいは2、3、4、5、6、8、9、10もしくは11位の単一アラニン置換又は2、3、4、5、6、8、9、10、11及び/又は12位の1〜5カ所の保存アミノ酸置換により配列番号4から変異したアミノ酸配列を含む重鎖CDR3ドメインをもつ抗体、又はその抗原結合部分を含有する。別の態様では、本発明の製剤は5×10−4s−1以下のKoff速度定数でヒトTNFαから解離する抗体、又はその抗原結合部分を含有する。本発明の更に別の態様では、製剤は1×10−4s−1以下のKoff速度定数でヒトTNFαから解離する抗体、又はその抗原結合部分を含有する。
配列番号3のアミノ酸配列を含むか、あるいは1、4、5、7もしくは8位の単一アラニン置換又は1、3、4、6、7、8及び/又は9位の1〜5カ所の保存アミノ酸置換により配列番号3から変異したアミノ酸配列を含む軽鎖CDR3ドメインと、
配列番号4のアミノ酸配列を含むか、あるいは2、3、4、5、6、8、9、10もしくは11位の単一アラニン置換又は2、3、4、5、6、8、9、10、11及び/又は12位の1〜5カ所の保存アミノ酸置換により配列番号4から変異したアミノ酸配列を含む重鎖CDR3ドメインを含む抗体、又はその抗原結合部分を含有する液体水性医薬製剤を提供する。1態様では、液体水性医薬製剤はヒトTNFαと結合し、配列番号3、配列番号11、配列番号12、配列番号13、配列番号14、配列番号15、配列番号16、配列番号17、配列番号18、配列番号19、配列番号20、配列番号21、配列番号22、配列番号23、配列番号24、配列番号25、配列番号26から構成される群から選択されるアミノ酸配列を含むCDR3ドメインをもつ軽鎖可変領域(LCVR)又は配列番号4、配列番号27、配列番号28、配列番号29、配列番号30、配列番号31、配列番号32、配列番号33及び配列番号34から構成される群から選択されるアミノ酸配列を含むCDR3ドメインをもつ重鎖可変領域(HCVR)を含む抗体を含有する。本発明の別の態様では、抗体、又はその抗原結合部分はヒトTNFαと結合し、抗体D2E7又はその抗原結合部分である。
本発明を理解し易くするために、まず所定の用語を定義する。
本発明はpH約4〜約8および好ましくは少なくとも約18か月間の長い保存期間をもつ製剤を形成する緩衝液中に治療有効量の抗体を含有する液体水性医薬製剤に関する。別の態様では、本発明の液体水性医薬製剤は高い安定性をもつ。本発明の別の態様では、製剤は光に感受性でない。本発明の更に別の態様では、本発明の製剤は製剤の少なくとも3回の凍結/解凍サイクル後に安定に維持される。更に別の態様では、本発明の医薬製剤は単回使用sc注射用に適している。
本発明は当分野の公認製剤に比較して改善された性質をもつ製剤(例えば蛋白質製剤及び/又は抗体製剤)に関する。例えば、本発明の製剤は当分野の公認製剤に比較して改善された保存期間及び/又は安定性をもつ。好ましい側面では、本発明の製剤は蛋白質濃度が高く、例えば、約45mg/mlを上回る蛋白質濃度、約50mg/mlを上回る蛋白質濃度、約100mg/mlを上回る蛋白質濃度、又は約150mg/mlを上回る蛋白質濃度である。本発明の好ましい態様では、蛋白質は抗体である。別の好ましい態様では、抗体はD2E7である。本発明は更に例えば約45mg/mlを上回る濃度で治療用抗体を製剤化するために十分な量のポリオール、界面活性剤、及びpH約4〜8のクエン酸及び/又はリン酸を含む緩衝液系を含有する水性医薬組成物を提供する。
本発明の製剤は各々参考として本明細書に援用されている米国特許第6,090,382号及び6,258,562号に記載されているものと同様の適応症に使用することができ、これらの疾患については追って詳述する。
腫瘍壊死因子は敗血症の病態生理に関与することが立証されており、低血圧、心筋抑制、血管外漏出症候群、臓器壊死、毒性二次メディエーター放出刺激及び凝固カスケードの活性化等の生体作用がある(例えばTracey,K.J.and Cerami,A.(1994)Annu.Rev.Med.45:491−503;Russell,D and Thompson,R.C.(1993)Curr.Opin.Biotech.4:714−721参照)。従って、発明の製剤は敗血性ショック、内毒素性ショック、グラム陰性敗血症及び毒素性ショック症候群等のその臨床症状の任意のものにおいて敗血症を治療するために使用することができる。
腫瘍壊死因子は種々の自己免疫疾患の病態生理に関与することが示されている。例えば、TNFαはリウマチ様関節炎で組織炎症を活性化し、関節破壊の原因となることが示されている(例えばTracey and Cerami,前出;Arend,W.P.and Dayer,J−M.(1995)Arth.Rheum.38:151−160;Fava,R.A.ら(1993)Clin.Exp.Immunol.94:261−266参照)。TNFαは糖尿病で膵島細胞死を促進し、インスリン抵抗性を媒介することも示されている(例えばTracey and Cerami,前出;PCT公開第WO94/08609号参照)。TNFαは多発性硬化症で希突起膠細胞への細胞毒性を媒介し、炎症性プラークを誘導することも示されている(例えばTracey and Cerami,前出参照)。キメラ及びヒト化マウス抗hTNFα抗体がリウマチ様関節炎の治療で臨床試験されている(例えばElliott,M.J.ら(1994)Lancet 344:1125−1127;Elliot,M.J.ら(1994)Lancet 344:1105−1110;Rankin,E.C.ら(1995)Br.J.Rheumatol.34:334−342参照)。
腫瘍壊死因子は種々の感染性疾患で観察される生体作用を媒介することが示されている。例えば、TNFαはマラリアで脳炎症と毛細血管血栓症及び梗塞を媒介することが示されている(例えばTracey and Cerami,前出参照)。TNFαは髄膜炎で脳炎症を媒介し、血液脳関門の損傷を誘導し、敗血性ショック症候群を誘発し、静脈梗塞を活性化することも示されている(例えばTracey and Cerami,前出参照)。TNFαは後天性免疫不全症候群(AIDS)で悪液質を誘導し、ウイルス増殖を刺激し、中枢神経系損傷を媒介することも示されている(例えばTracey and Cerami,前出参照)。従って、本発明の抗体、及び抗体部分は細菌性髄膜炎(例えばヨーロッパ特許出願公開第EP585 705号参照)、脳マラリア、AIDS及びAIDS関連症候群(ARC)(例えばヨーロッパ特許出願公開第EP230 574号参照)、並びに移植に続発するサイトメガロウイルス感染(例えばFietze,E.ら(1994)Transplantation 58:675−680参照)等の感染性疾患の治療に使用することができる。本発明の製剤は感染による発熱や筋肉痛(例えばインフルエンザ)及び感染に続発(例えばAIDS又はARCに続発)する悪液質等の感染性疾患に伴う症状を緩和するためにも使用することができる。
腫瘍壊死因子は同種移植拒絶反応と移植片対宿主疾患(GVHD)の主要メディエーターであり、T細胞受容体CD3複合体に対するラット抗体OKT3を使用して腎移植拒絶反応を抑制する場合に観察された有害反応を媒介することが示されている(例えばTracey and Cerami,前出;Eason,J.D.ら(1995)Transplantation 59:300−305;Suthanthiran,M.and Strom,T.B.(1994)New Engl.J.Med.331:365−375参照)。従って、本発明の製剤は同種移植及び異種移植拒絶反応等の移植拒絶反応を抑制したり、GVHDを抑制するために使用することができる。抗体又は抗体部分は単独で使用してもよいが、同種移植に対する免疫応答を抑制又はGVHDを抑制する1種以上の他の物質と併用するとより好ましい。例えば、1態様では、本発明の製剤をOKT3と併用し、OKT3により誘導される反応を抑制する。別の態様では、細胞表面分子CD25(インターロイキン−2受容体−α)、CD11a(LFA−1)、CD54(ICAM−1)、CD4、CD45、CD28/CTLA4、CD80(B7−1)及び/又はCD86(B7−2)等の免疫応答の調節に関与する他のターゲットに対する1種以上の抗体と本発明の製剤を併用する。更に別の態様では、シクロスポリンA又はFK506等の1種以上の汎用免疫抑制剤と本発明の製剤を併用する。
腫瘍壊死因子は悪性腫瘍で悪液質を誘導し、腫瘍増殖を刺激し、転移能力を増強し、細胞毒性を媒介することが示されている(例えばTracey and Cerami,前出参照)。従って、本発明の製剤は腫瘍増殖又は転移を抑制するため及び/又は悪性腫瘍に続発する悪液質を緩和するために悪性腫瘍の治療で使用することができる。製剤は全身又は腫瘍部位に局所投与することができる。
腫瘍壊死因子は白血球−内皮細胞活性化の刺激、肺細胞に対する細胞毒性の誘導及び血管外漏出症候群の誘導等の成人呼吸窮迫症候群の病態生理に関与することが示されてい(例えばTracey and Cerami,前出参照)。従って、本発明の製剤は成人呼吸窮迫症候群(例えばPCT公開第WO91/04054号参照)、ショック肺、慢性肺炎症性疾患、肺サルコイドーシス、肺線維症及び珪肺症等の各種肺疾患を治療するために使用することができる。製剤は全身又は例えばエアゾールとして肺表面に局所投与することができる。
腫瘍壊死因子は炎症性腸疾患の病態生理に関与することが示されている(例えばTracy,K.J.ら(1986)Science 234:470−474;Sun,X−M.ら(1988)J.Clin.Invest.81:1328−1331;MacDonald,T.T.ら(1990)Clin.Exp.Immunol.81:301−305参照)。キメラマウス抗hTNFα抗体がクローン病の治療で臨床試験されている(van Dullemen,H.M.ら(1995)Gastroenterology 109:129−135)。本発明の製剤はクローン病と潰瘍性大腸炎の2種の症候群を含む特発性炎症性腸疾患等の腸疾患を治療するためにも使用することができる。
本発明の製剤は心臓虚血(例えばヨーロッパ特許出願公開第EP453 898号参照)や心不全(心筋衰弱)(例えばPCT公開第WO94/20139号参照)等の各種心疾患を治療するためにも使用することができる。
本発明の医薬製剤はTNFα活性が有害となる他の各種疾患を治療するためにも使用することができる。TNFα活性が病態生理に関与することが示されており、従って、本発明の製剤を使用して治療することができる他の疾病及び疾患の例としては炎症性骨疾患及び骨吸収疾患(例えば、Bertolini,D.R.ら(1986)Nature 319:516−518;Konig,A.ら(1988)J.Bone Miner.Res.3:621−627;Lerner,U.H.and Ohlin,A.(1993)J.Bone Miner.Res.8:147−155;及びShankar,G.and Stern,P.H.(1993)Bone 14:871−876参照);アルコール性肝炎(例えばMcClain,C.J.and Cohen,D.A.(1989)Hepatology 9:349−351;Felver,M.E.ら(1990)Alcohol.Clin.Exp.Res.14:255−259;及びHansen,J.ら(1994)Hepatology 20:461−474参照)及びウイルス性肝炎(Sheron,N.ら(1991)J.Hepatol.12:241−245;及びHussain,M.J.ら(1994)J.Clin.Pathol.47:1112−1115)等の肝炎;凝固障害(例えばvan der Poll,T.ら(1990)N.Engl.J.Med.322:1622−1627;及びvan der Poll,T.ら(1991)Prog.Clin.Biol.Res.367:55−60参照);火傷(例えばGiroir,B.P.ら(1994)Am.J.Physiol.267:H118−124;及びLiu,X.S.ら(1994)Burns 20:40−44参照);再潅流傷害(例えばScales,W.E.ら(1994)Am.J.Physiol.267:G1122−1127;Serrick,C.ら(1994)Transplantation 58:1158−1162;及びYao,Y.M.ら(1995)Resuscitation 29:157−168参照);ケロイド形成(例えばMcCauley,R.L.ら(1992)J.Clin.Immunol.12:300−308参照);瘢痕組織形成;発熱;歯周病;肥満症及び放射線中毒が挙げられる。
以下のプロトコールに従って本発明の医薬製剤を製造した。
以下の成分:マンニトール240.0g、クエン酸1水和物26.1g、クエン酸ナトリウム6.1g、リン酸2ナトリウム2水和物30.6g、リン酸2水素ナトリウム2水和物17.2g、塩化ナトリウム123.3g、ポリソルベート80 20.0g、及び水19,715.7〜19,716.1gを配量した。
濾過した緩衝液を次に、以下のように製造した解凍プール抗体濃縮物(医薬製剤の活性成分)に加えた。抗体(濃縮物)は医薬製剤の製造前に水浴で解凍した。抗体濃縮物34.207g(蛋白質濃縮物中蛋白質濃度60mg/mLの蛋白質2.0kgに等価)を使用した。濃縮物の密度は1.0262g/mLとした。25.655〜37.316(蛋白質濃縮物中蛋白質濃度55〜80mg/mLに等価)の範囲の任意蛋白質濃縮物を使用することができる。バルク溶液の最終重量に達するまで撹拌下に緩衝液を加えた。
D2E7抗体用製剤緩衝液を選択した後に、薬剤物質を最終製剤と同一マトリックスで製剤化した。
製剤が微生物増殖を助長できるか否かを調べるために試験を実施した。これらの実験の結果、製剤は20〜25℃で14日間保存した場合に微生物増殖を助長しないことが判明した。この結果は滅菌製剤に微生物(例えばStaphylococous aureus,ATCC−No.:6538P,Candida albicans,ATCC−No.:10231,Aspergillus niger,ATCCC−No.:16404,Pseudomonas aeruginosa,ATCC−No.:9027,環境単離株)を低レベル(NMT100cfu/mL)で直接接種することにより判定した。その後、接種した製剤の総合微生物増殖(例えば濁度変化)を試験した。濁度が認められなければ総合増殖がないという基準で14日後に接種容器で検出した。更に、これらの容器から生物を再単離することはできなかった。従って、製剤はこれらの条件下で微生物増殖を助長しないと結論された。
本明細書に引用する全文献及び特許の内容は、全体を参考として本明細書に援用している。
本明細書に記載する本発明の特定態様の多数の等価物が当業者に自明であるか、又は単なる日常的実験を使用して確認することができよう。このような等価物も特許請求の範囲に含むものとする。
Claims (5)
- リウマチ性関節炎に罹患しているヒト患者を治療するための薬剤の製造における、
(a)D2E7の軽鎖可変領域及び重鎖可変領域を含むヒト抗腫瘍壊死因子α(TNFα)抗体又はその抗原結合部分40〜75mg/ml、
(b)(i)1.0〜1.5mg/mlのクエン酸1水和物
(ii)0.25〜0.5mg/mlのクエン酸ナトリウム
(iii)1.25〜1.75mg/mlのリン酸2ナトリウム2水和物
(iv)0.7〜1.1mg/mlのリン酸2水素ナトリウム2水和物
(v)6.0〜6.4mg/mlの塩化ナトリウム
を含むクエン酸及びリン酸を含む緩衝液、
(c)10〜14mg/mlのマンニトール
(d)0.1〜5.0mg/mlのポリソルベート80
を含み、pHが4〜8である処方物の使用。 - 前記抗体の濃度が50mg/mlである請求項1に記載の使用。
- 抗体がD2E7である請求項1又は2に記載の使用。
- 処方物が1.3mg/mlのクエン酸1水和物、
0.3mg/mlのクエン酸ナトリウム、
1.53mg/mlのリン酸2ナトリウム2水和物、
0.86mg/mlのリン酸2水素ナトリウム2水和物、
6.2mg/mlの塩化ナトリウム、
12mg/mlのマンニトール、
1mg/mlのポリソルベート80
を含み、pHが5.0〜5.2である請求項1〜3のいずれか1項に記載の使用。 - 処方物が単回使用皮下注射用に適している請求項1〜4のいずれか1項に記載の使用。
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