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Description
別の実施形態において、ヒト患者におけるｐ－ａＨＵＳ（例えば、産後ａＨＵＳ）を治療するためのキットであって、（ａ）ある用量のラブリズマブ及び（ｂ）本明細書に記載の方法においてラブリズマブを使用するための指示書を含むキットが提供される。
本発明は、例えば、以下の項目を提供する。
（項目１）
妊娠関連非典型溶血性尿毒症症候群（ｐ－ａＨＵＳ）を有するヒト患者を治療する方法であって、前記患者に有効量の抗Ｃ５抗体、又はその抗原結合断片を投与することを含み、
前記抗Ｃ５抗体、又はその抗原結合断片は、それぞれ配列番号１９、１８及び３に記載されるＣＤＲ１、ＣＤＲ２及びＣＤＲ３重鎖配列と、それぞれ配列番号４、５及び６に記載されるＣＤＲ１、ＣＤＲ２及びＣＤＲ３軽鎖配列とを含む方法。
（項目２）
前記抗体は、ヒト胎児性Ｆｃ受容体（ＦｃＲｎ）に結合するバリアントヒトＦｃ領域を含み、前記バリアントヒトＦｃ ＣＨ３領域は、それぞれＥＵ番号付けで、ネイティブヒトＩｇＧ Ｆｃ領域のメチオニン４２８及びアスパラギン４３４に対応する残基においてＭｅｔ－４２９－Ｌｅｕ及びＡｓｎ－４３５－Ｓｅｒ置換を含む、項目１に記載の方法。
（項目３）
前記抗Ｃ５抗体、又はその抗原結合断片は、配列番号１２に記載される重鎖可変領域と配列番号８に記載される軽鎖可変領域とを含む、項目１又は２に記載の方法。
（項目４）
前記抗Ｃ５抗体、又はその抗原結合断片は、配列番号１３に示される重鎖定常領域をさらに含む、項目１～３のいずれか一項に記載の方法。
（項目５）
前記抗Ｃ５抗体、又はその抗原結合断片は、配列番号１４に記載される重鎖と、配列番号１１に記載される軽鎖とを含む、項目１～４のいずれか一項に記載の方法。
（項目６）
前記抗Ｃ５抗体、又はその抗原結合断片は、ｐＨ７．４及び２５℃で、０．１ｎＭ≦ＫＤ≦１ｎＭの範囲内の親和性解離定数（ＫＤ）でヒトＣ５に結合する、項目１～５のいずれか一項に記載の方法。
（項目７）
前記抗Ｃ５抗体、又はその抗原結合断片は、ｐＨ６．０及び２５℃で、ＫＤ≧１０ｎＭでヒトＣ５に結合する、項目１～５のいずれか一項に記載の方法。
（項目８）
前記抗Ｃ５抗体、又はその抗原結合断片は、静脈内投与のために配合される、項目１～７のいずれか一項に記載の方法。
（項目９）
前記抗Ｃ５抗体、又はその抗原結合断片を、前記患者に
（ａ）１日目に１回、≧４０～＜６０ｋｇの体重の患者に対して２４００ｍｇ、≧６０～＜１００ｋｇの体重の患者に対して２７００ｍｇ、又は≧１００ｋｇの体重の患者に対して３０００ｍｇの用量で；
（ｂ）１５日目及びその後８週間毎に、≧４０～＜６０ｋｇの体重の患者に対して３０００ｍｇ、≧６０～＜１００ｋｇの体重の患者に対して３３００ｍｇ、又は≧１００ｋｇの体重の患者に対して３６００ｍｇの用量で
投与する、項目１～８のいずれか一項に記載の方法。
（項目１０）
ｐ－ａＨＵＳを有するヒト患者を治療する方法であって、前記患者に有効量の抗Ｃ５抗体、又はその抗原結合断片を投与することを含み、
前記抗Ｃ５抗体、又はその抗原結合断片は、それぞれ配列番号１９、１８及び３に記載されるＣＤＲ１、ＣＤＲ２及びＣＤＲ３重鎖配列と、それぞれ配列番号４、５及び６に記載されるＣＤＲ１、ＣＤＲ２及びＣＤＲ３軽鎖配列と、ヒト胎児性Ｆｃ受容体（ＦｃＲｎ）に結合するバリアントヒトＦｃ領域とを含み、前記バリアントヒトＦｃ ＣＨ３領域は、それぞれＥＵ番号付けで、ネイティブヒトＩｇＧ Ｆｃ領域のメチオニン４２８及びアスパラギン４３４に対応する残基においてＭｅｔ－４２９－Ｌｅｕ及びＡｓｎ－４３５－Ｓｅｒ置換を含み、
前記抗Ｃ５抗体、又はその抗原結合断片を、前記患者に
（ａ）１日目に１回、≧４０～＜６０ｋｇの体重の患者に対して２４００ｍｇ、≧６０～＜１００ｋｇの体重の患者に対して２７００ｍｇ、又は≧１００ｋｇの体重の患者に対して３０００ｍｇの用量で；
（ｂ）１５日目及びその後８週間毎に、≧４０～＜６０ｋｇの体重の患者に対して３０００ｍｇ、≧６０～＜１００ｋｇの体重の患者に対して３３００ｍｇ、又は≧１００ｋｇの体重の患者に対して３６００ｍｇの用量で
投与する方法。
（項目１１）
前記抗Ｃ５抗体、又はその抗原結合断片を、≧４０～＜６０ｋｇの体重の患者に
（ａ）１日目に１回、２４００ｍｇの用量で；
（ｂ）１５日目及びその後８週間毎に、３０００ｍｇの用量で
投与する、項目１～１０のいずれか一項に記載の方法。
（項目１２）
前記抗Ｃ５抗体、又はその抗原結合断片を、≧６０～＜１００ｋｇの体重の患者に
（ａ）１日目に１回、２７００ｍｇの用量で；
（ｂ）１５日目及びその後８週間毎に、３３００ｍｇの用量で
投与する、項目１～１１のいずれか一項に記載の方法。
（項目１３）
前記抗Ｃ５抗体、又はその抗原結合断片を、≧１００ｋｇの体重の患者に
（ａ）１日目に１回、３０００ｍｇの用量で；
（ｂ）１５日目及びその後８週間毎に、３６００ｍｇの用量で
投与する、項目１～１１のいずれか一項に記載の方法。
（項目１４）
前記治療は、前記治療の間、１００μｇ／ｍｌ以上の前記抗Ｃ５抗体の血清トラフ濃度を維持する、項目１～１３のいずれか一項に記載の方法。
（項目１５）
前記治療は、前記治療の間、２００μｇ／ｍｌ以上の前記抗Ｃ５抗体の血清トラフ濃度を維持する、項目１～１４のいずれか一項に記載の方法。
（項目１６）
前記治療は、遊離Ｃ５濃度を前記治療期間全体にわたり９９％超だけ低減させる、項目１～１５のいずれか一項に記載の方法。
（項目１７）
前記抗Ｃ５抗体、又はその抗原結合断片を、前記治療後８週間毎に最長２年間、３０００ｍｇ、３３００ｍｇ、又は３６００ｍｇの用量で投与する、項目１～１６のいずれか一項に記載の方法。
（項目１８）
前記治療は、終末補体阻害をもたらす、項目１～１７のいずれか一項に記載の方法。
（項目１９）
前記治療は、乳酸デヒドロゲナーゼ（ＬＤＨ）レベルにより評価して、ベースラインと比較して溶血の低減をもたらす、項目１～１８のいずれか一項に記載の方法。
（項目２０）
前記治療は、ＬＤＨレベルの正常化をもたらす、項目１～１９のいずれか一項に記載の方法。
（項目２１）
前記治療は、遊離ヘモグロビン、ハプトグロビン、網状赤血球数、ＰＮＨ赤血球（ＲＢＣ）クローン及びＤ－ダイマーからなる群から選択される溶血関連血液学的バイオマーカーの正常レベルに向かうシフトを生じさせる、項目１～２０のいずれか一項に記載の方法。
（項目２２）
前記治療は、ベースラインと比較して、重症高血圧症、タンパク尿症、尿毒症、嗜眠、疲労、易怒性、血小板減少症、微小血管症性溶血性貧血、及び腎機能障害の低減又は休止からなる群から選択される少なくとも１つの治療効果を生じさせる、項目１～２１のいずれか一項に記載の方法。
（項目２３）
前記治療は、Ｂａ因子、可溶性腫瘍壊死因子受容体１［ｓＴＮＦＲ１］）、可溶性血管接着分子１［ｓＶＣＡＭ１］、トロンボモジュリン、Ｄ－ダイマー、及びシスタチンＣの正常レベルに向かうシフトを生じさせる、項目１～２２のいずれか一項に記載の方法。
（項目２４）
前記治療は、ベースラインと比較してヘモグロビン安定化の増加を生じさせる、項目１～２３のいずれか一項に記載の方法。
（項目２５）
前記治療は、ベースラインと比較して輸血の必要性の低減を生じさせる、項目１～２４のいずれか一項に記載の方法。
（項目２６）
前記治療は、主要血管有害事象（ＭＡＶＥ）の低減を生じさせる、項目１～２５のいずれか一項に記載の方法。
（項目２７）
前記治療は、慢性疾患治療の機能的評価（ＦＡＣＩＴ）－疲労スケール、バージョン４及び欧州癌研究治療機関の生活の質アンケート－コア３０スケールを介して評価される、ベースラインからの生活の質の変化を生じさせる、項目１～２６のいずれか一項に記載の方法。
（項目２８）
前記治療は、血小板正常化をもたらす、項目１～２７のいずれか一項に記載の方法。
（項目２９）
前記治療は、ベースラインからの血清クレアチニンの≧２５％の改善をもたらす、項目１～２８のいずれか一項に記載の方法。
（項目３０）
完全ＴＭＡ奏効をもたらす、項目１～２９のいずれか一項に記載の方法。
（項目３１）
前記治療は、修正された完全ＴＭＡ奏効をもたらす、項目１～３０のいずれか一項に記載の方法。
（項目３２）
前記治療は、ｅＧＦＲの正常レベル（例えば、≧９０）に向かうシフトをもたらす、項目１～３１のいずれか一項に記載の方法。
（項目３３）
前記治療は、透析の低減又は中止をもたらす、項目１～３２のいずれか一項に記載の方法。
（項目３４）
前記治療は、末期腎疾患（ＥＳＲＤ）を予防し、又はそれまでの時間を延長させる、項目１～３３のいずれか一項に記載の方法。
（項目３５）
前記治療は、前記患者の生存期間を延長させる、項目１～３４のいずれか一項に記載の方法。
（項目３６）
前記ｐ－ａＨＵＳは、産後ａＨＵＳである、項目１～３５のいずれか一項に記載の方法。
（項目３７）
ヒト患者における妊娠関連非典型溶血性尿毒症症候群（ｐ－ａＨＵＳ）を治療するためのキットであって、
（ａ）ある用量の抗Ｃ５抗体、又はその抗原結合断片であって、それぞれ配列番号１９、１８及び３に記載のＣＤＲ１、ＣＤＲ２及びＣＤＲ３重鎖配列と、それぞれ配列番号４、５及び６に記載のＣＤＲ１、ＣＤＲ２及びＣＤＲ３軽鎖配列とを含む抗Ｃ５抗体、又はその抗原結合断片；並びに
（ｂ）項目１～３２のいずれか一項に記載の方法において前記抗Ｃ５抗体、又はその抗原結合断片を使用するための指示書
を含むキット。
（項目３８）
ヒト患者における妊娠関連非典型溶血性尿毒症症候群（ｐ－ａＨＵＳ）を治療するためのキットであって、
（ａ）ある用量の抗Ｃ５抗体、又はその抗原結合断片であって、それぞれ配列番号１９、１８及び３に記載されるＣＤＲ１、ＣＤＲ２及びＣＤＲ３重鎖配列と、それぞれ配列番号４、５及び６に記載されるＣＤＲ１、ＣＤＲ２及びＣＤＲ３軽鎖配列と、ヒト胎児性Ｆｃ受容体（ＦｃＲｎ）に結合するバリアントヒトＦｃ領域とを含み、前記バリアントヒトＦｃ ＣＨ３領域は、それぞれＥＵ番号付けで、ネイティブヒトＩｇＧ Ｆｃ領域のメチオニン４２８及びアスパラギン４３４に対応する残基においてＭｅｔ－４２９－Ｌｅｕ及びＡｓｎ－４３５－Ｓｅｒ置換を含む抗Ｃ５抗体、又はその抗原結合断片；並びに
（ｂ）項目１～３２のいずれか一項に記載の方法において前記抗Ｃ５抗体、又はその抗原結合断片を使用するための指示書
を含むキット。
（項目３９）
前記ｐ－ａＨＵＳは、産後ａＨＵＳである、項目３５又は３６に記載のキット。
In another embodiment, a kit for treating p-aHUS (e.g., postpartum aHUS) in a human patient, comprising: (a) a dose of ravulizumab; and (b) the use of ravulizumab in a method described herein. A kit is provided that includes instructions for doing so.
The present invention provides, for example, the following items.
(Item 1)
A method of treating a human patient with pregnancy-associated atypical hemolytic uremic syndrome (p-aHUS), the method comprising: administering to said patient an effective amount of an anti-C5 antibody, or antigen-binding fragment thereof;
The anti-C5 antibody or antigen-binding fragment thereof has CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 4, 5, and 6, respectively. CDR3 light chain sequence.
(Item 2)
The antibody comprises a variant human Fc region that binds the human fetal Fc receptor (FcRn), and the variant human Fc CH3 region corresponds to methionine 428 and asparagine 434 of the native human IgG Fc region, respectively in EU numbering. 2. The method of item 1, comprising Met-429-Leu and Asn-435-Ser substitutions at the residues.
(Item 3)
3. The method according to item 1 or 2, wherein the anti-C5 antibody or antigen-binding fragment thereof comprises a heavy chain variable region set forth in SEQ ID NO: 12 and a light chain variable region set forth in SEQ ID NO: 8.
(Item 4)
The method according to any one of items 1 to 3, wherein the anti-C5 antibody or antigen-binding fragment thereof further comprises a heavy chain constant region shown in SEQ ID NO: 13.
(Item 5)
5. The method according to any one of items 1 to 4, wherein the anti-C5 antibody or antigen-binding fragment thereof comprises a heavy chain set forth in SEQ ID NO: 14 and a light chain set forth in SEQ ID NO: 11.
(Item 6)
The anti-C5 antibody or antigen-binding fragment thereof binds to human C5 at pH 7.4 and 25°C with an affinity dissociation constant (KD) in the range of 0.1 nM≦KD≦1 nM, The method described in any one of the above.
(Item 7)
The method according to any one of items 1 to 5, wherein the anti-C5 antibody, or antigen-binding fragment thereof, binds to human C5 at pH 6.0 and 25° C. with a KD≧10 nM.
(Item 8)
8. The method of any one of items 1-7, wherein the anti-C5 antibody, or antigen-binding fragment thereof, is formulated for intravenous administration.
(Item 9)
The anti-C5 antibody or antigen-binding fragment thereof is administered to the patient.
(a) Once on day 1, 2400 mg for patients weighing ≧40 to <60 kg, 2700 mg for patients weighing ≧60 to <100 kg, or 3000 mg for patients weighing ≧100 kg. In dose;
(b) 3000 mg for patients weighing ≧40 to <60 kg, 3300 mg for patients weighing ≧60 to <100 kg, or 3300 mg for patients weighing ≧100 kg on day 15 and every 8 weeks thereafter; at a dose of 3600mg
The method according to any one of items 1 to 8, wherein the method according to any one of items 1 to 8 is administered.
(Item 10)
A method of treating a human patient with paHUS, the method comprising administering to said patient an effective amount of an anti-C5 antibody, or antigen-binding fragment thereof,
The anti-C5 antibody or antigen-binding fragment thereof has CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 4, 5, and 6, respectively. CDR3 light chain sequence and a variant human Fc region that binds the human fetal Fc receptor (FcRn), wherein the variant human Fc CH3 region is methionine 428 and asparagine of the native human IgG Fc region, each with EU numbering. containing a Met-429-Leu and Asn-435-Ser substitution at the residue corresponding to 434;
The anti-C5 antibody or antigen-binding fragment thereof is administered to the patient.
(a) Once on day 1, 2400 mg for patients weighing ≧40 to <60 kg, 2700 mg for patients weighing ≧60 to <100 kg, or 3000 mg for patients weighing ≧100 kg. In dose;
(b) 3000 mg for patients weighing ≧40 to <60 kg, 3300 mg for patients weighing ≧60 to <100 kg, or 3300 mg for patients weighing ≧100 kg on day 15 and every 8 weeks thereafter; at a dose of 3600mg
How to administer.
(Item 11)
The anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≧40 to <60 kg.
(a) at a dose of 2400 mg once on day 1;
(b) at a dose of 3000 mg on day 15 and every 8 weeks thereafter.
The method according to any one of items 1 to 10, wherein the method according to any one of items 1 to 10 is administered.
(Item 12)
The anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≧60 to <100 kg.
(a) at a dose of 2700 mg once on day 1;
(b) at a dose of 3300 mg on day 15 and every 8 weeks thereafter.
The method according to any one of items 1 to 11, wherein the method according to any one of items 1 to 11 is administered.
(Item 13)
The anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≧100 kg.
(a) at a dose of 3000 mg once on day 1;
(b) at a dose of 3600 mg on day 15 and every 8 weeks thereafter.
The method according to any one of items 1 to 11, wherein the method according to any one of items 1 to 11 is administered.
(Item 14)
14. The method of any one of items 1-13, wherein the treatment maintains a serum trough concentration of the anti-C5 antibody of 100 μg/ml or greater during the treatment.
(Item 15)
15. The method of any one of items 1-14, wherein the treatment maintains a serum trough concentration of the anti-C5 antibody of 200 μg/ml or greater during the treatment.
(Item 16)
16. The method of any one of items 1-15, wherein the treatment reduces free C5 concentration by more than 99% over the treatment period.
(Item 17)
17. The method of any one of items 1-16, wherein said anti-C5 antibody, or antigen-binding fragment thereof, is administered at a dose of 3000 mg, 3300 mg, or 3600 mg every 8 weeks after said treatment for up to 2 years.
(Item 18)
18. The method of any one of items 1-17, wherein the treatment results in terminal complement inhibition.
(Item 19)
19. The method of any one of items 1-18, wherein the treatment results in a reduction in hemolysis compared to baseline, as assessed by lactate dehydrogenase (LDH) levels.
(Item 20)
20. The method of any one of items 1-19, wherein the treatment results in normalization of LDH levels.
(Item 21)
Items 1 to 1, wherein the treatment produces a shift towards normal levels of a hemolysis-related hematological biomarker selected from the group consisting of free hemoglobin, haptoglobin, reticulocyte count, PNH red blood cell (RBC) clone, and D-dimer. 21. The method according to any one of 20.
(Item 22)
The treatment reduces or abolishes severe hypertension, proteinuria, uremia, lethargy, fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and renal dysfunction compared to baseline. 22. The method according to any one of items 1 to 21, which produces at least one therapeutic effect selected from the group consisting of:
(Item 23)
The treatment produces a shift towards normal levels of factor Ba, soluble tumor necrosis factor receptor 1 [sTNFR1]), soluble vascular adhesion molecule 1 [sVCAM1], thrombomodulin, D-dimer, and cystatin C, items 1- 23. The method according to any one of 22.
(Item 24)
24. The method of any one of items 1-23, wherein the treatment results in increased hemoglobin stabilization compared to baseline.
(Item 25)
25. The method of any one of items 1-24, wherein the treatment results in a reduction in the need for blood transfusion compared to baseline.
(Item 26)
26. The method of any one of items 1-25, wherein the treatment results in a reduction in major vascular adverse events (MAVE).
(Item 27)
The treatment improved quality of life from baseline as assessed via the Functional Assessment of Chronic Disease Treatment (FACIT)-Fatigue Scale, Version 4 and the European Agency for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Scale. 27. The method of any one of items 1-26, wherein the method causes a change.
(Item 28)
28. The method of any one of items 1-27, wherein the treatment results in platelet normalization.
(Item 29)
29. The method of any one of items 1-28, wherein the treatment results in a ≧25% improvement in serum creatinine from baseline.
(Item 30)
30. The method of any one of items 1-29, resulting in a complete TMA response.
(Item 31)
31. The method of any one of items 1-30, wherein the treatment results in a modified complete TMA response.
(Item 32)
32. The method of any one of items 1-31, wherein the treatment results in a shift towards normal levels of eGFR (eg, ≧90).
(Item 33)
33. The method of any one of items 1-32, wherein the treatment results in a reduction or discontinuation of dialysis.
(Item 34)
34. The method of any one of items 1-33, wherein the treatment prevents or prolongs end-stage renal disease (ESRD).
(Item 35)
35. The method of any one of items 1-34, wherein the treatment prolongs survival of the patient.
(Item 36)
36. The method according to any one of items 1 to 35, wherein the p-aHUS is postpartum aHUS.
(Item 37)
A kit for treating pregnancy-associated atypical hemolytic uremic syndrome (p-aHUS) in a human patient, the kit comprising:
(a) a dose of an anti-C5 antibody, or antigen-binding fragment thereof, having CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and as set forth in SEQ ID NOs: 4, 5 and 6, respectively; an anti-C5 antibody, or an antigen-binding fragment thereof, comprising the CDR1, CDR2 and CDR3 light chain sequences of
(b) instructions for using said anti-C5 antibody, or antigen-binding fragment thereof, in the method according to any one of items 1 to 32;
kit including.
(Item 38)
A kit for treating pregnancy-associated atypical hemolytic uremic syndrome (p-aHUS) in a human patient, the kit comprising:
(a) a dose of an anti-C5 antibody, or antigen-binding fragment thereof, having CDR1, CDR2 and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18 and 3, respectively, and SEQ ID NOs: 4, 5 and 6, respectively; The variant human Fc CH3 region contains the described CDR1, CDR2 and CDR3 light chain sequences and a variant human Fc region that binds the human fetal Fc receptor (FcRn), each with EU numbering an anti-C5 antibody, or an antigen-binding fragment thereof, comprising Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434 in the Fc region; and
(b) instructions for using said anti-C5 antibody, or antigen-binding fragment thereof, in the method according to any one of items 1 to 32;
kit including.
(Item 39)
The kit according to item 35 or 36, wherein the p-aHUS is postpartum aHUS.
Claims (15)
前記抗Ｃ５抗体、又はその抗原結合断片は、それぞれ配列番号１９、１８及び３に記載されるＣＤＲ１、ＣＤＲ２及びＣＤＲ３重鎖配列と、それぞれ配列番号４、５及び６に記載されるＣＤＲ１、ＣＤＲ２及びＣＤＲ３軽鎖配列とを含む、組成物。 A composition for use in a method of treating a human patient with pregnancy-associated atypical hemolytic uremic syndrome (p-aHUS), the composition comprising an anti -C5 antibody, or an antigen-binding fragment thereof;
The anti-C5 antibody or antigen-binding fragment thereof has CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 4, 5, and 6, respectively. CDR3 light chain sequence .
（ａ）１日目に１回、≧４０～＜６０ｋｇの体重の患者に対して２４００ｍｇ、≧６０～＜１００ｋｇの体重の患者に対して２７００ｍｇ、又は≧１００ｋｇの体重の患者に対して３０００ｍｇの用量で；(a) Once on day 1, 2400 mg for patients weighing ≧40 to <60 kg, 2700 mg for patients weighing ≧60 to <100 kg, or 3000 mg for patients weighing ≧100 kg. In dose;
（ｂ）１５日目及びその後８週間毎に、≧４０～＜６０ｋｇの体重の患者に対して３０００ｍｇ、≧６０～＜１００ｋｇの体重の患者に対して３３００ｍｇ、又は≧１００ｋｇの体重の患者に対して３６００ｍｇの用量で(b) 3000 mg for patients weighing ≧40 to <60 kg, 3300 mg for patients weighing ≧60 to <100 kg, or 3300 mg for patients weighing ≧100 kg on day 15 and every 8 weeks thereafter; at a dose of 3600mg
投与される、請求項１に記載の組成物。The composition of claim 1, wherein the composition is administered to a patient.
（ｉ）前記治療の間、１００μｇ／ｍｌ以上の前記抗Ｃ５抗体の血清トラフ濃度を維持する；(i) maintaining a serum trough concentration of said anti-C5 antibody of 100 μg/ml or greater during said treatment;
（ｉｉ）前記治療の間、２００μｇ／ｍｌ以上の前記抗Ｃ５抗体の血清トラフ濃度を維持する；且つ／又は(ii) maintaining a serum trough concentration of said anti-C5 antibody of 200 μg/ml or greater during said treatment; and/or
（ｉｉｉ）遊離Ｃ５濃度を前記治療期間全体にわたり９９％超だけ低減させる、(iii) reducing free C5 concentration by more than 99% over the treatment period;
請求項１又は２に記載の組成物。The composition according to claim 1 or 2.
（ｉ）終末補体阻害をもたらす；(i) results in terminal complement inhibition;
（ｉｉ）乳酸デヒドロゲナーゼ（ＬＤＨ）レベルにより評価して、ベースラインと比較して溶血の低減をもたらす；(ii) resulting in a reduction in hemolysis compared to baseline, as assessed by lactate dehydrogenase (LDH) levels;
（ｉｉｉ）ＬＤＨレベルの正常化をもたらす；且つ／又は(iii) results in normalization of LDH levels; and/or
（ｉｖ）遊離ヘモグロビン、ハプトグロビン、網状赤血球数、ＰＮＨ赤血球（ＲＢＣ）クローン及びＤ－ダイマーからなる群から選択される溶血関連血液学的バイオマーカーの正常レベルに向かうシフトを生じさせる、(iv) producing a shift towards normal levels of a hemolysis-related hematological biomarker selected from the group consisting of free hemoglobin, haptoglobin, reticulocyte count, PNH red blood cell (RBC) clones and D-dimer;
請求項１～４のいずれか一項に記載の組成物。Composition according to any one of claims 1 to 4.
（ｉ）ベースラインと比較して、重症高血圧症、タンパク尿症、尿毒症、嗜眠、疲労、易怒性、血小板減少症、微小血管症性溶血性貧血、及び腎機能障害の低減又は休止からなる群から選択される少なくとも１つの治療効果を生じさせる；(i) from reduction or cessation of severe hypertension, proteinuria, uremia, lethargy, fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and renal dysfunction compared to baseline; producing at least one therapeutic effect selected from the group consisting of;
（ｉｉ）Ｂａ因子、可溶性腫瘍壊死因子受容体１［ｓＴＮＦＲ１］、可溶性血管接着分子１［ｓＶＣＡＭ１］、トロンボモジュリン、Ｄ－ダイマー、及びシスタチンＣの正常レベルに向かうシフトを生じさせる；(ii) producing a shift towards normal levels of Ba factor, soluble tumor necrosis factor receptor 1 [sTNFR1], soluble vascular adhesion molecule 1 [sVCAM1], thrombomodulin, D-dimer, and cystatin C;
（ｉｉｉ）ベースラインと比較してヘモグロビン安定化の増加を生じさせる；(iii) producing an increase in hemoglobin stabilization compared to baseline;
（ｉｖ）ベースラインと比較して輸血の必要性の低減を生じさせる；(iv) resulting in a reduction in the need for blood transfusion compared to baseline;
（ｖ）主要血管有害事象（ＭＡＶＥ）の低減を生じさせる；(v) producing a reduction in major vascular adverse events (MAVE);
（ｖｉ）慢性疾患治療の機能的評価（ＦＡＣＩＴ）－疲労スケール、バージョン４及び欧州癌研究治療機関の生活の質アンケート－コア３０スケールを介して評価される、ベースラインからの生活の質の変化を生じさせる；(vi) Change in quality of life from baseline assessed via the Functional Assessment of Chronic Disease Treatment (FACIT)-Fatigue Scale, Version 4 and the European Agency for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 scales. cause;
（ｖｉｉ）血小板正常化をもたらす；(vii) bringing about platelet normalization;
（ｖｉｉｉ）ベースラインからの血清クレアチニンの≧２５％の改善をもたらす；(viii) resulting in a ≧25% improvement in serum creatinine from baseline;
（ｉｘ）完全ＴＭＡ奏効をもたらす；(ix) producing a complete TMA response;
（ｘ）修正された完全ＴＭＡ奏効をもたらす；且つ／又は(x) results in a modified complete TMA response; and/or
（ｘｉ）ｅＧＦＲの正常レベル（例えば、≧９０）に向かうシフトをもたらす、(xi) effecting a shift towards normal levels of eGFR (e.g. ≧90);
請求項１～５のいずれか一項に記載の組成物。Composition according to any one of claims 1 to 5.
（ｉ）透析の低減又は中止をもたらす；(i) resulting in a reduction or discontinuation of dialysis;
（ｉｉ）末期腎疾患（ＥＳＲＤ）を予防し、又はそれまでの時間を延長させる；且つ／又は(ii) prevent or prolong end-stage renal disease (ESRD); and/or
（ｉｉｉ）前記患者の生存期間を延長させる、(iii) prolonging the survival of said patient;
請求項１～６のいずれか一項に記載の組成物。Composition according to any one of claims 1 to 6.
（ｉｉ）前記抗Ｃ５抗体、又はその抗原結合断片は、ｐＨ６．０及び２５℃で、ＫＤ≧１０ｎＭでヒトＣ５に結合する；又は
（ｉｉｉ）前記抗体の［（ｐＨ６．０及び２５℃におけるヒトＣ５に対する抗体又はその抗原結合断片のＫＤ）／（ｐＨ７．４及び２５℃におけるヒトＣ５に対する抗体又はその抗原結合断片のＫＤ）］は、２５超である、
請求項１、及び８～１１のいずれか一項に記載の組成物。 (i) the anti-C5 antibody, or antigen-binding fragment thereof, binds to human C5 at pH 7.4 and 25°C with an affinity dissociation constant (KD) in the range of 0.1 nM≦KD≦1 nM ;
(ii) the anti-C5 antibody, or antigen-binding fragment thereof, binds to human C5 at pH 6.0 and 25°C with a KD≧10 nM; or
(iii) [(KD of antibody against human C5 or antigen-binding fragment thereof at pH 6.0 and 25°C)/(KD of antibody against human C5 or antigen-binding fragment thereof at pH 7.4 and 25°C)] of the antibody is , more than 25 ,
The composition according to claim 1 and any one of 8 to 11 .
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
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| US201962952971P | 2019-12-23 | 2019-12-23 | |
| US62/952,971 | 2019-12-23 | ||
| US202063007489P | 2020-04-09 | 2020-04-09 | |
| US63/007,489 | 2020-04-09 | ||
| US202062704879P | 2020-06-01 | 2020-06-01 | |
| US62/704,879 | 2020-06-01 | ||
| PCT/US2020/065924 WO2021133660A1 (en) | 2019-12-23 | 2020-12-18 | Methods of treating pregnancy-associated atypical hemolytic uremic syndrome using an anti-c5 antibody |
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| US (1) | US20230043576A1 (en) |
| EP (1) | EP4081805A1 (en) |
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| US6074642A (en) | 1994-05-02 | 2000-06-13 | Alexion Pharmaceuticals, Inc. | Use of antibodies specific to human complement component C5 for the treatment of glomerulonephritis |
| US8367805B2 (en) | 2004-11-12 | 2013-02-05 | Xencor, Inc. | Fc variants with altered binding to FcRn |
| JP5815403B2 (en) | 2008-08-05 | 2015-11-17 | ノバルティス アーゲー | Compositions and methods relating to antibodies targeting complement protein C5 |
| WO2014099546A1 (en) | 2012-12-19 | 2014-06-26 | Promerus, Llc | Process for the preparation of high purity norbornene alkanols and derivatives thereof |
| NZ711451A (en) | 2014-03-07 | 2016-05-27 | Alexion Pharma Inc | Anti-c5 antibodies having improved pharmacokinetics |
| KR102515796B1 (en) | 2014-12-19 | 2023-03-30 | 추가이 세이야쿠 가부시키가이샤 | Anti-c5 antibodies and methods of use |
| AU2017283470B2 (en) | 2016-06-14 | 2024-03-21 | Regeneron Pharmaceuticals, Inc. | Anti-C5 antibodies and uses thereof |
| KR20200070355A (en) * | 2017-10-26 | 2020-06-17 | 알렉시온 파마슈티칼스, 인코포레이티드 | Dosage and administration of anti-C5 antibodies for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (AHUS) |
| EP3802603A1 (en) * | 2018-06-04 | 2021-04-14 | Alexion Pharmaceuticals, Inc. | Dosage and administration of anti-c5 antibodies for treatment of atypical hemolytic uremic syndrome (ahus) in pediatric patients |
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