JP5898286B2 - 免疫グロブリンおよびヒアルロニダーゼを皮下投与するための組み合わせおよび方法 - Google Patents
免疫グロブリンおよびヒアルロニダーゼを皮下投与するための組み合わせおよび方法 Download PDFInfo
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- JP5898286B2 JP5898286B2 JP2014192938A JP2014192938A JP5898286B2 JP 5898286 B2 JP5898286 B2 JP 5898286B2 JP 2014192938 A JP2014192938 A JP 2014192938A JP 2014192938 A JP2014192938 A JP 2014192938A JP 5898286 B2 JP5898286 B2 JP 5898286B2
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- 229940053819 winrho Drugs 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
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Description
米国仮出願No.61/069,841(Richard Schiff、Heinz Leibl、およびGregory Frost;発明の名称「免疫グロブリンおよびヒアルロニダーゼを皮下投与するための組み合わせおよび方法」(2008年3月17日出願))の優先権の利益を主張する。許容されるならば、上記出願の内容は本明細書の一部を構成する。
(技術分野)
本発明は、免疫グロブリンを皮下投与し、IGで処置可能な疾患または病状を治療するための方法、組成物、組み合わせ、およびキットを提供する。IGで処置可能な疾患または病状を治療するために対象に水溶性ヒアルロニダーゼおよび免疫グロブリン(IG)を皮下投与することにより対象のIGで処置可能な疾患または病状を治療する方法を提供する。IGおよびヒアルロニダーゼの同時投与は、皮下投与されたIGのバイオアベイラビリティを増大し、特定の疾患または病状のための静脈内IG(IVIG)投与と実質的に同じ投与計画を用いたIGの皮下投与を可能にする。IGの投与は、投与量と投与頻度が同じ疾患または病状のためにIVを介して同量をIV(静脈内)投与するためのものと実質的に同じであるように行われる。IVを介した投与量は、特定疾患または病状のために予め決定することができるか、または知られている。典型的には、可溶性ヒアルロニダーゼ存在下の皮下投与用の投与速度はIV投与より速くすることができる。したがって、特定用量の投与回数を減らすことができる。投与速度は、例えばポンプによって調節するか、重力によることができる。
(詳細な説明)
概 要
B. 免疫グロブリン(IG)の皮下投与
C. 免疫グロブリン
D. ヒアルロニダーゼ
可溶性ヒアルロニダーゼ
可溶性ヒトPH20
可溶性組み換えヒトPH20(rHuPH20)
E. 可溶性ヒアルロニダーゼをコードする核酸およびそのポリペプチドの製造方法
1. ベクターおよび細胞
2. 発現
a. 原核細胞
b. 酵母細胞
c. 昆虫細胞
d. 哺乳動物細胞
e. 植物
3. 精製技術
F. 免疫グロブリンおよび可溶性ヒアルロニダーゼポリペプチドの製造、製剤、および投与
1. 製剤
凍結乾燥粉末
2. 用量および投与
G. 活性、バイオアベイラビリティ、および薬物動態の評価方法
1. 薬物動態および許容性(忍容性)
2. 生物活性
a. 免疫グロブリン
b. ヒアルロニダーゼ
H. 治療的使用
1. 抗体欠損症を伴う原発性免疫不全
2. 血液悪性腫瘍に続発する後天性低ガンマグロブリン血症
3. 川崎病
4. 慢性炎症性脱髄性多発神経障害
5. ギランバレー症候群
6. 特発性血小板減少性紫斑病
7. 炎症性筋疾患:多発性筋炎、皮膚筋炎、および封入体筋炎
8. ランバート・イートン筋無力症候群
9. 多巣性運動ニューロパシー
10. 重症筋無力症
11. メルシュ・ヴォルトマン症候群
12. アルツハイマー病
13. 他の疾患および病状
I. 製品およびキット
J. 実施例
A. 定義
表1−対応表
B. 免疫グロブリン(IG)の皮下投与
C. 免疫グロブリン
D. ヒアルロニダーゼ
可溶性ヒアルロニダーゼ
可溶性ヒトPH20
組換え可溶性ヒトPH20(rHuPH20)
E. 可溶性ヒアルロニダーゼをコードする核酸およびそのポリペプチドの製造方法
1. ベクターおよび細胞
2. 発現
a. 原核細胞
b. 酵母細胞
c. 昆虫細胞
d. 哺乳動物細胞
e. 植物
3. 精製技術
F. 免疫グロブリンおよび可溶性ヒアルロニダーゼポリペプチドの製造、製剤化、および投与
1. 製剤
凍結乾燥粉末
2. 用量および投与
G. 活性、バイオアベイラビリティ、および薬物動態の評価方法
1. 薬物動態および許容性
2. 生物活性
a. 免疫グロブリン
b. ヒアルロニダーゼ
H. 治療的使用
1. 抗体欠損症を伴う原発性免疫不全
2. 血液悪性腫瘍に続発する後天性低ガンマグロブリン血症
3. 川崎病
4. 慢性炎症性脱髄性多発神経障害
5. ギランバレー症候群
ギランバレー症候群は、末梢神経の炎症性脱髄を伴う神経学的自己免疫障害である。第1症状には、程度の異なる脚の虚弱および刺痛感が含まれ、これが腕や上体に広がり得る。この症状は、筋肉が全く使えなくなり、患者がほぼ全身麻痺となり、生命を脅かす上体になるまで激しさが増しうる。
6. 特発性血小板減少性紫斑病
7. 炎症性筋疾患:多発性筋炎、皮膚筋炎、および封入体筋炎
8. ランバート・イートン筋無力症候群
9. 多巣性運動ニューロパシー
10. 重症筋無力症
重症筋無力症は、すべての民族群および両性に生じる。該疾患は、最も一般的には40歳以下の若い成人女性と60歳以上の高齢男性が罹患するが、あらゆる年齢で生じうる。ある場合には、症状を減少させるために胸腺摘出が行われる。
11.メルシュ・ヴォルトマン症候群
12. アルツハイマー病
13. 他の疾患および病状
I. 製品およびキット
以下の実施例は例示のためだけに記載するものであり、本発明の範囲を限定するものではない。
免疫グロブリン(IG)の皮下(SQ)投与は、静脈内(IV)投与に比べてバイオアベイラビリティの低下をもたらす。ある研究報告によれば、IV投与に比べて63%のバイオアベイラビリティであり、等価なバイオアベイラビリティ、すなわち時間濃度曲線下面積(AUC)を達成するにはIVの137%のSQ用量が必要であった(Ochs et al.(2006)J Clin. Immunol.、26:265-273)。すなわち、可溶性組み換えヒトPH20(rHuPH20)存在下のIG(GAMMAGARD LIQUID(GGL)、Baxter Biosciences)の皮下投与が、SQ投与によるIGのバイオアベイラビリティを増加させ、用量の増加を不要にするか否かを決定するための実験を行った。実験は以下の評価を行うために計画した:
1)皮下(SQ)経路による単一部位へのGGLの1月1回投与を許容する対象の能力;2)GGLの1月1回と投与を許容する(薬剤の軽度のわずかな局所副作用)のに必要なrHuPH20/g GGLの用量;3)SC投与に必要な時間、および3)GGL IV対SQの曲線下面積(AUG)により測定したバイオアベイラビリティの比較。
HZ24プラスミド(配列番号52に記載)を用いてチャイニーズハムスター卵巣(CHO細胞)をトランスフェクトした(例えば、出願No. 10,795,095、11/065,716、および11/238,171参照)。可溶性rHuPH20を発現するためのHZ24プラスミドベクターは、pCIベクター骨格(Promega)、ヒアルロニダーゼのアミノ酸1〜482をコードするDNA(配列番号49)、ECMVウイルス(Clontech)由来の内部リボソーム侵入部位(IRES)、およびマウスジヒドロ葉酸還元酵素(DHFR)遺伝子を含む。pCIベクター骨格は、ベータラクタマーゼ耐性遺伝子(AmpR)をコードするDNA、f1複製起点、サイトメガロウイルス即初期エンハンサー/プロモーター領域(CMV)、キメライントロン、およびSV40後期ポリアデニル化シグナル(SV40)も含む。可溶性rHuPH20構築物をコードするDNAは、ヒトPH20の天然35アミノ酸シグナル配列の1位アミノ酸のメチオニンをコードするDNAの前にNheI部位とKozakコンセンサス配列と、配列番号1に示すヒトPH20ヒアルロニダーゼのアミノ酸482位に対応するチロシンをコードするDNAの後に終止コドン、次いでBamHI制限部位を含む。したがって、構築物pCI-PH20-IRES-DHFR-SV40pa(HZ24)は、内部リボソーム侵入部位(IRES)により分離したヒトPH20のアミノ酸1〜482(配列番号3に示す)およびマウスジヒドロ葉酸還元酵素のアミノ酸1〜186(配列番号53に示す)をコードするCMVプロモーターにより誘導される単一mRNA種を生じる。
細胞培養、精製分画、および精製溶液のような試料中の可溶性rHuPH20のヒアルロニダーゼ活性を、ヒアルロン酸が血清アルブミンと結合したときの不溶性沈殿物の形成に基づき比濁分析を用いて測定した。可溶性rHuPH20をヒアルロン酸ナトリウム(ヒアルロン酸)と一定期間(10分間)インキュベーションし、次いで酸性化血清アルブミンを加えて未消化のヒアルロン酸ナトリウムを沈殿させることに活性を測定する。得られた試料の濁度を30分間の発色期後640nmで測定した。ヒアルロン酸ナトリウム基質に対する酵素活性から得られた濁度の低下は、可溶性rHuPH20ヒアルロニダーゼ活性の測定値である。該方法は、可溶性rHuPH20アッセイの操作参照標準の希釈物を用いて得られる較正曲線を用いて行い、試料の活性測定はこの較正曲線に対してなされる。
A. 5Lバイオリアクタープロセス
3D35Mのバイアルを解凍し、100nMメトトレキセートおよびGlutaMAX(登録商標)-1(Invitrogen)を添加したCD-CHO培地(Invitrogen、Carlsbad Calif.)中、1Lスピナーフラスコを経て振盪フラスコから拡大培養した。細胞をスピナーフラスコから5Lバイオリアクター(Braun)に4×105生細胞/mLの接種密度で移した。パラメーターは温度の設定値37℃、pH7.2(出発設定値)であり、希釈酸素設定値25%、および空気の重層は0〜100cc/minであった。168時間で、250mlのフィード#1培地(50g/Lグルコース添加CD CHO)を加えた。216時間で、250mlのフィード#2培地(50g/Lグルコースおよび10mM酪酸ナトリウム含有CD CHO)を加え、264時間で、250mlのフィード#2培地を加えた。このプロセスは、最大細胞密度6×106細胞/mlで1600単位/mLの最終生産性をもたらした。酪酸ナトリウムの添加は最終生成段階における可溶性rHuPH20の産生を顕著に増強した。
B. 100Lバイオリアクター細胞培養中の上流細胞培養の拡大培養(エクスパンジョン)プロセス
実施例2に記載のGen1 3D35M細胞系はより高レベルのメトトレキセートに適合し、2世代(Gen2)クローンを生成した。3D35M細胞を樹立メトトレキセート含有培地から4mM GlutaMAX-1(登録商標)および1.0μMメトトレキセートを含むCD CHO培地に接種した。細胞を、37℃の7%CO2加湿インキュベーター中46日間にわたり9回増殖および継代して高レベルのメトトレキセートに適合させた。増幅した細胞ポピュレーションを、2.0μMメトトレキセート含有培地を含む96ウェル組織培養プレート中で限界希釈してクローニングした。約4週間後、クローンを同定し、クローン3E10Bを拡大培養用に選んだ。3E10B細胞を4mM GlutaMAX-1(登録商標)および2.0μMメトトレキセート含有CD CHO培地中で増殖させ、20回継代した。3E10B細胞系のマスター細胞バンク(MCB)を作製し、凍結し、その後の研究に用いた。
HZ24-2B2のバイアルを解凍し、20μMメトトレキセートおよびGlutaMAX-1(登録商標)(Invitrogen)添加CD-CHO培地(Invitrogen、Carlsbad、CA)中、振盪フラスコから36Lスピナーフラスコに拡大培養した。簡単には、細胞のバイアルを37℃の水浴中で解凍し、培地を加えて細胞を遠心した。細胞を20mLの新鮮培地を入れた125mL振盪フラスコに再浮遊させ、37℃、7% CO2インキュベーター中に置いた。細胞を、125mL振盪フラスコ中で40mLまで拡大培養した。細胞密度が1.5×106 細胞/mL以上に達したら、培養を100mL培養容量の125mLスピナーフラスコ中で拡大培養した。フラスコを37℃、7% CO2でインキュベーションした。細胞密度が1.5×106 細胞/mL以上に達したら、培養を200mL培養容量の250mLスピナーフラスコ中で拡大培養した。フラスコを37℃、7% CO2でインキュベーションした。細胞密度が1.5×106 細胞/mL以上に達したら、培養を800mL培養容量の1Lスピナーフラスコ中で拡大培養し、37℃、7% CO2でインキュベーションした。細胞密度が1.5×106 細胞/mL以上に達したら、培養を5000mL培養容量の6Lスピナーフラスコ中で拡大培養し、37℃、7% CO2でインキュベーションした。細胞密度が1.5×106 細胞/mL以上に達したら、培養を32L培養容量の36Lスピナーフラスコ中で拡大培養し、37℃、7% CO2でインキュベーションした。
B. Gen2可溶性rHuPH20の精製
C. Gen1可溶性rHuPH20およびGen2可溶性rHuPH20の生成および精製の比較
Claims (29)
- 皮下単回投与するために製剤化された0.5g〜70gの免疫グロブリン(IG)を含む第1液体組成物であって、
第1液体組成物中のIGのタンパク質濃度は5〜15%w/vであり、
第1液体組成物の量は50ml〜700mlである、
第1液体組成物、
および、
IGと組み合わせて皮下単回投与するために製剤化された可溶性ヒアルロニダーゼを含む第2液体組成物であって、
第2液体組成物は第1液体組成物とは分離して製剤化されており、
第2液体組成物の量は5〜30mlであり、
第2液体組成物は、単位(U)ヒアルロニダーゼ/グラム(g)IG比で10〜500U/gである量の可溶性ヒアルロニダーゼを含み、
第2液体組成物は、第1液体組成物の投与の前に第1液体組成物と同じ部位に投与されるためのものであり、それにより、同じIGで処置可能な疾患または病状の治療のために静脈内投与で投与されるのと同じ単回投与量のIGのバイオアベイラビリティの少なくとも90%まで、IGのバイオアベイラビリティを増大させる、
第2液体組成物
を含む、対象におけるIGで処置可能な疾患または病状の治療のために皮下投与されるIGのバイオアベイラビリティを増大させるためのキット。 - 該第1および第2液体組成物が、二重チャンバー容器または互いに分離している単一容器に入っている請求項1記載のキット。
- 該容器がシリンジ、チューブ、または瓶である請求項2記載のキット。
- 該容器が、さらに注射用針を含む請求項3記載のキット。
- 該可溶性ヒアルロニダーゼがPH20またはそのトランケート型である請求項1〜4のいずれかに記載のキット。
- PH20がヒツジ、ウシ、またはトランケートヒトPH20から選ばれる請求項5記載のキット。
- 該トランケートヒトPH20が、配列番号4〜9のいずれかに記載のアミノ酸配列、または、配列番号4〜9のいずれかに記載のアミノ酸配列に少なくとも91%の配列同一性を示すアミノ酸配列を有するポリペプチドから選ばれる請求項6記載のキット。
- 該可溶性ヒアルロニダーゼがrHuPH20である請求項1〜7のいずれかに記載のキット。
- IGがヒト血漿から精製される請求項1〜8のいずれかに記載のキット。
- 第1液体組成物の量が、100ml、150ml、200ml、300ml、400ml、500ml、600ml、または700mlである、請求項1〜9のいずれかに記載のキット。
- 第1液体組成物中のIGのタンパク質濃度が6〜15%w/vまたは8〜12%w/vである請求項1〜10のいずれかに記載のキット。
- 該タンパク質濃度が10%w/vである請求項11記載のキット。
- 第1液体組成物が、20〜30g、あるいは5g、10g、15g、20g、21g、22g、23g、24g、25g、26g、27g、28g、29g、30g、31g、32g、33g、34g、35g、36g、37g、38g、39g、または40gのIGを含む、請求項1〜12のいずれかに記載のキット。
- 第2液体組成物の量が、5ml、6ml、7ml、8ml、9ml、10ml、20mlまたは30mlである、請求項1〜13のいずれかに記載のキット。
- 第2液体組成物が、1,000単位〜10,000単位または5000単位〜7500単位である量の可溶性ヒアルロニダーゼを含む、請求項1〜14のいずれかに記載のキット。
- 第2液体組成物が、単位ヒアルロニダーゼ/グラムIG比で10U/g、20U/g、30U/g、40U/g、50U/g、60U/g、70U/g、80U/g、90U/g、100U/g、150U/g、200U/g、300U/g、400U/gまたは500U/gである量の可溶性ヒアルロニダーゼを含む、請求項1〜15のいずれかに記載のキット。
- 第1液体組成物が27〜61gまたは25.5〜61.2gのIGを含み、第2液体組成物が単位ヒアルロニダーゼ/グラムIG比で50U/gである量の可溶性ヒアルロニダーゼを含む、請求項1〜16のいずれかに記載のキット。
- 第1液体組成物および第2液体組成物が、1日1回、1週間に1回、2週間に1回、2〜3週間に1回、3〜4週間に1回、または1月に1回投与するための量で製剤化される請求項1〜17のいずれかに記載のキット。
- 該IGで処置可能な疾患または病状が以下から選ばれる請求項1〜18のいずれかに記載のキット:免疫不全;血液悪性腫瘍に続発する後天性低ガンマグロブリン血症;川崎病;慢性炎症性脱髄性多発神経障害(CIDP);ギランバレー症候群;特発性血小板減少性紫斑病;炎症性筋疾患;ランバート・イートン(Lambert-Eaton)筋無力症候群;多巣性運動ニューロパシー;重症筋無力症;メルシュ・ヴォルトマン(Moersch-Woltmann)症候群;続発性低ガンマグロブリン血症(医原性免疫不全を含む);特異抗体欠損症;急性播種性脳脊髄炎;ANCA陽性全身性壊死性血管炎;自己免疫性溶血性貧血;水疱性類天疱瘡;瘢痕性類天疱瘡;エバンス(Evans)症候群(免疫性血小板減少症を伴う自己免疫性溶血性貧血を含む);胎児(Foeto)-妊婦/新生児同種免疫性血小板減少症(FMAIT/NAIT);血球貪食症候群;ハイリスク同種造血幹細胞移植;IgMパラプロテイン血症性ニューロパシー;腎臓移植;多発性硬化症;眼球クローヌス・ミオクローヌス運動失調;落葉状天疱瘡;尋常性天疱瘡;輸血後紫斑病;中毒性表皮剥離症/スティーブンス・ジョンソン症候群(TEN/SJS);毒素性ショック症候群;アルツハイマー病;全身性エリテマトーデス;多発性骨髄腫;敗血症;B細胞腫瘍;外傷;および細菌、ウイルス、または真菌感染症。
- 該IGで処置可能な疾患または病状が免疫不全であり、該免疫不全が以下から選ばれる請求項19に記載のキット:分類不能型免疫不全症(CVID)、先天性無ガンマグロブリン血症、ウィスコット・アルドリッチ症候群、重症複合免疫不全(SCID)、原発性低ガンマグロブリン血症、抗体欠損症を伴う原発性免疫不全疾患、X連鎖無ガンマグロブリン血症(XLA)、新生児低ガンマグロブリン血症、および抗体を伴わない傍腫瘍性小脳変性症。
- 該IGで処置可能な疾患または病状が、血液悪性腫瘍に続発する後天性低ガンマグロブリン血症であり、該血液悪性腫瘍が、慢性リンパ球性白血病(CLL)、多発性骨髄腫(MM)、および非ホジキンリンパ腫(NHL)から選ばれる請求項19に記載のキット。
- 該IGで処置可能な疾患または病状が炎症性筋疾患であり、該炎症性筋疾患が多発性筋炎、皮膚筋炎、および封入体筋炎から選ばれる請求項19に記載のキット。
- 該IGで処置可能な疾患または病状が、細菌、ウイルス、または真菌性病状であり、該細菌、ウイルス、または真菌が以下から選ばれる請求項19に記載のキット:ヘモフィルス・インフルエンザエ(Haemophilus influenzae)タイプB、シュードモナス・エルジノーサ(Pseudomonas aeruginosa)タイプAおよびB、黄色ブドウ球菌(Staphylococcus aureus)、B群連鎖球菌、肺炎連鎖球菌(Streptococcus pneumoniae)タイプ1、3、4、6、7、8、9、12、14、18、19、および23、アデノウイルスタイプ2および5、サイトメガロウイルス、エプスタイン・バー・ウイルスVCA、A型肝炎ウイルス、B型肝炎ウイルス、単純ヘルペスウイルス-1、単純ヘルペスウイルス-2、A型インフルエンザ、麻疹、パラインフルエンザ(Parainfluenza)タイプ1、2および3、ポリオ、水痘帯状疱疹ウイルス、アスペルギルス、およびカンジダ・アルビカンス(Candida albicans)。
- 対象のIGで処置可能な疾患または病状を治療するための医薬を製造するための、請求項1に記載の第1液体組成物および第2液体組成物の使用。
- 該IGで処置可能な疾患または病状が以下から選ばれる請求項24に記載の使用:免疫不全;血液悪性腫瘍に続発する後天性低ガンマグロブリン血症;川崎病;慢性炎症性脱髄性多発神経障害(CIDP);ギランバレー症候群;特発性血小板減少性紫斑病;炎症性筋疾患;ランバート・イートン(Lambert-Eaton)筋無力症候群;多巣性運動ニューロパシー;重症筋無力症;メルシュ・ヴォルトマン(Moersch-Woltmann)症候群;続発性低ガンマグロブリン血症(医原性免疫不全を含む);特異抗体欠損症;急性播種性脳脊髄炎;ANCA陽性全身性壊死性血管炎;自己免疫性溶血性貧血;水疱性類天疱瘡;瘢痕性類天疱瘡;エバンス(Evans)症候群(免疫性血小板減少症を伴う自己免疫性溶血性貧血を含む);胎児(Foeto)-妊婦/新生児同種免疫性血小板減少症(FMAIT/NAIT);血球貪食症候群;ハイリスク同種造血幹細胞移植;IgMパラプロテイン血症性ニューロパシー;腎臓移植;多発性硬化症;眼球クローヌス・ミオクローヌス運動失調;落葉状天疱瘡;尋常性天疱瘡;輸血後紫斑病;中毒性表皮剥離症/スティーブンス・ジョンソン症候群(TEN/SJS);毒素性ショック症候群;アルツハイマー病;全身性エリテマトーデス;多発性骨髄腫;敗血症;B細胞腫瘍;外傷;および細菌、ウイルス、または真菌感染症。
- 該IGで処置可能な疾患または病状が免疫不全であり、該免疫不全が以下から選ばれる請求項25に記載の使用:分類不能型免疫不全症(CVID)、先天性無ガンマグロブリン血症、ウィスコット・アルドリッチ症候群、重症複合免疫不全(SCID)、原発性低ガンマグロブリン血症、抗体欠損症を伴う原発性免疫不全疾患、X連鎖無ガンマグロブリン血症(XLA)、新生児低ガンマグロブリン血症、および抗体を伴わない傍腫瘍性小脳変性症。
- 該IGで処置可能な疾患または病状が、血液悪性腫瘍に続発する後天性低ガンマグロブリン血症であり、該血液悪性腫瘍が、慢性リンパ球性白血病(CLL)、多発性骨髄腫(MM)、および非ホジキンリンパ腫(NHL)から選ばれる請求項25に記載の使用。
- 該IGで処置可能な疾患または病状が炎症性筋疾患であり、該炎症性筋疾患が多発性筋炎、皮膚筋炎、および封入体筋炎から選ばれる請求項25記載の使用。
- 該IGで処置可能な疾患または病状が、細菌、ウイルス、または真菌性病状であり、該細菌、ウイルス、または真菌が以下から選ばれる請求項25に記載の使用:ヘモフィルス・インフルエンザエ(Haemophilus influenzae)タイプB、シュードモナス・エルジノーサ(Pseudomonas aeruginosa)タイプAおよびB、黄色ブドウ球菌(Staphylococcus aureus)、B群連鎖球菌、肺炎連鎖球菌(Streptococcus pneumoniae)タイプ1、3、4、6、7、8、9、12、14、18、19、および23、アデノウイルスタイプ2および5、サイトメガロウイルス、エプスタイン・バー・ウイルスVCA、A型肝炎ウイルス、B型肝炎ウイルス、単純ヘルペスウイルス-1、単純ヘルペスウイルス-2、A型インフルエンザ、麻疹、パラインフルエンザ(Parainfluenza)タイプ1、2および3、ポリオ、水痘帯状疱疹ウイルス、アスペルギルス、およびカンジダ・アルビカンス(Candida albicans)。
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