JP2010506925A - Cd27アゴニストを単独でまたは他の免疫調節剤と併用して用いる、ヒト免疫療法 - Google Patents
Cd27アゴニストを単独でまたは他の免疫調節剤と併用して用いる、ヒト免疫療法 Download PDFInfo
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Abstract
【選択図】図1
Description
[0072](以下の材料および方法を実施例1〜6で用いた。)
[0073]動物および細胞株。BALB/cおよびC57Bl/6マウスは、Harlan(英国、オクソン、ブラックソーン)によって供給され、そして現地の動物施設で維持された。BCL1(SlavinおよびStrober 1978)マウスBリンパ腫細胞株は、BALB/cマウスにおけるi.p.継代によって、in vivoで維持された。疾患の最終段階で脾臓を除去し、そして先に記載するように、単細胞懸濁物を調製した。P BCL1細胞は、BCL1由来の亜系統であり、そして培養中で増殖させた(Illidge, Honeychurchら 2000)。英国内務省認可指針にしたがった認可の下で動物実験を行い、そしてこれらは、サザンプトン大学倫理委員会によって認可された。
[0079]年齢一致BALB/cマウスに、5x107 BCL1細胞を第0日に投与し(i.v.)、そして次いで、脾臓における腫瘍細胞レベルが、総細胞のおよそ5%に到達したとき、典型的には腫瘍後4日目に、1mgの抗CD40 mAbまたはアイソタイプ一致対照を投与した(i.v.)。抗CD40 mAb処置の応答に対する、抗4−1BBLおよび抗CD70 mAbの影響を見る実験において、抗CD40注射の4時間前に0.5mgの遮断性mAbをi.p.注射し、そして次いで、抗CD40 mAb後、1日目および3日目にも注射した。示した日に動物を屠殺し、脾臓を除去し、そして懸濁物を調製した。PE抗CD19およびFITC抗BCL1 Idを用いて、BCL1腫瘍細胞を検出した。APC抗CD8aおよびPE抗4−1BBおよび抗CD27を用いて、CD8+リンパ球の数および表現型の変化を追跡した。FACSCalibur(BD Biosciences)を用いて、フローサイトメトリー分析を行った。
[0095]図6に示す本実験において、マウスに、2x107 BCL1細胞をiv注射し、そして次いで、後に、対照IgG、抗CD40 mAb、抗CD27または抗4−1BB mAb(1mg)でiv処置した。マウスを毎日2回監視し、そして図中の結果は、2つの類似の実験のうちの1つを示す。特に、4x106CD8+ OT−Iリンパ球の養子免疫伝達1日後(第0日)、レシピエントB6マウスを30mmol OVAペプチド(SINFEKL、OVA 257−264)でiv免疫した。動物にはまた、組換え可溶性CD70または抗マウスCD27(その調製を次の実施例に示す)または対照mAbを4回、iv注射した(第90、1、2および3日;注射あたり250マイクログラム)。OVA特異的CD8+ T細胞をin vivoで追跡するため、血液試料をPE H−2KB OVA 257−264四量体およびAPC抗CD8アルファで染色した。OVA特異的CD8+ T細胞の拡大は、応答のピーク時、第4日で示される。
[0097]マウスCD27−huFc分泌CHO細胞を調製し、そしてそこからの上清をプロテインA上でプロセシングして、融合タンパク質を精製した。標準法にしたがって、CFA、IFCA、次いでPBS中の50マイクログラム/用量の融合タンパク質でLouラットを免疫した。最初に融合タンパク質に対して、そして次いで細胞に対して、ハイブリドーマをスクリーニングした。細胞はConA活性化脾臓細胞、すなわち活性化T細胞であった。
[00101]BCL1リンパ腫の抗CD40処置中の脾臓CD8 T細胞およびDCの表現型変化
[00102]
[00103]
[00104]抗CD40への療法的応答に対する、4−1BBL/4−1BBおよびCD70/CD27相互作用遮断の影響
[00105]本発明者らは、腫瘍所持マウスのCD40 mAb処置後に見られる療法的応答への、4−1BBおよびCD27分子の重要性を調べた。4−1BBLおよびCD70に特異的な遮断性mAbを用いて、4−1BBL/4−1BBおよびCD70/CD27相互作用破壊の影響を調べた。AT113−2(抗4−1BBL)およびTAN1−6(抗CD70)が、それぞれ、4−1BBL/4−1BBおよびCD70/CD27相互作用を破壊可能であることは、これらが、活性化T細胞へのs4−1BBL−FcおよびsCD70−Fcの結合を遮断することを示すことによって、確認された(図1aおよびb)。さらに、両mAbは、BIACore分析によって決定されたものと類似のアフィニティーで、ターゲット抗原に結合した。AT113−2(抗4−1BBL)およびTAN1−6(抗CD70)のKD値は、それぞれ、3.8x10−9および3.0x10−9であった。抗CD70および抗4−1BBL mAbがin vivoで応答を遮断可能であることを確認するため、本発明者らは、C57BL/6マウスにおいて、OVAに対する内因性CD8応答に対するその影響を調べた(図1c)。先に示されるように(Taraban, Rowleyら 2004)、CD40が仲介する、内因性OVA特異的CD8 T細胞の拡大は、抗CD70 mAbによって、ほぼ完全に阻害された。比較すると、抗4−1BBL mAbは、抗CD40が誘導するOVA特異的T細胞レベルの50%の減少を生じた。
[00112]上記結果は、腫瘍接種およびCD40 mAb処置後に見られる驚くべきCTL応答が、4−1BBを介する誘発に部分的に依存し、そしてCD27およびCD70間の相互作用に完全に依存することを示唆する。したがって、CD40を介したアゴニスト活性をショートカットし、そしてこれらの共受容体を直接刺激することが可能であるかを調べるため、本発明者らは次に、BCL1リンパ腫に対する、アゴニスト性抗4−1BBまたは抗CD27の療法的有効性を調べる。図6に示すように、抗CD70 mAbは、BCL1腫瘍を完全に防御し、そして抗CD40 mAbで得た結果と非常に類似の結果を生じた。対照的に、抗4−1BB mAbは、この腫瘍に関して穏やかな療法活性を有し、生存をほとんど延長しなかった。
Claims (104)
- アゴニスト性抗ヒトCD27抗体またはその抗原結合性断片。
- ヒトCD27の細胞外部分を認識する、請求項1のアゴニスト性抗体。
- 前記抗体の結合が、ヒトCD70またはCD70関連リガンドによって認識可能に影響を受けない、請求項1のアゴニスト性抗ヒトCD27抗体。
- 前記抗体がCD70と競合する、請求項1のアゴニスト性抗体。
- 場合によってエフェクター部分に付着していてもよい、ヒト抗体、キメラ抗体、ヒト化抗体、二重特異性抗体、霊長類化(primatized)抗体および一本鎖抗体より選択される、アゴニスト性抗体。
- IgG1、IgG2、IgG3、IgG4、IgM、IgA1、IgA2、IgD、およびIgE定常ドメインより選択される、少なくとも1つのヒト定常ドメインを含有する、請求項1のアゴニスト性抗体。
- 抗体が、抗体エフェクター系への結合を修飾する(増進するかまたは減少させる)よう操作されている、請求項1のアゴニスト性抗体。
- 抗体が、Fcグリコシル化、FcRへの結合、FcRnへの結合、および補体系タンパク質との相互作用の少なくとも1つを改変するよう修飾されている、請求項1のアゴニスト性抗体。
- ヒトにおけるT細胞免疫応答を促進する、請求項1のアゴニスト性抗体。
- Th1免疫を促進する、請求項9のアゴニスト性抗体。
- 免疫を促進する必要がある被験体において、免疫を促進する方法であって、少なくとも1つのCD27アゴニスト性抗体または非抗体CD27アゴニストを、増進された免疫が療法的に望ましい状態または治療を伴う被験体に、免疫を促進するのに有効な量で投与する工程を含む、前記方法。
- Th1免疫を増進する、請求項11の方法。
- 前記CD27アゴニストが、抗原特異的T細胞の増殖または生存を促進する、請求項11の方法。
- 前記T細胞がCD8+ T細胞である、請求項13の方法。
- 前記T細胞が未処置(naive)Cd8 T細胞、CD8+エフェクター細胞、またはメモリー細胞、あるいはin vitroで拡大されて、そして次いでヒトに移植されたT細胞(遺伝子操作細胞を含む)である、請求項13の方法。
- 抗原特異的メモリーT細胞の生成を生じる、請求項13の方法。
- CD27アゴニストが、少なくとも1つの抗原に付随して投与される、請求項11の方法。
- CD27アゴニストが、ヒトCD27に特異的に結合する抗体または抗体断片である、請求項11の方法。
- CD27アゴニストが、抗原依存性方式で、T細胞の拡大を駆動可能な抗体または抗体断片である、請求項11の方法。
- 前記抗体が、ヒト抗体、霊長類抗体、キメラ抗体、ヒト化抗体、霊長類化抗体および一本鎖抗体より選択される、請求項19の方法。
- 前記抗体が、抗体エフェクター系への結合を修飾する(増進するかまたは減少させる)よう操作されている、請求項19における方法。
- 前記抗体が(i)Fcグリコシル化を欠くかまたは修飾されたFcグリコシル化を伴う抗体、(ii)突然変異Fcアミノ酸を含む抗体、(iii)選択されたFcRへの増進されたまたは減少した結合を所持する抗体、あるいは前記修飾の組み合わせを含む抗体を含む、請求項21の方法。
- 前記抗体が、FcRn(Brambell受容体)への結合に干渉することによって、抗体半減期を増進するかまたは減少させる修飾を含有する、請求項22の方法。
- 前記抗体が、(i)補体系のタンパク質との相互作用を減少させるかまたは増進する修飾、あるいは(ii)望ましくない毒性の減少より選択される修飾を含む、請求項22の方法。
- 望ましくない毒性がサイトカインの望ましくない放出を含む、請求項24の方法。
- 抗体が、ヒトIgG1、IgG2、IgG3、IgG4、IgM、IgA1、IgA2、IgDおよびIgE定常ドメインの少なくとも1つを含有する、請求項10の方法。
- 抗体が:真核細胞においてグリコシル化されている、損なわれていない(intact)IgG1抗体、損なわれていないIgG2抗体、損なわれていないIgG3抗体、損なわれていないIgG4抗体、損なわれていないIgM抗体、損なわれていないIgA1抗体、損なわれていないIgA2抗体、損なわれていない分泌性IgA抗体、損なわれていないIgD抗体、損なわれていないIgE抗体からなる群より選択される、損なわれていない抗体である、請求項19の方法。
- 癌、感染性疾患、炎症状態、自己免疫疾患、およびアレルギー状態より選択される状態を治療するのに用いられる、請求項11の方法。
- 感染性疾患が、細菌、ウイルス、マイコバクテリウム、真菌、酵母または寄生虫によって引き起こされる、請求項28の方法。
- 寄生虫が、バベシア属(Babesia)種、エントアメーバ属(Entomoeba)種、ジアルジア属(Giarda)種、プラスモジウム属(Plasmodium)種、リーシュマニア属(Leishmania)種、トリパノソーマ属(Trypanosome)種、トキソプラズマ属(Toxoplasma)種、扁平動物および回虫寄生虫より選択される、請求項29の方法。
- 細菌が、エシェリキア属(Escherichia)、スタフィロコッカス属(Staphylococcus)、シュードモナス属(Pseudomonas)、ストレプトコッカス属(Streptococcus)、カンピロバクター属(Campylobacter)、リステリア属(Listeria)、クロストリジウム属(Clostridium)、パスツレラ属(Pasteurella)、シュードモナス属(Pseudomonas)、ナイセリア属(Neisseria)、エンテロコッカス属(Enterococcus)、クレブシエラ属(Klebsiella)、ヘリコバクター属(Heliobacter)、リステリア属(Listeria)、サルモネラ属(Salmonella)、コリネバクテリウム属(Corynebacterium)、ヘモフィルス属(Haemophilus)、パスツレラ属(Pasteurella)、バクテロイデス属(Bacteroides)、フソバクテリウム属(Fusobacterium)、ストレプトバチルス属(Streptobacillus)、トレポネーマ属(Treponema)、レプトスピラ属(Leptospira)、リケッチア属(Rickettsia)、およびアクチノミセス属(Actinomyces)より選択される、請求項29の方法。
- ウイルスが、レトロウイルス、ピコルナウイルス、エンテロウイルス、肝炎ウイルス、ポリオウイルス、コクサッキーウイルス、ライノウイルス、エコーウイルス、カリシウイルス科(Calciviridae)、トガウイルス科(Togaviridae)、フラビウイルス科(Flaviviridae)、ラブドウイルス科(Rhabdoviridae)、コロナウイルス科(Coronaviridae)、パラミクソウイルス科(Paramyxoviridae)、オルトミクソウイルス科(Orthomyxoviridae)、フィロウイルス科(Filoviridae)、ブンガウイルス科(Bungaviridae)、レオウイルス科(Reoviridae)、アデノウイルス科(Adenoviridae)、ビマウイルス科(Bimaviridae)、パポバウイルス科(Papovaviridae)、ヘルペスウイルス科(Herpeviridae)、イリドウイルス科(Iridoviridae)、および未分類ウイルスより選択される、請求項29の方法。
- 真菌が、アスペルギルス属(Aspergillus)、コクシジオイデス属(Coccidoides)、ブラストミセス属(Blastomyces)、ヒストプラズマ属(Histoplasma)、クラミジア属(Chlamydia)、ノカルジア属(Nocardia)、およびニューモシスチス属(Pneumocytis)より選択される、請求項29の方法。
- 癌が、リンパ腫、白血病、慢性リンパ球性白血病、乳癌、前立腺癌、結腸癌、骨癌、膵臓癌、胃癌、肝癌、子宮頸癌、膀胱癌、精巣癌、腎臓癌、肺癌(小細胞および大細胞)、脳癌、網膜芽細胞種、食道癌、目の癌、頭部および頸部の癌、子宮内膜癌、喉頭癌、黒色腫、神経芽腫、神経芽腫、甲状腺癌、横紋筋肉腫、口腔癌、子宮癌、卵巣癌、肉腫、結合組織癌および皮膚癌より選択される、請求項28の方法。
- 自己免疫疾患が、多発性硬化症、糖尿病、乾癬、クローン病、炎症性腸疾患、SLE、重症筋無力症、グッドパスチャー症候群、ITP、グレーブス病、溶血性貧血、関節リウマチ、橋本甲状腺炎、強皮症、およびアジソン病より選択される、請求項28の方法。
- 前記CD27アゴニストが、被験体において投与され、該アゴニストが、ワクチンによって誘発される免疫応答を増進するために、ワクチンとともに投与される、請求項11の方法。
- 前記ワクチンが抗腫瘍ワクチンである、請求項36の方法。
- 前記ワクチンが、感染性病原体に対して免疫を与える、請求項36の方法。
- 感染性病原体が、細菌、ウイルス、酵母、真菌、マイコバクテリウム、または寄生虫より選択される、請求項38の方法。
- CD27アゴニストが、少なくとも1つの抗原またはアレルゲンと組み合わせて投与される、請求項11の方法。
- CD27アゴニストが、ワクチン組成物の前に、後に、または該組成物と組み合わせて投与される、請求項36の方法。
- CD27アゴニストが、併用組成物として、ワクチンと併用される、請求項41の方法。
- ワクチンが、肝炎ウイルス、HIV、ピコルナウイルス、ポリオウイルス、エンテロウイルス、ヒト・コクサッキーウイルス、インフルエンザウイルス、ライノウイルス、エコーウイルス、風疹ウイルス、脳炎ウイルス、狂犬病ウイルス、ヘルペスウイルス、パピローマウイルス、ポリオーマウイルス、RSV、アデノウイルス、黄熱病ウイルス、デングウイルス、パラインフルエンザウイルス、出血熱ウイルス、ポックスウイルス、水痘帯状疱疹ウイルス、パラインフルエンザウイルス、レオウイルス、オルビウイルス、ロタウイルス、パルボウイルス、アフリカブタ熱ウイルス、麻疹ウイルス、ムンプスウイルス、およびノーウォークウイルスより選択されるウイルスに対する免疫を与えるウイルスワクチンである、請求項36の方法。
- ワクチンが、パスツレラ属、エシェリキア属、スタフィロコッカス属、ストレプトコッカス属、サルモネラ属、ヘリコバクター属、マイコバクテリウム属、カンピロバクター属、エンテロコッカス属、クロストリジウム属、コリネバクテリウム属、トレポネーマ属、バクテロイデス属、フソバクテリウム属、フソバクテリウム属、ナイセリア属、バチルス属(Bacillus)、エンテロバクター属(Enterobacter)、ストレプトバチルス属、レプトスピラ属、ヘモフィルス属、ボレリア属(Borrelia)、レジオネラ属(Legionella)、エリシペロスリクス属(Erysipelothrix)、およびリステリア属より選択される細菌に対する免疫を与える細菌ワクチンである、請求項36の方法。
- ワクチンが、バベシア属、エントアメーバ属、ジアルジア属、リーシュマニア属、プラスモジウム属、トキソプラズマ属、トリパノソーマ属、回虫および扁平動物より選択される寄生虫に特異的である、請求項36の方法。
- CD27アゴニスト性抗体が、CD8 T細胞増殖増進、生存および/または細胞毒性リンパ球溶解性(CTL)応答を誘発する必要がある被験体において、これらを誘発する、請求項11の方法。
- 前記CD27アゴニストが、別の療法部分と併用投与される、請求項11〜36のいずれか一項記載の方法。
- 前記の他の部分が、別の免疫アゴニスト、抗体、サイトカイン、化学療法剤、放射療法剤、免疫調節剤および免疫刺激剤からなる群より選択される、請求項47の方法。
- 第二の免疫アゴニストおよび所望のターゲットに特異的な抗原と一緒の、CD27アゴニストの投与を含む、請求項48の方法。
- ターゲットが腫瘍である、請求項49の方法。
- 抗原が、腫瘍関連ペプチド(TAA)、腫瘍溶解物、アポトーシス性腫瘍細胞、および腫瘍抗原所持樹状細胞からなる群より選択される、請求項50の方法。
- 腫瘍ターゲットが黒色腫であり、そして併用が、ターゲット抗原を発現する腫瘍細胞に対して誘発される免疫応答を増進する(ブーストする)、請求項51の方法。
- 他の部分が、免疫刺激性抗体またはタンパク質(正の共刺激剤)、負の共刺激剤として作用する免疫抗体またはタンパク質、T細胞への阻害性シグナルを遮断する抗体または他の部分、および腫瘍細胞または血管系または間質に結合する抗体からなる群より選択される、請求項47の方法。
- 他の部分が、抗CD40抗体、抗OX40抗体、抗4−1BB抗体、抗CD70抗体、抗B7.1抗体、抗B7.2抗体、抗CTLA−4抗体、抗CD28抗体、制御性T細胞を枯渇させるかまたは遮断する部分、およびサイトカインからなる群より選択される、請求項47の方法。
- 他の部分が、アゴニスト性CD40抗体またはアゴニスト性OX40抗体またはアゴニスト性4−1BB(CD137)抗体である、請求項54の方法。
- アゴニスト性CD40抗体がLOB7/4である、請求項55の方法。
- T細胞応答増進を付加的にまたは相乗的に誘発するための方法であって:
付加的にまたは相乗的に有効な量の(i)少なくとも1つのCD27アゴニスト、ならびに(ii)CD40アゴニスト、4−1BB(CD137)抗体、OX−40抗体、CD28抗体、およびCTLA−4抗体より選択される少なくとも1つのアゴニスト
を、その必要がある被験体に投与する工程を含む、前記方法。 - 免疫応答がTh1免疫応答である、請求項57の方法。
- CD40アゴニストが、CD40アゴニスト性抗体または可溶性CD40L融合タンパク質または可溶性CD40断片あるいはそのコンジュゲートである、請求項57の方法。
- CD40アゴニストが、ヒトCD40に特異的に結合する、キメラ、ヒトまたはヒト化抗体である、請求項59の方法。
- 前記抗体が、SC26、CP−870,893、LOB7/4またはその誘導体、あるいは同じエピトープ特異性を所持する抗体である、請求項59の方法。
- CD27アゴニストが、抗CD27アゴニスト性抗体または可溶性CD70融合タンパク質あるいはその可溶性断片または可溶性コンジュゲートである、請求項11の方法。
- 腫瘍抗原、細菌抗原、ウイルス抗原、寄生虫抗原、アレルゲン、および自己抗原より選択される抗原の投与をさらに含む、請求項62の方法。
- アゴニスト性CD27抗体が、損なわれていなくてもまたは修飾されていてもよい、キメラ、ヒトまたはヒト化抗体である、請求項51の方法。
- CD27アゴニストまたは他のアゴニストが、エフェクター部分に付着している、請求項58の方法。
- エフェクター部分が毒素、薬剤または放射性核種である、請求項65の方法。
- CD27アゴニストおよびCD40アゴニストが一緒にまたは別個に投与される、請求項58の方法。
- CD40およびCD27アゴニストが、同じ組成物中に含有される、請求項67の方法。
- どちらかまたは両方のアゴニストがアゴニスト性抗体である、請求項68の方法。
- CD40アゴニストが可溶性CD40Lである、請求項67の方法。
- CD40アゴニストおよびCD27アゴニストが、互いに別個に投与され、そして投与がどちらの順でも達成可能である、請求項67の方法。
- 前記アゴニストが、互いに1日以内に投与される、請求項67の方法。
- 前記アゴニストが、互いに8時間以内に投与される、請求項71の方法。
- 前記アゴニストが、互いに1〜4時間以内に投与される、請求項71の方法。
- CD27アゴニストが最初に投与される、請求項67の方法。
- CD40アゴニストが最初に投与される、請求項67の方法。
- いずれかまたは両方のアゴニストがアゴニスト性抗体である、請求項67の方法。
- 4−1BBアゴニストの投与をさらに含む、請求項67の方法。
- 前記アゴニストが抗体である、請求項78の方法。
- 前記抗体が、抗原特異的CD8+ T細胞免疫をさらに増強する、請求項79の方法。
- ヒト癌を治療するために用いられる、請求項67の方法。
- CD40を発現している癌を治療するために用いられる、請求項67の方法。
- 前記癌が固形腫瘍を含む、請求項81の方法。
- 前記癌が:乳癌、肝癌、卵巣癌、結腸直腸癌、肺癌、胃癌、腎臓癌、黒色腫、卵巣癌およびリンパ腫からなる群より選択される、請求項81の方法。
- 前記リンパ腫が非ホジキンリンパ腫である、請求項73の方法。
- CD40アゴニストが、キメラ、ヒトまたはヒト化抗ヒトCD40抗体である、請求項70の方法。
- 投与される抗体が、LOB7/4またはそのヒト化変異体を含む、請求項86の方法。
- 治療される癌が非ホジキンリンパ腫である、請求項81の方法。
- 治療される癌が腎臓癌である、請求項81の方法。
- 前記療法が、少なくとも1つの化学療法剤をさらに含む、請求項70の方法。
- 前記CD27アンタゴニストが、少なくとも1つのサイトカインと併用して投与される、請求項11の方法。
- 前記サイトカインが、インターフェロン、インターロイキン、腫瘍壊死因子またはコロニー刺激因子である、請求項91の方法。
- 前記アゴニストが、ヒト免疫グロブリン重鎖および軽鎖定常領域を含むアゴニスト性抗体を含む、請求項11の方法。
- 前記免疫グロブリンが、IgG1、IgG2、IgG3、IgG4、IgM、IgEおよびIgAからなる群より選択される、請求項93の方法。
- 自己免疫疾患、炎症状態、またはアレルギー状態を伴う被験体を治療するために用いられる、請求項52の方法。
- 自己免疫疾患を治療するために用いられる、請求項80の方法。
- 炎症状態を治療するために用いられる、請求項67の方法。
- アレルギー状態を治療するために用いられる、請求項67の方法。
- 感染状態を治療するために用いられる、請求項67の方法。
- ヒトにおいて、in vivoで、CTL免疫応答およびCD8+ T細胞増殖を増進する際に使用するために適応した、付加的または相乗的アゴニスト併用であって、相乗的に有効な量の(i)少なくとも1つのCD27アゴニスト、および(ii)少なくとも1つの抗CD40、OX−40、4−1BBまたはCTLA−4アゴニスト性抗体を含む、前記併用。
- CD40アゴニストが、アゴニスト性CD40抗体または可溶性CD40L、断片、あるいは含有融合タンパク質である、請求項100の相乗的アゴニスト併用。
- アゴニスト性抗体が、キメラ、ヒト、ヒト化、または別の方式で遺伝子操作された抗体である、請求項100の相乗的アゴニスト併用。
- CD27アゴニストがアゴニスト性CD27抗体である、請求項100の相乗的アゴニスト併用。
- CD27抗体が、キメラ、ヒト、ヒト化、または別の方式で遺伝子操作された抗体である、請求項103の相乗的アゴニスト併用。
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JP2013532978A (ja) * | 2010-07-09 | 2013-08-22 | バイオノビオン・ホールディング・ベスローテン・フエンノートシャップ | Cd27に対するアゴニスト抗体 |
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US20130336976A1 (en) | 2013-12-19 |
JP2014221795A (ja) | 2014-11-27 |
WO2008051424A2 (en) | 2008-05-02 |
US20180273631A1 (en) | 2018-09-27 |
US20110033449A1 (en) | 2011-02-10 |
US9926374B2 (en) | 2018-03-27 |
EP2083858A2 (en) | 2009-08-05 |
WO2008051424A8 (en) | 2009-05-22 |
WO2008051424A3 (en) | 2008-08-21 |
CA2667020C (en) | 2021-09-07 |
EP2083858A4 (en) | 2010-12-08 |
EP2698382A1 (en) | 2014-02-19 |
US20160215056A1 (en) | 2016-07-28 |
CA2667020A1 (en) | 2008-05-02 |
US20200247898A1 (en) | 2020-08-06 |
EP2083858B1 (en) | 2013-12-11 |
JP5867983B2 (ja) | 2016-02-24 |
US9248183B2 (en) | 2016-02-02 |
DK2083858T3 (da) | 2014-02-03 |
JP6117150B2 (ja) | 2017-04-19 |
GB0620894D0 (en) | 2006-11-29 |
ES2440721T3 (es) | 2014-01-30 |
US8481029B2 (en) | 2013-07-09 |
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