JP6097690B2 - 抗cxcl13抗体およびそれを用いる方法 - Google Patents
抗cxcl13抗体およびそれを用いる方法 Download PDFInfo
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- JP6097690B2 JP6097690B2 JP2013527309A JP2013527309A JP6097690B2 JP 6097690 B2 JP6097690 B2 JP 6097690B2 JP 2013527309 A JP2013527309 A JP 2013527309A JP 2013527309 A JP2013527309 A JP 2013527309A JP 6097690 B2 JP6097690 B2 JP 6097690B2
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Description
本出願とともにファイルし、ASCIIテキストファイルで電子的に提出した配列表(名称:「sequencelisting_ascii.txt」;サイズ:16,923バイト;および作成日時:2011年4月28日)の内容は、その全体が参照により本明細書に組み込まれる。
本発明は、CXCL13中和結合分子、例えば抗体およびその抗原結合断片、例えばヒト化モノクローナル抗体、該結合分子を用いる方法、ならびにCXCL13発現細胞に関連する状態および疾患を処置するための方法に関する。
用語「1つの(a)」または「1つの(an)」実体は、1または複数の実体のことをいうことに注意されたい。例えば、「抗CXCL13抗体」は、1または複数の抗CXCL13抗体を表すと理解される。したがって、用語「1つの(a)」(または「1つの(an)」)、「1または複数」および「少なくとも1つの」は、本明細書において交換可能に用いることができる。
本明細書で用いる場合、用語「CXCL13」および「CXCL13ポリペプチド」は、交換可能に用いられる。特定の実施形態では、CXCL13は、完全サイズCXCL13もしくはその断片、またはCXCL13バリアントポリペプチドを含んでよく、ここで、CXCL13の断片またはCXCL13バリアントポリペプチドは、完全サイズCXCL13のいくらかまたは全ての機能的特性を保持する。ヒトCXCL13ポリペプチドおよびポリヌクレオチド配列(それぞれ配列番号19および20)は記載されており、例えばLeglerら、J.Exp.Med.187(4):655〜660頁(1998)を参照されたい。マウスCXCL13ポリペプチドおよびポリヌクレオチド配列(それぞれ配列番号21および22)は記載されており、例えばGunnら、Nature391(6669):799〜803頁(1998)を参照されたい。さらに、カニクイザルCXCL13ポリペプチド配列は、配列番号23に示すように、記載されている。
CXCL13に結合する市販の抗体、例えばラット抗マウスMAb470(R&D Systems)およびマウス抗ヒトMAb801(R&D Systems)は、当技術分野において開示されている。さらに、マウス抗CXCL13抗体は、米国特許出願公開第2008 0227704A1号に開示されている。
本発明は、本発明の抗CXCL13抗体またはその抗原結合断片、バリアントもしくは誘導体をコードする核酸分子も提供する。
本明細書の他の場所でより詳細に論じるように、抗CXCL13結合分子、例えば本発明の抗体またはその抗原結合断片、バリアントもしくは誘導体は、さらに、N末端もしくはC末端にて異種ポリペプチドと組換えにより融合できるか、またはポリペプチドもしくはその他の組成物と化学的にコンジュゲート(共有的および非共有的コンジュゲーションを含む)できる。例えば、抗CXCL13抗体は、検出アッセイにおいて標識として有用な分子および異種ポリペプチド、薬物、放射性核種もしくは毒素のようなエフェクター分子と組換えにより融合またはコンジュゲートできる。例えば、国際公開第92/08495号;国際公開第91/14438号;国際公開第89/12624号;米国特許第5,314,995号;および欧州特許第396,387号を参照されたい。
抗体の軽鎖および重鎖をコードするDNA配列は、逆転写酵素およびDNAポリメラーゼを公知の方法に従って用いて、同時にまたは別々に作製できる。PCRは、コンセンサス定常領域プライマーによりまたは発表された重鎖および軽鎖のDNAおよびアミノ酸配列に基づくより特異的なプライマーにより開始できる。上で論じたように、PCRを用いて、抗体軽鎖および重鎖をコードするDNAクローンを単離できる。この場合、ライブラリーを、コンセンサスプライマーまたはマウス定常領域プローブのようなより大きい相同プローブによりスクリーニングできる。
リンパ系ケモカインCXCL13は、濾胞樹状細胞(FDC)およびマクロファージにより発現される。様々な免疫細胞(例えばB細胞、濾胞ヘルパーT細胞および活性化されたばかりのT細胞)上で見出されるその受容体であるCXCR5を介して、CXCL13は、免疫系恒常性の維持、リンパ器官形成、白血球のやり取りおよび化学走性移動ならびに2次リンパ組織(例えば胚中心)の発達に必要な細胞内変化を誘発する。CXCL13およびその受容体CXCR5の過剰発現は、様々な自己免疫疾患に関わっている(例えば多発性硬化症(例えばCorcioneら、PNAS101(30):11064〜11069頁(2004);Serafiniら、Brain Pathol.14:164〜174頁(2004);Magliozziら、Brain130:1089〜1104頁(2007)を参照されたい)、関節炎(例えば関節リウマチ(例えばRiojaら、Arthritis&Rheumatism58(8):2257〜2267頁(2008);Shiら、J.Immuno.166:650〜655頁(2001);Schmutzら、Arthritis Restearch and Therapy7:R217〜R229頁(2005);Hjelmstromら、J.Leukocyte Bio.69:331〜339頁(2001)を参照されたい)、慢性胃炎(例えばHjelmstromら;Mazzucchelliら、Brain130:1089〜1104頁(2007)を参照されたい)、胃リンパ腫(例えば同著;Nobutaniら、FEMS Immunol Med Microbiol60:156〜164頁(2010)を参照されたい)、移植片拒絶(例えばSteinmetzら、Kidney International67:1616〜1621頁(2005)を参照されたい)、シェーグレン症候群(SS)(例えばBaroneら、J.Immuno.180:5130〜5140頁(2008);Hjelmstromらを参照されたい)、全身性エリテマトーデス(SLE)(例えばSteinmetzら、Leeら、J.Rheum.37(1):45〜52頁(2010);Schifferら、J.Immun.171:489〜497頁(2003)を参照されたい)、C型肝炎ウイルス感染における活動性混合型クリオグロブリン血症(MC)血管炎(例えばSansonnoら、Blood112(5):1620〜1627頁(2008)を参照されたい)、若年性皮膚筋炎(例えばde Padillaら、Arthritis&Rheumatism60(4):1160〜1172頁(2009)を参照されたい)および重症筋無力症(例えばMatsumotoら、J.Immuno.176:5100〜5107頁(2006);Meraounaら、Blood108(2):432〜440頁(2006);Saitoら、J.Neuroimmunol170:172〜178頁(2005)を参照されたい)ならびにある種のがん(例えばバーキットリンパ腫(例えばForsterら、Blood84:830〜840頁(1994);Forsterら、Cell87:1037〜1047頁(1996)を参照されたい)、非ホジキンリンパ腫(例えばTrentinら、Ann.Rev.Immunol.6:251〜81頁(1988);Gongら、J.Immunol.174:817〜826頁(2005);Hamaguchiら、J.Immunol.174:4389〜4399頁(2005)を参照されたい)、癌(例えば結腸および膵臓)(例えばGuntherら、Int.J.Cancer116:726〜733頁(2005);Meijerら、Cancer Res.66:9576〜9582頁(2006)を参照されたい)、乳がん(例えばPanseら、British Journal of Cancer99:930〜938頁(2008)を参照されたい)、慢性リンパ性白血病(CLL)(例えばBurkleら、Blood110:3316〜3325頁(2007)を参照されたい)および前立腺がん(例えばSinghら、Cancer Letters283(1):29〜35頁(2009)を参照されたい)。CXCL13活性の阻害のための本発明の方法は、上記の障害に対して治療効果を有することが予期される。
必要とする対象に本発明の抗CXCL13結合分子、例えば抗体またはその抗原結合断片、バリアントもしくは誘導体を調製して投与する方法は、当業者に公知であるかまたは当業者により容易に決定する。抗CXCL13結合分子、例えば抗体またはその抗原結合断片、バリアントもしくは誘導体の投与経路は、例えば、経口、非経口、吸入によるかまたは局所的であってよい。用語「非経口」は、本明細書で用いる場合、例えば静脈内、動脈内、腹腔内、筋内、皮下、直腸または膣投与を含む。これらの全ての投与の形態は本発明の範囲内であると明確に考えられるが、投与の形態の例は、注射用、特に静脈内もしくは動脈内注射または点滴用の液剤である。通常、注射用の適切な医薬組成物は、緩衝剤(例えば酢酸塩、リン酸塩またはクエン酸塩緩衝剤)、界面活性剤(例えばポリソルベート)、場合によって安定化剤(例えばヒトアルブミン)などを含み得る。しかし、本明細書における教示に適合するその他の方法において、本発明の抗CXCL13結合分子、例えば抗体またはその抗原結合断片、バリアントもしくは誘導体は、有害な細胞集団の部位に直接送達することにより、疾患組織が治療剤により多く曝露されるようにできる。
本発明は、ある型のがんおよび自己免疫疾患を含む炎症性疾患のようなCXCL13発現細胞仲介疾患の診断中に有用な診断方法をさらに提供し、これは、個体からの組織またはその他の細胞または体液中のCXCL13タンパク質または転写産物の発現レベルを測定するステップと、測定された発現レベルを、正常組織または体液中の標準CXCL13発現レベルと比較することにより、標準と比較した発現レベルの増加が障害を示すステップとを含む。特定の実施形態では、本発明の抗CXCL13抗体またはその抗原結合断片、バリアントおよび誘導体、例えばMAb MAb5261、MAb5378、MAb5080、MAb1476、3D2または3C9は、がん、多発性硬化症、関節炎またはループスの診断において用いられる。
本発明の抗CXCL13抗体またはその抗原結合断片、バリアントもしくは誘導体は、免疫特異的結合について、当技術分野において知られる任意の方法によりアッセイしてよい。用いることができるイムノアッセイは、それらに限定されないが(ほんの数例を挙げれば)、ウェスタンブロット、ラジオイムノアッセイ、ELISA(酵素結合免疫吸着アッセイ)、「サンドイッチ」イムノアッセイ、免疫沈降アッセイ、沈降素反応、ゲル拡散沈降素反応、免疫拡散アッセイ、凝集アッセイ、補体結合アッセイ、免疫放射線アッセイ、蛍光イムノアッセイ、プロテインAイムノアッセイのような技術を用いる競合および非競合アッセイ系を含む。このようなアッセイは慣例的であり、当技術分野において公知である(例えばAusubelら編、(1994)Current Protocols in Molecular Biology(John Wiley&Sons,Inc.、NY)第1巻(これは、その全体が本明細書に参照により組み込まれる)を参照されたい)。
<ヒトCXCL13に特異的なマウス抗体の選択および特徴決定>
ハイブリドーマ作製。Swiss Websterマウスを、キーホールリンペットヘモシアニン(KLH)コンジュゲートヒトCXCL13で免疫化した。3回の免疫化の後に、最高の抗CXCL13力価を有するマウスから脾臓を採集し、脾臓細胞とSP2/0ミエローマ細胞とを標準的な手順を用いて融合することによりハイブリドーマを作製した。
<ヒトB細胞移動の抗CXCL13抗体阻害>
CXCL13機能、例えばB細胞移動の阻害を、ヒトおよびマウス両方の系におけるB細胞移動をシミュレートする確立されたモデルを用いて評価した。非CXCL13ケモカインであるSDF−1α(CXCL12としても知られる)に向かう移動を対照として用いて、B細胞移動の阻害に対する抗CXCL13抗体の特異性を確認した。つまり、抗CXCL13抗体を、ヒトCXCL13誘発性移動の阻害およびSDF−1α誘発性移動に対する影響がないことについて試験した。
<ヒトCXCR5のCXCL13仲介エンドサイトーシスの抗CXCL13抗体阻害>
CXCL13ケモカイン機能、例えばCXCR5受容体のCXCL13仲介エンドサイトーシスの抗CXCL13抗体を用いる阻害を、ヒトCXCR5受容体のヒトCXCL13仲介エンドサイトーシスについての確立されたモデルを用いて評価した(Burkeら、Blood110:2216〜3325頁(2007))。
<多発性硬化症についてのマウス疾患モデルにおける抗CXCL13抗体の評価>
多発性硬化症のマウスモデル。実験的自己免疫性脳脊髄炎(EAE)は、多発性硬化症の広く受け入れられている動物モデルである。EAEは、脊髄を主に標的にする炎症を伴う、程度が拡大する上行性麻痺を累進的にもたらすCNSの脱髄疾患である。この疾患は、誘発の方法および用いる動物の型に依存して、急性、慢性または再発−寛解経過を呈することができる。つまり、EAEは、CNSの成分、ペプチド(能動誘発)および一方の動物から別の動物への細胞移動(受動誘発)によっても誘発できる。完全フロイントアジュバント(CFA)を抽出物またはペプチドとともに用い、これは、百日咳毒素とともに頻繁に用いられる。
A.0日目に開始する対照(マウスIgG)
B.0日目に開始する3D2
C.スコア≧1にて開始する3D2
A.0日目に開始する対照(マウスIgG)
B.0日目に開始する3D2
C.7日目に開始する3D2
D.EAEの発症時に開始する3D2(スコア≧2)
<ループスについてのマウス疾患モデルにおける抗CXCL13抗体の評価>
全身性エリテマトーデス(SLE)のマウスモデル。SLEは、複数の器官に関わり、異所性胚中心の自発的形成およびいくつかの核抗原に対する自己抗体生成を特徴とする自己免疫疾患である。抗CXCL13 3D2抗体の影響を、ループスのマウスモデルにおいて試験した。ループス易発性New Zealand Black X New Zealand White F1(NZB/NZWF1)マウスは、高力価の抗dsDNA抗体および腎臓の糸球体における免疫複合体の形成を原因とする重症増殖性糸球体腎炎を自発的に発生する。
<キメラおよびヒト化抗CXCL13モノクローナル抗体の調製>
3D2ハイブリドーマV遺伝子の単離およびキメラ3D2抗体のクローニング。マウス3D2抗体を、キメラ抗CXCL13モノクローナル抗体の作製のための原型として用いた。可変(V)遺伝子を、標準的な方法を用いて3D2ハイブリドーマから単離した。3D2の重鎖(H1609)および軽鎖(L0293)のポリヌクレオチドおよびアミノ酸配列を、図13に示す。VHおよびVK相補性決定領域(CDR)に下線を付す(それぞれ配列番号4、5、6、9、10および11)。
<抗CXCL13 MAb5261の機能的特徴決定>
ヒトおよびマウスB細胞移動の阻害。ヒトCXCL13誘発性ヒトB細胞化学走性を阻害するMAb5261の能力を、安定株化細胞ヒトプレB−697−hCXCR5および初代ヒト扁桃腺細胞の両方について試験した。
<抗CXCL13 MAb5261のマウスバージョンの作製および特徴決定>
MAb5261は、ヒト重鎖および軽鎖可変領域とヒトIgガンマ1−Fアロタイプとヒトカッパとを含有する。マウスの対応物(「MAb5378」)を、マウスIgG2a(ガンマ2a鎖)を用いて工学的に作製した。IgG2aアイソタイプは、補体を固定し、Fc受容体に結合する能力を含めてヒトIgG1と密接な類似性を有する。MAb5378は、MAb5261と同じヒト重鎖および軽鎖可変遺伝子を、マウスIgG2a定常およびマウスカッパそれぞれとともに含有する。
<関節リウマチについてのマウス疾患モデルにおける抗CXCL13抗体の評価>
関節リウマチのマウスモデル。マウスおよびラットにおけるコラーゲン誘発関節炎(CIA)は、ヒト関節リウマチ(RA)の十分に確立されたモデルである。疾患は、完全フロイントアジュバント(CFA)中で乳化したウシII型コラーゲンの皮内注射により典型的に誘発され、マウスコラーゲン抗体の生成と、その後の足における関節炎の進行性の発展を特徴とする。
A.マウスIgGアイソタイプ(対照)
B.MAb5378
C.エタネルセプト(TNF阻害剤;陽性対照)
A.マウスIgGアイソタイプ対照
B.MAb5378
C.エタネルセプト(TNF阻害剤;陽性対照)
D.MAb470
<ヘリコバクター感染についてのマウスモデルにおける抗CXCL13抗体の評価>
ヘリコバクター感染のマウスモデル。H.heilmanniiおよびH.Pyloriのようなヘリコバクター種は、患者において胃MALTリンパ腫を誘発する。ヘリコバクター誘発性胃リンパ濾胞のマウスモデルは、Nobutaniら、FEMS Immunol Med Microbiol60:156〜164頁(2010)(これは、その全体が参照により本明細書に組み込まれる)に記載された。Nobutaniらのマウスモデルは、本明細書において、胃リンパ濾胞の低下における抗CXCL13抗体の影響を試験するために用いた。マウスのH.heilmannii感染についての処置スケジュールおよび本実施例で用いた抗体投与を図29に示す。
F:5’−TTGGGAGGCTTTGTCTTTCCA−3’(配列番号24)
R:5’−GATTAGCTCTGCCTCGCGGCT−3’(配列番号25)
Claims (22)
- a)配列番号4と同一である重鎖相補性決定領域1(VH−CDR1)アミノ酸配列、配列番号5と同一である重鎖相補性決定領域2(VH−CDR2)アミノ酸配列、および配列番号6と同一である重鎖相補性決定領域3(VH−CDR3)アミノ酸配列を含む重鎖可変領域(VH)を含み、かつ、
配列番号16または配列番号9と同一である軽鎖相補性決定領域1(VL−CDR1)アミノ酸配列、配列番号10と同一である軽鎖相補性決定領域2(VL−CDR2)アミノ酸配列、および配列番号11と同一である軽鎖相補性決定領域3(VL−CDR3)アミノ酸配列を含む軽鎖可変領域(VL)を含む抗体またはその抗原結合断片、
b)VHが、配列番号3または13のアミノ酸配列を含み、かつ、VLが、配列番号8、15または17のアミノ酸配列を含む抗体またはその抗原結合断片、ならびに、
c)基準モノクローナル抗体を競合的に阻害する、または、前記基準モノクローナル抗体と同じCXCL13エピトープに対して特異的に結合し、かつ、前記基準モノクローナル抗体と同じ抗原結合部位を含む抗体またはその抗原結合断片であって、ここで、前記基準モノクローナル抗体が、前記a)またはb)の抗体もしくはその抗原結合断片である、抗体またはその抗原結合断片
からなる群から選択される、ヒト、マウスおよびカニクイザルCXCL13に特異的に結合する単離抗体またはその抗原結合断片。 - 前記抗体またはその抗原結合断片のVHが、配列番号4、配列番号5および配列番号6とそれぞれ同一のVH−CDR1、VH−CDR2およびVH−CDR3アミノ酸配列を含み、かつ、前記抗体またはその抗原結合断片のVLが、配列番号9または配列番号16、配列番号10および配列番号11とそれぞれ同一のVL−CDR1、VL−CDR2およびVL−CDR3アミノ酸配列を含む、請求項1に記載の抗体またはその抗原結合断片。
- VHが、配列番号3または13のアミノ酸配列を含み、かつ、VLが、配列番号8、15または17のアミノ酸配列を含む抗体またはその抗原結合断片を含む、請求項1または2に記載の抗体またはその抗原結合断片。
- 前記VHおよび前記VLが、
(i)それぞれ配列番号13および配列番号15、
(ii)それぞれ配列番号13および配列番号17、ならびに、
(iii)それぞれ配列番号3および配列番号8
からなる群から選択されるVHおよびVL配列のアミノ酸配列を含む、請求項1〜3のいずれか一項に記載の抗体またはその抗原結合断片。 - 請求項1〜4のいずれか一項に記載の抗体またはその抗原結合断片と薬学的に許容される担体とを含む組成物。
- VHをコードする単離ポリヌクレオチドとVLをコードする単離ポリヌクレオチドとを含む組成物であって、
VHをコードする前記ポリヌクレオチドが、それぞれ配列番号4、配列番号5および配列番号6からなるVH−CDR1、VH−CDR2およびVH−CDR3アミノ酸配列を含むVHポリペプチドをコードし、かつ、
VLをコードする前記ポリヌクレオチドが、それぞれ配列番号9または配列番号16、配列番号10および配列番号11からなるVL−CDR1、VL−CDR2およびVL−CDR3アミノ酸配列を含むVLポリペプチドをコードし、
VHおよびVLをコードする前記ポリヌクレオチドによりコードされる抗体またはその抗原結合断片が、CXCL13に特異的に結合する、組成物。 - VHをコードする前記ポリヌクレオチドおよびVLをコードする前記ポリヌクレオチドが、単一のベクターに含有される、請求項6に記載の組成物。
- VHをコードする前記ポリヌクレオチドが、第1のベクターに含有され、VLをコードする前記ポリヌクレオチドが、前記第1のベクターと同一でない第2のベクターに含有される、請求項6に記載の組成物。
- 前記第1のベクターおよび前記第2のベクターが、単一の宿主細胞に含有される、請求項8に記載の組成物。
- 前記第1のベクターおよび前記第2のベクターが、別々の宿主細胞に含有される、請求項8に記載の組成物。
- 請求項7に記載の組成物、または、請求項9に記載の第1のベクターおよび第2のベクターを含む宿主細胞。
- CXCL13に特異的に結合する抗体またはその抗原結合断片を生成する方法であって、請求項11に記載の宿主細胞を培養するステップと、前記抗体またはその抗原結合断片を回収するステップとを含む方法。
- CXCL13に特異的に結合する抗体またはその抗原結合断片を生成する方法であって、請求項10に記載の組成物の第1のベクターおよび第2のベクターを含む個々の宿主細胞を同時培養するステップと、前記抗体またはその抗原結合断片を回収するステップとを含む方法。
- CXCL13に特異的に結合する抗体またはその抗原結合断片を生成する方法であって、請求項10に記載の組成物の第1のベクターおよび第2のベクターを含む個々の宿主細胞を別々に培養するステップと、前記VHおよびVLコードポリペプチドを組み合わせるステップと、前記抗体またはその抗原結合断片を回収するステップとを含む方法。
- 動物においてCXCL13を中和するための医薬組成物であって、前記医薬組成物が、請求項1〜4のいずれか一項に記載の単離抗体もしくはその抗原結合断片を含む医薬組成物。
- がん、自己免疫疾患または炎症性疾患を処置するための医薬組成物であって、前記医薬組成物が、請求項1〜4のいずれか一項に記載の単離抗体もしくはその抗原結合断片を含む医薬組成物。
- 前記自己免疫疾患または前記炎症性疾患が、多発性硬化症、全身性エリテマトーデス(SLE)または関節炎である、請求項16に記載の組成物。
- 前記がんが、前立腺または結腸がんである、請求項16に記載の組成物。
- 動物において胃リンパ濾胞を阻害するための医薬組成物であって、前記医薬組成物が、請求項1〜4のいずれか一項に記載の単離抗体もしくはその抗原結合断片を含む医薬組成物。
- 胃潰瘍もしくは十二指腸潰瘍、または粘膜関連リンパ組織(MALT)リンパ腫を防止または処置するための医薬組成物であって、前記医薬組成物が、請求項1〜4のいずれか一項に記載の単離抗体もしくはその抗原結合断片を含む医薬組成物。
- 前記動物が、ヘリコバクター細菌に感染している、請求項19または20に記載の医薬組成物。
- 前記動物がヒトである、請求項15〜21のいずれか一項に記載の医薬組成物。
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Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ618067A (en) | 2009-05-08 | 2015-07-31 | Vaccinex Inc | Anti-cd100 antibodies and methods for using the same |
DK2611832T3 (en) | 2010-09-02 | 2018-02-26 | Vaccinex Inc | ANTI-CXCL13 ANTIBODIES AND PROCEDURES FOR USE THEREOF |
JP2014505239A (ja) * | 2010-12-14 | 2014-02-27 | モアハウス スクール オブ メディスン | 癌の治療または検出のための抗cxcl13および抗cxcr5抗体の使用 |
CN110105452A (zh) | 2011-10-11 | 2019-08-09 | 瓦西尼斯公司 | 臂板蛋白-4d结合分子用于调节血脑屏障渗透性的用途 |
IN2014DN08199A (ja) * | 2012-03-02 | 2015-05-01 | Vaccinex Inc | |
US9708601B2 (en) | 2012-04-26 | 2017-07-18 | Vaccinex, Inc. | Fusion proteins to facilitate selection of cells infected with specific immunoglobulin gene recombinant vaccinia virus |
EP2866830A4 (en) * | 2012-06-27 | 2015-12-09 | Jyant Technologies | ANTI-CXCL9, ANTI-CXCL10, ANTI-CXCL11, ANTI-CXCL13, ANTI-CXCR3 AND ANTI-CXCR5 AGENTS FOR THE INHIBITION OF INFLAMMATION |
CN104884955B (zh) * | 2012-12-07 | 2017-06-27 | 巴克斯特国际公司 | 抗‑mif抗体的细胞迁移测定方法 |
WO2014121053A1 (en) * | 2013-01-31 | 2014-08-07 | Vaccinex, Inc. | Methods for increasing immunoglobulin a levels |
BR112015021964A2 (pt) * | 2013-03-08 | 2017-08-29 | Vaccinex Inc | Anticorpo isolado ou um fragmento ligante de antígenos do mesmo que se liga especificamente a cxcl13, composição e seus usos |
BR112015032690B1 (pt) | 2013-06-25 | 2020-03-10 | Vaccinex, Inc. | Uso de moléculas inibidoras de semaforina-4d em combinação com uma terapia imunomoduladora para inibir o crescimento tumoral e metástase |
KR20180042449A (ko) * | 2015-09-15 | 2018-04-25 | 보드 오브 리전츠, 더 유니버시티 오브 텍사스 시스템 | T 세포 수용체(tcr) 결합 항체 및 이의 용도 |
NZ746657A (en) | 2016-04-22 | 2024-07-05 | Vaccinex Inc | Integral membrane protein display on poxvirus extracellular enveloped virions |
WO2018026715A1 (en) | 2016-08-02 | 2018-02-08 | Vaccinex, Inc. | Improved methods for producing polynucleotide libraries in vaccinia virus/eukaryotic cells |
SG11202003930YA (en) | 2017-12-01 | 2020-05-28 | Pfizer | Anti-cxcr5 antibodies and compositions and uses thereof |
CA3113069A1 (en) * | 2018-09-17 | 2020-03-26 | Abcuro, Inc. | Anti-klrg1 antibodies |
SG11202010499UA (en) * | 2018-09-18 | 2020-11-27 | I Mab Biopharma Us Ltd | Anti-cxcl13 antibodies for treating autoimmune diseases and cancer |
CN116782930A (zh) | 2020-06-11 | 2023-09-19 | 瓦西尼斯公司 | Cxcl13结合分子促进周围神经再生的用途 |
Family Cites Families (76)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4474893A (en) | 1981-07-01 | 1984-10-02 | The University of Texas System Cancer Center | Recombinant monoclonal antibodies |
US4714681A (en) | 1981-07-01 | 1987-12-22 | The Board Of Reagents, The University Of Texas System Cancer Center | Quadroma cells and trioma cells and methods for the production of same |
NZ201918A (en) | 1981-09-18 | 1987-04-30 | Genentech Inc | N-terminal methionyl analogues of bovine growth hormone |
US4741900A (en) | 1982-11-16 | 1988-05-03 | Cytogen Corporation | Antibody-metal ion complexes |
US4683195A (en) | 1986-01-30 | 1987-07-28 | Cetus Corporation | Process for amplifying, detecting, and/or-cloning nucleic acid sequences |
WO1986005807A1 (en) | 1985-04-01 | 1986-10-09 | Celltech Limited | Transformed myeloma cell-line and a process for the expression of a gene coding for a eukaryotic polypeptide employing same |
GB8601597D0 (en) | 1986-01-23 | 1986-02-26 | Wilson R H | Nucleotide sequences |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
US4873192A (en) | 1987-02-17 | 1989-10-10 | The United States Of America As Represented By The Department Of Health And Human Services | Process for site specific mutagenesis without phenotypic selection |
US5892019A (en) | 1987-07-15 | 1999-04-06 | The United States Of America, As Represented By The Department Of Health And Human Services | Production of a single-gene-encoded immunoglobulin |
GB8717430D0 (en) | 1987-07-23 | 1987-08-26 | Celltech Ltd | Recombinant dna product |
DE68921982D1 (de) | 1988-06-14 | 1995-05-04 | Cetus Oncology Corp | Kupplungsmittel und sterisch gehinderte, mit disulfid gebundene konjugate daraus. |
US4925648A (en) | 1988-07-29 | 1990-05-15 | Immunomedics, Inc. | Detection and treatment of infectious and inflammatory lesions |
US5601819A (en) | 1988-08-11 | 1997-02-11 | The General Hospital Corporation | Bispecific antibodies for selective immune regulation and for selective immune cell binding |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5225538A (en) | 1989-02-23 | 1993-07-06 | Genentech, Inc. | Lymphocyte homing receptor/immunoglobulin fusion proteins |
US5116964A (en) | 1989-02-23 | 1992-05-26 | Genentech, Inc. | Hybrid immunoglobulins |
ZA902949B (en) | 1989-05-05 | 1992-02-26 | Res Dev Foundation | A novel antibody delivery system for biological response modifiers |
WO1991000360A1 (en) | 1989-06-29 | 1991-01-10 | Medarex, Inc. | Bispecific reagents for aids therapy |
US5859205A (en) | 1989-12-21 | 1999-01-12 | Celltech Limited | Humanised antibodies |
EP1690935A3 (en) | 1990-01-12 | 2008-07-30 | Abgenix, Inc. | Generation of xenogeneic antibodies |
US5314995A (en) | 1990-01-22 | 1994-05-24 | Oncogen | Therapeutic interleukin-2-antibody based fusion proteins |
JP3319594B2 (ja) | 1990-03-20 | 2002-09-03 | ザ・トラスティーズ・オブ・コランビア・ユニバーシティー・イン・ザ・シティー・オブ・ニューヨーク | 定常領域の代わりに受容体結合性リガンドを有するキメラ抗体 |
DE69130709T3 (de) | 1990-10-05 | 2005-12-22 | Celldex Therapeutics, Inc. | Gezielte immunostimulierung mit bispezifischen stoffen |
WO1992008802A1 (en) | 1990-10-29 | 1992-05-29 | Cetus Oncology Corporation | Bispecific antibodies, method of production, and uses thereof |
DK0574395T3 (da) | 1990-11-09 | 2002-10-07 | Stephen D Gillies | Cytokin-immunkonjugater |
ATE144624T1 (de) | 1991-04-26 | 1996-11-15 | Surface Active Ltd | Neue antikörper und verfahren zu ihrer verwendung |
FR2686087A1 (fr) | 1992-01-13 | 1993-07-16 | Inst Nat Sante Rech Med | Nouvel antigene lymphocytaire, anticorps correspondant et leurs applications. |
WO1993017715A1 (en) | 1992-03-05 | 1993-09-16 | Board Of Regents, The University Of Texas System | Diagnostic and/or therapeutic agents, targeted to neovascular endothelial cells |
US6692920B1 (en) | 1994-12-07 | 2004-02-17 | Incyte Corporation | Antibodies to a chemokine expressed in inflamed adenoid |
US5633149A (en) | 1994-12-07 | 1997-05-27 | Incyte Pharmaceuticals, Inc. | Polynucleotide encoding novel chemokine expressed in inflamed adenoid |
US5731168A (en) | 1995-03-01 | 1998-03-24 | Genentech, Inc. | Method for making heteromultimeric polypeptides |
AU723891B2 (en) | 1995-06-05 | 2000-09-07 | Human Genome Sciences, Inc. | Human chemokine beta-11 and human chemokine alpha-1 |
AU4243097A (en) | 1996-09-10 | 1998-04-02 | Schering Corporation | Mammalian chemokines, related reagents |
US6852508B1 (en) | 1997-02-28 | 2005-02-08 | Genetics Institute, Llc | Chemokine with amino-terminal modifications |
US6110695A (en) | 1997-12-02 | 2000-08-29 | The Regents Of The University Of California | Modulating the interaction of the chemokine, B Lymphocyte Hemoattractant, and its Receptor, BLR1 |
US6737056B1 (en) | 1999-01-15 | 2004-05-18 | Genentech, Inc. | Polypeptide variants with altered effector function |
US6897044B1 (en) | 1999-01-28 | 2005-05-24 | Biogen Idec, Inc. | Production of tetravalent antibodies |
US6723538B2 (en) | 1999-03-11 | 2004-04-20 | Micromet Ag | Bispecific antibody and chemokine receptor constructs |
US6849425B1 (en) | 1999-10-14 | 2005-02-01 | Ixsys, Inc. | Methods of optimizing antibody variable region binding affinity |
EP1268554A2 (de) | 2000-03-31 | 2003-01-02 | IPF Pharmaceuticals GmbH | Diagnostik- und arzneimittel zur untersuchung des zelloberflächenproteoms von tumor- und entzündungszellen sowie zur behandlung von tumorerkrankungen und entzündlichen erkrankungen vorzugsweise mit hilfe einer spezifischen chemokinrezeptor-analyse und der chemokinrezeptor-ligand-interaktion |
GB2361003A (en) | 2000-04-07 | 2001-10-10 | Astrazeneca Ab | Novel compounds |
US7052676B2 (en) | 2000-09-26 | 2006-05-30 | The Regents Of The University Of Michigan | Methods for inhibition of HIV replication using a small molecule inhibitor |
WO2002102855A2 (en) | 2000-11-17 | 2002-12-27 | University Of Rochester | In vitro methods of producing and identifying immunoglobulin molecules in eukaryotic cells |
MXPA03004913A (es) | 2000-12-01 | 2003-09-05 | Schering Corp | Usos de genes de mamifero y reactivos relacionados. |
US7319139B2 (en) | 2001-01-29 | 2008-01-15 | Biogen Idec, Inc. | TAG-72 specific CH2 domain deleted antibodies |
US6818406B2 (en) | 2001-03-23 | 2004-11-16 | Mayo Foundation For Medical Education And Research | Rheumatoid arthritis markers |
US20030020733A1 (en) | 2001-07-24 | 2003-01-30 | Yin Memphis Zhihong | Computer display having selective area magnification |
US7413866B2 (en) | 2001-11-30 | 2008-08-19 | Chemocentryx, Inc. | Compositions and methods for detecting and treating diseases and conditions related to chemokine receptors |
US7442512B2 (en) | 2001-11-30 | 2008-10-28 | Chemocentryx, Inc. | Compositions and methods for detecting and treating diseases and conditions related to chemokine receptors |
US20040132101A1 (en) | 2002-09-27 | 2004-07-08 | Xencor | Optimized Fc variants and methods for their generation |
JP4524181B2 (ja) | 2002-05-30 | 2010-08-11 | マクロジェニクス,インコーポレーテッド | Cd16a結合タンパク質および免疫障害治療のための使用 |
JP2006517785A (ja) | 2002-10-29 | 2006-08-03 | ジェネンテック・インコーポレーテッド | 免疫関連疾患の治療のための新規組成物と方法 |
WO2004045525A2 (en) | 2002-11-15 | 2004-06-03 | Morehouse School Of Medicine | Anti-chemokine and associated receptor antibodies and uses for inhibition of inflammation. |
WO2004045526A2 (en) | 2002-11-15 | 2004-06-03 | Morehouse School Of Medicine | Anti-chemokine and associated receptors antibodies for inhibition of growth of neoplasms |
EP1572116A4 (en) | 2002-11-26 | 2007-12-12 | Genentech Inc | COMPOSITIONS AND METHODS FOR THE TREATMENT OF IMMUNE DISEASES |
CA2520853A1 (en) | 2003-03-28 | 2005-03-31 | Centocor, Inc. | Anti-amyloid antibodies, compositions, methods and uses |
EP1570857A1 (en) | 2004-02-27 | 2005-09-07 | Nederlandse Organisatie voor toegepast-natuurwetenschappelijk Onderzoek TNO | Method for inhibiting the transendothelal migration of cells such as leukocytes or tumor cells by a CD81 binding agent and uses thereof |
JP2007532656A (ja) | 2004-04-12 | 2007-11-15 | アメリカ合衆国 | アデノウイルスベクターを用いて免疫応答を誘導するための方法 |
CA2501422C (en) | 2004-04-29 | 2014-08-12 | University Of Rochester | Lymphoid chemokines in the diagnosis, monitoring and treatment of autoimmune disease |
ES2353967T3 (es) * | 2004-07-09 | 2011-03-08 | Chugai Seiyaku Kabushiki Kaisha | Anticuerpo anti-glipicano 3 . |
AP2007004034A0 (en) | 2004-12-31 | 2007-06-30 | Genentech Inc | Polypeptides sthat bind br3 and uses thereof |
AU2006236439B2 (en) | 2005-04-15 | 2012-05-03 | Macrogenics, Inc. | Covalent diabodies and uses thereof |
WO2006117910A1 (ja) * | 2005-04-28 | 2006-11-09 | Mochida Pharmaceutical Co., Ltd. | 抗血小板膜糖蛋白質ⅵモノクローナル抗体 |
WO2007064911A1 (en) * | 2005-12-02 | 2007-06-07 | Biogen Idec Inc. | Anti-mouse cd20 antibodies and uses thereof |
GB0607774D0 (en) | 2006-04-20 | 2006-05-31 | Renovo Group Plc | Medicaments |
KR101484025B1 (ko) | 2006-04-21 | 2015-01-19 | 얀센 바이오테크 인코포레이티드 | 염증성 질환의 치료를 위한 cxcl13 길항제 및 이의 용도 |
US20080227704A1 (en) * | 2006-12-21 | 2008-09-18 | Kamens Joanne S | CXCL13 binding proteins |
US20080199481A1 (en) * | 2007-02-21 | 2008-08-21 | Astrazeneca Ab | Compounds |
MX2009010633A (es) | 2007-03-30 | 2009-11-26 | Centocor Ortho Biotech Inc | Antagonistas de la quimiocina interleucina-13 y su uso para el tratamiento de enfermedades inflamatorias. |
WO2010053547A2 (en) | 2008-11-04 | 2010-05-14 | Anchor Therapeutics, Inc. | Cxcr5 receptor compounds |
DK2611832T3 (en) | 2010-09-02 | 2018-02-26 | Vaccinex Inc | ANTI-CXCL13 ANTIBODIES AND PROCEDURES FOR USE THEREOF |
JP2015504060A (ja) | 2011-12-28 | 2015-02-05 | ノーベルメッド セラピューティクス インコーポレイテッド. | アグリコシル化ヒト抗体および融合タンパク質、ならびにその使用 |
IN2014DN08199A (ja) | 2012-03-02 | 2015-05-01 | Vaccinex Inc | |
WO2014121053A1 (en) | 2013-01-31 | 2014-08-07 | Vaccinex, Inc. | Methods for increasing immunoglobulin a levels |
BR112015021964A2 (pt) | 2013-03-08 | 2017-08-29 | Vaccinex Inc | Anticorpo isolado ou um fragmento ligante de antígenos do mesmo que se liga especificamente a cxcl13, composição e seus usos |
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