JP2021516966A - 組織への生物学的薬物の送達 - Google Patents
組織への生物学的薬物の送達 Download PDFInfo
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Abstract
Description
これは2018年3月9日に出願された米国仮出願第62/640,859号の利益を主張し、該仮出願は参照によりその全体が本明細書に組み込まれる。
添付の配列表に列記される核酸およびアミノ酸配列は、37 C.F.R. 1.822において定義されるような、ヌクレオチド塩基のための標準的な略語、およびアミノ酸のための3文字コードを使用して示される。各核酸配列の1つの鎖のみを示しているが、示される鎖への任意の言及により相補鎖が含まれるものと理解される。配列表は、2019年3月9日に作成された21KBのASCIIテキストファイルとして提出され、これは参照により本明細書に組み込まれる。添付の配列表において、以下の通りである。
融合タンパク質、および融合タンパク質をコードする単離された核酸分子が本明細書に開示される。これらの融合タンパク質は、アンカードメインおよび治療用ポリペプチドを含む。一部の実施形態では、融合タンパク質は、炎症性または免疫障害を治療するために有用である。
他に記載されなければ、技術用語は、従来の用法にしたがって使用される。分子生物学における一般的な用語の定義は、Lewin B, Genes VII, 1999;Kendrew et al., The Encyclopedia of Molecular Biology, 1994;Meyers R, Molecular Biology and Biotechnology: a Comprehensive Desk Reference, 1995;および他の類似の参考文献において見出され得る。
1)アラニン(A)、セリン(S)、スレオニン(T);
2)アスパラギン酸(D)、グルタミン酸(E);
3)アスパラギン(N)、グルタミン(Q);
4)アルギニン(R)、リシン(K);
5)イソロイシン(I)、ロイシン(L)、メチオニン(M)、バリン(V);および
6)フェニルアラニン(F)、チロシン(Y)、トリプトファン(W)。
ヒト被験体の組織への治療用化合物の局所的な適用は特に困難であり、その理由は、該化合物は一部の組織において顕著な効果を有するにはあまりにも急速に洗浄除去されるからである。組織の表面に治療用タンパク質をアンカーするドメインを取り付けて、それを組織表面上に保持し、したがって、長期的な期間にわたり作用できるようにすることは、多くの状態を治療するために適用できる汎用的な解決策を提供する。アンカードメインおよび治療用タンパク質を含む融合タンパク質のための方法および組成物が本明細書に開示される。本明細書に記載の方法および組成物は、医薬組成物中の融合タンパク質を被験体の組織に投与することにより、炎症を治療することを含む。
開示される融合タンパク質は、融合タンパク質が非共有結合によって組織表面に付着することを可能とするアンカードメインを含む。これらのアンカードメインは、コラーゲン、ヘパリン、ヘパラン硫酸、または炭水化物に結合し得る。フォンウィルブランド因子(vWF)からの例示的なコラーゲン結合アンカードメインは、GENBANK(登録商標)アクセッション番号AAB59458.1、AAP41950.1、およびQ62935.2(2017年9月14日において利用可能であり、参照により本明細書に組み込まれる)において見出され、以下の通りである:
開示される融合タンパク質は治療用ポリペプチドを含む。一部の実施形態では、治療用ポリペプチドは、例えば、被験体の組織に治療有効量の請求項1に記載の融合タンパク質を投与することであり得、治療用ポリペプチドは、(1)抗炎症性サイトカイン、例えば、インターロイキン(IL)−10、IL−1Ra、IL−6、IL−9、IL−21、IL−22、顆粒球コロニー刺激因子(G−CSF)、血管内皮増殖因子A(VEGF−A)、IL−4、IL−5、IL−13、およびトランスフォーミング増殖因子(TGF)β、または(2)炎症促進性サイトカイン、例えば、IL−9、IL−6、IL−1β、IL−1α、腫瘍壊死因子アルファ(TNFα)、IL−18、インターフェロン(IFN)γ、IL−12、顆粒球マクロファージコロニー刺激因子(GM−CSF)、TGFβ、IL−21、IL−22、IL−23、IL−4、IL−5、IL−13、IL−17F、IL−17A、およびVEGF−Aのアンタゴニスト、もしくはそれに特異的に結合する抗体の少なくとも1つを含む。例示的な実施形態では、治療用ポリペプチドは、IL−10、IL−1Ra、IL−6、IL−9、IL−21、IL−22、G−CSF、TGFβ、P17、P144、TNF受容体1ポリペプチド(例えば、TBP1)、IL−4、IL−5、IL−13、またはVEGF−Aを含む。一部の例示的な実施形態では、治療用ポリペプチドは、IL−9、IL−6、IL−1β、IL−1α、TNFα、IL−18、インターフェロンIFNγ、IL−12、GM−CSF、TGFβ、IL−21、IL−22、IL−23、IL−4、IL−5、IL−13、IL−17A、もしくはVEGF−Aのアンタゴニスト、またはそれに特異的に結合する抗体を含む。一部の例示的な実施形態では、治療用ポリペプチドは、免疫グロブリン結合(Ig)ポリペプチドならびに/またはIFNγ、プロテインA、プロテインG、および/もしくはプロテインLに特異的に結合する抗体を含む。特定の例では、アンタゴニストは抗体ではなく、または非抗体アンタゴニストである。
本明細書に開示される方法において有用な融合タンパク質は、少なくとも2つの成分:アンカードメインおよび治療用タンパク質を含む。一部の実施形態では、アンカードメインは、GGGGSリンカー(配列番号9)などのリンカーポリペプチドにより治療用タンパク質に取り付けられ得る。一実施形態では、治療用タンパク質は、N末端からC末端の順序において、アンカードメインおよび治療用ポリペプチドを含む。別の実施形態では、治療用タンパク質は、N末端からC末端の順序において、治療用ポリペプチドおよびアンカードメインを含む。これらの実施形態のいずれかにおいて、リンカーは、アンカードメインと治療用ポリペプチドとの間に含まれ得る。必要に応じて、標識または溶解度および/もしくは精製のために使用されるドメインなどの他の成分がNまたはC末端において含まれ得る。他の実施形態では、融合タンパク質は、アンカードメイン、治療用ポリペプチド(例えば、P144もしくはP17のより多くのコピーの1つ、例えば、P144もしくはP17の少なくとも約1、2、3、4、もしくは5つのコピーもしくはP144もしくはP17の約2つのコピー)、またはリンカー(例えば、配列番号9もしくは配列番号19のより多くのコピーの1つ、例えば、配列番号9もしくは配列番号19の少なくとも約1、2、3、4、もしくは5つのコピーもしくは配列番号9もしくは配列番号19の約2つのコピー)の1つまたは複数のコピーを含み得る。治療用ポリペプチドおよび融合タンパク質に関する追加の情報は以下において提供される。
本明細書に開示される融合タンパク質をコードするポリヌクレオチドもまた提供される。これらのポリヌクレオチドとしては、融合タンパク質をコードする、DNA、cDNA、およびRNA配列が挙げられる。コーディング配列は、1つより多くのコドンが同じアミノ酸残基をコードし得る遺伝コードの縮重(すなわち、冗長性)に起因するバリアントを含む。そのため、例えば、ロイシンは、CTT、CTC、CTA、CTG、TTA、またはTTGによりコードされ得、セリンは、TCT、TCC、TCA、TCG、AGT、またはAGCによりコードされ得、アスパラギンはAATまたはAACによりコードされ得、アスパラギン酸はGATまたはGACによりコードされ得、システインはTGTまたはTGCによりコードされ得、アラニンは、GCT、GCC、GCA、またはGCGによりコードされ得、グルタミンはCAAまたはCAGによりコードされ得、チロシンはTATまたはTACによりコードされ得、イソロイシンは、ATT、ATC、またはATAによりコードされ得る。標準的な遺伝コードを示す表は様々な供給源において見出すことができる(例えば、Stryer, 1988, Biochemistry, 3.sup.rd Edition, W.H. 5 Freeman and Co., NYを参照)。
融合タンパク質を合成するために分子的方法が使用され得るが、アンカードメインを治療用ポリペプチドに連結することにより融合タンパク質を合成するために化学的方法が代替的に使用され得る。一部の例では、アンカードメイン(例えば、レクチン炭水化物結合ドメイン、例えば、WGA、conA、およびJac、またはコラーゲンもしくはヘパリン結合ドメイン)は、化学的コンジュゲーションを通じて治療用ポリペプチド(例えば、Ig結合ポリペプチドまたはTGFβアンタゴニスト、TNFαアンタゴニスト、IL−1βアンタゴニスト、IL−6アンタゴニスト、またはIFNγアンタゴニスト)に共有結合され得る。様々な種類の化学試薬が使用され得る(例えば、Ido et al., JBC, 287(31): 26377-26387, 2012、および米国特許出願公開第2003/0040496号を参照;共に参照により本明細書に組み込まれる)。一部の例では、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド塩酸塩(EDC)が化学的コンジュゲーションのために使用される(例えば、Ido et al., JBC, 287(31): 26377-26387, 2012を参照;参照により本明細書に組み込まれる)。一部の非限定的な例では、少なくとも約1〜2、2〜5、5〜10、10〜15、15〜20、20〜25、もしくは25〜30mMまたは少なくとも約2、5、6、10、15、20、もしくは25mMのEDCが使用され得る。さらなる非限定的な実施形態では、N−ヒドロキシスルホスクシンイミド(スルホ−NHS)がECDに加えて使用され得る(例えば、Ido et al., JBC, 287(31): 26377-26387, 2012を参照;参照により本明細書に組み込まれる)。一部の例では、少なくとも約5〜10、10〜20、20〜30、30〜40−、40〜50、50〜75、75〜100、もしくは100〜200mMまたは少なくとも約5、10、25、50、もしくは100mMのスルホ−NHSがECDに加えて使用され得る。
組織中に炎症性または免疫障害(例えば、自己免疫疾患)を有する、哺乳動物被験体(例えば、ヒトまたは獣医学的被験体)などの被験体を治療するための組成物および方法が本明細書に開示される。一部の例では、方法は、被験体において炎症性または免疫障害の徴候または症状を好転させることができる。融合タンパク質の投与は、炎症性または免疫障害を治療し、阻害し、かつ/または予防するために充分である。
以下の実施例は、ある特定の実施形態の特定の特徴を実例により説明するために提供されるが、特許請求の範囲は、例示されるそれらの特徴に限定されるべきではない。
異種タンパク質に融合したアンカードメインの結合
4つの異なるコラーゲン結合ドメインに対するドメインをレポータータンパク質(LacZ)に融合させた。LacZ融合タンパク質をコラーゲンIIIカラム(Sigma−Aldrich(登録商標))にこれらの化合物の結合を分析するために適用し、高い塩濃度で溶出させた。LacZをオルト−ニトロフェニル−β−ガラクトシドの加水分解により検出した。図1は、LacZを有する全てのアンカードメインがコラーゲンに結合したことを示す。アンカードメインを有しない対照タンパク質は結合しなかった。アンカードメインを含有する4つの融合タンパク質の結合は、アンカードメインが機能的であることを実証する。
コラーゲンIおよびIVへの結合
角膜は2つの主要な形態のコラーゲン:間質中に大量に存在するコラーゲンI、および基底膜中に存在し、角膜への表層性の損傷後に接近可能なコラーゲンIVを含有する。図2に示されるように、4つ全てのコラーゲン結合アンカードメインに連結したLacZは、両方の種類のコラーゲンに類似の効率で結合する。指し示されるLacZ融合タンパク質は、CORNING(商標)BIOCOAT(商標)Collagen IまたはIVプレートに結合した。
ex vivoでのウサギの目への係留されたLacZ融合タンパク質の結合
角膜への結合を決定するために、LacZ融合タンパク質を創傷を負ったウサギの目にex vivoで適用した。インキュベーションを2分間行って、点眼剤において適用される場合の角膜上の短い残存時間をシミュレートした。結合は広く異なり、それは組織中の結合部位がマスクされていたことに起因し得る。ウシフォンウィルブランド因子(vWF)からの10アミノ酸配列およびClostridium histolyticumコラゲナーゼHからの223アミノ酸ドメインは最も効率的に結合した(図3を参照)。タンパク質は創傷を負っていない目に結合しなかった。vWF結合ドメイン(WREPSFMALS)を使用した。なぜなら、それが容易にクローニングおよび操作(例えば、異なる結合親和性を有する変異体を作製するため)され、かつ免疫応答を誘導する可能性が低い短鎖配列であるからである。
アダプターは抗体の結合を媒介する
以下に記載されるようにアルカリホスファターゼコンジュゲートヤギ抗ヒトIgG(Invitrogen(登録商標))をvWFアンカーありまたはなしの10倍モル過剰のアダプターと共にインキュベートした。0.1%のBSAを含むhepes緩衝食塩水(HBS)中に試料を50μlに希釈し、コラーゲンIコーティングBioCoat(商標)96ウェルプレート(Corning(登録商標))中で一定の撹拌と共に2時間インキュベートした。広範な洗浄後、パラ−ニトロフェニルホスフェートを用いる標準的な比色アッセイを使用して結合抗体を検出した(図4を参照)。上は結合抗体を示し、下はインプット抗体の量を示す。「アダプター」は、vWFドメイン、および、抗体への強い親和性を有し、タンデムアフィニティー精製手順においてアフィニティータグとして広く使用されてきたプロテインGの2つのC末端抗体結合ドメインを含有する。アダプターは、プロテインGへの親和性を有する任意の抗体に取り付けることができ、複合体はコラーゲンに結合する。プロテインAおよびLを用いて類似の融合タンパク質を構築することができ、そのため、ほぼ任意の抗体をアダプターを用いてコラーゲンに取り付けることができる。
アンカーとしてのレクチン小麦胚芽アグルチニンの取付け
ウサギの目をPseudomonas aeruginosaに曝露し、それにより目の多くにおいて病変を誘導した。翌日、0.1%のBSAを含む10μlのHBS中の等量のフルオレセイン標識レクチン(ConA、コンカナバリンA;DBA、Drichos biflorusアグルチニン;PNA、ピーナッツアグルチニン;RCA、Ricinus communisアグルチニン;SBA、大豆アグルチニン;UEA、Ulex europaeusアグルチニン;WGA、小麦胚芽アグルチニン;Jac、ジャカリン;Vector Labs製)を目の表面に2分間適用し、目を洗浄し、蛍光実体顕微鏡を使用して写真撮影した。図5は2つの実験からの結果を示す。小麦胚芽アグルチニン(WGA)は角膜および強膜の表面の他に、創傷を負った領域に強く結合した。
マウスにおけるFITC標識WGAの保持
Algerbrushを用いてマウスに創傷を負わせた。FITC標識WGA(Vector Laboratories)を目に適用し、図7に示すように目を写真撮影した。指し示した時間における同じマウスを示す。蛍光標識WGAの保持時間は、生きたマウスを使用して決定することができる。図7に示すように、単回用量の標識WGAからの蛍光を少なくとも5日間追跡することができる。上皮はこのモデルにおいて1〜2日後に創傷を覆い、それは薬物の含有を補助するはずであることが留意されるべきである。
WGAは抗体にGlcNAc結合活性を付与する
200マイクログラムの抗マウスIL−17A抗体(クローンTC11−18H10、BD(登録商標)Biosciences)をAmicon(登録商標)100kDaカットオフスピンフィルターに移し、100μlのコンジュゲーション緩衝液(0.1M HEPES、pH7.5)を用いて2回洗浄し、2倍濃縮のコンジュゲーション緩衝液を用いて1回洗浄した。Alexa Fluor(登録商標)488 TFP ester(Invitrogen(登録商標))をアセトンに溶解させ、40μgのアリコートを0.2mlのPCRチューブ(Thermo Scientific(商標))において乾かした。この標識試薬を濃縮抗体溶液に溶解させ、6〜8時間室温で反応させた後、使用前に少なくとも2日間4℃で貯蔵した。
WGAをコンジュゲートした抗体は複数の組織に結合する
ニュージーランドホワイトウサギ(7〜8週齢)を安楽死させ、臓器を回収および解剖した。膀胱および頬側上皮を顕微鏡スライドガラスに広げ、5μlのWGAコンジュゲートおよび対照Alexa Fluor(登録商標)標識抗体を実施例7に記載のように調製した後、10分のインキュベーションを適用した。20×の対物レンズを使用する蛍光顕微鏡を用いて写真を収集した(図9を参照)。
WGAにコンジュゲートした抗体はヒト角膜に結合する
アイバンクからの古いヒト角膜を実施例8に記載されるようにAlexa Fluor(登録商標)標識抗体を用いて処理した。10×の対物レンズを用いて写真を収集した。図10は、ヒト角膜に結合した蛍光標識された抗体の画像を示す。
WGAはin vivoで少なくとも25時間マウスの目に結合する
200マイクロリットルのフルオレセイン標識WGA(Vector Labs)をリン酸緩衝食塩水中で洗浄し、Amicon(商標)10kDaカットオフスピンフィルターユニット中で濃縮した。次に、0.5μlを6〜8週齢C57BL/6マウスの目に適用し、適用後の指し示した時点において蛍光顕微鏡法用に適合させたカメラを用いて写真撮影した。図11は、結合抗体からの蛍光が25時間までにわたり続くことを示す。
WGAにコンジュゲートした抗体は目の表面に少なくとも8時間結合する
記載(Stevenson, W. et al. (2014), Cornea, 33, 1336-1341)されたように6〜8週齢の雌c57BL/6マウスの眼窩外涙腺を除去することによりドライアイを誘導した。マウスを2か月後に使用した。標識されたIL−17A抗体を産生し、実施例7に記載されるようにコンジュゲートさせた。これらの抗体を目に適用し、蛍光写真撮影用に適合させたカメラを用いて写真撮影した。図12Aは、標識された抗体がWGAアンカーなしでは急速に洗浄除去されたが、アンカーありでは保持されたことを示す。図12Bは、標識された抗体がWGAアンカーにコンジュゲートしている場合に適用の8時間後に検出され得ることを示す。ドライアイのマウスモデルにおいてWGAにコンジュゲートした抗体は目の表面に少なくとも8時間結合した一方、コンジュゲートしていない抗体は5〜15分以内に洗浄除去された。
WGAにコンジュゲートした抗体はリガンドに結合する能力を保持する
実施例7に記載されるように非標識抗体をGlcNAcアガロースビーズに結合させた。リガンドをPeproTech(登録商標)から得、100mg/mlにおいて溶解させ、実施例7における抗体と同じ方法で標識した。エタノールアミンを5mMまで加えることにより反応をクエンチし、5倍に希釈し、さらなる精製なしで実施例7に記載されるようにGlcNAcビーズとのインキュベーションにより使用した。図13Aは、Alexa Fluor(登録商標)488標識IL−1βまたはTGFβと共にインキュベートされた指し示される抗体に結合したビーズを示す。図13Bは、抗IL−17A抗体に結合しかつAlexa Fluor 488(登録商標)標識IL−17Aとインキュベートされたビーズを示す。
1日1回適用されたIL−17Aに対する抗体はWGAにコンジュゲートした場合に炎症状態(ドライアイ)の治療において有効である
Claims (28)
- アンカードメインおよび治療用ポリペプチドを含む融合タンパク質であって、
(a)前記アンカードメインが、レクチン炭水化物結合アンカードメイン、フォンウィルブランド因子(vWF)コラーゲン結合アンカードメイン、Clostridiumコラゲナーゼ(ColH)コラーゲン結合アンカードメイン、もしくはヘパリン結合(HS)アンカードメインを含み、かつ、
前記治療用ポリペプチドが、
(i)インターロイキン(IL)−17A、IL−6、IL−1β、IL−1α、IL−18、インターフェロン(IFN)γ、IL−12、顆粒球マクロファージコロニー刺激因子(GM−CSF)、トランスフォーミング増殖因子ベータ(TGFβ)、IL−21、IL−22、IL−23、IL−4、IL−5、IL−13、IL−17F、IL−9、もしくはVEGF−Aに特異的に結合する抗体、もしくはそれらのアンタゴニスト、または
(ii)免疫グロブリン結合(Ig)ポリペプチドもしくは腫瘍壊死因子アルファ(TNFα)のアンタゴニスト
を含むか、あるいは、
(b)前記アンカードメインが、レクチン炭水化物結合アンカードメイン、フォンウィルブランド因子(vWF)コラーゲン結合アンカードメイン、もしくはClostridiumコラゲナーゼ(ColH)コラーゲン結合アンカードメインを含み、かつ、
前記治療用ポリペプチドが、
(i)抗炎症性サイトカイン、または
(ii)炎症促進性サイトカインのアンタゴニスト、もしくは炎症促進性サイトカインに特異的に結合する抗体
を含む、
融合タンパク質。 - (a)前記抗炎症性サイトカインがIL−10を含み、
(b)前記炎症促進性サイトカインの前記アンタゴニストがインターロイキン−1受容体アンタゴニスト(IL−1Ra)を含み、または、
(c)炎症促進性サイトカインに特異的に結合する前記抗体が、腫瘍壊死因子アルファ(TNFα)に特異的に結合する抗体を含む、
請求項1に記載の融合タンパク質。 - 前記レクチン炭水化物結合アンカードメインが、小麦胚芽アグルチニン(WGA)、ジャカリン(Jac)、またはコンカナバリンA(conA)炭水化物結合アンカードメインである、請求項1または請求項2に記載の融合タンパク質。
- TGFβの前記アンタゴニストがP17もしくはP144であり、
TNFαの前記アンタゴニストがTNF受容体1ポリペプチドを含み、かつ/または、
前記Ig結合ポリペプチドが、プロテインA、プロテインG、もしくはプロテインLもしくはそのIg結合断片を含む、
請求項1に記載の融合タンパク質。 - (a)前記アンカードメインがレクチン炭水化物結合アンカードメインを含み、かつ、前記治療用ポリペプチドが、TNF受容体1からのTNFαポリペプチドの阻害剤、IL−10、IL−1Ra、もしくはTGFβ、TNFα、IL−1β、IL−6、IFNγ、IL−23、もしくはIL−17Aに特異的に結合する抗体を含み、
(b)前記アンカードメインが前記vWFコラーゲン結合アンカードメインもしくは前記ColHコラーゲン結合アンカードメインを含み、かつ、前記治療用ポリペプチドが、TNF受容体1からのTNFαポリペプチドの阻害剤、IL−1Ra、IL−10、P17、P144、もしくは前記Ig結合ポリペプチドを含み、または、
(c)前記アンカードメインが前記HSアンカードメインを含み、かつ、前記治療用ポリペプチドがTNF受容体1からのTNFαポリペプチドの阻害剤を含む、
請求項1に記載の融合タンパク質。 - 前記レクチン炭水化物結合アンカードメインがWGAを含む、請求項5に記載の融合タンパク質。
- 前記レクチン炭水化物結合アンカードメインが、配列番号6、配列番号7、もしくは配列番号8のアミノ酸配列を含み、
前記vWFコラーゲン結合アンカードメインが、配列番号1、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、もしくは配列番号26のアミノ酸配列を含み、
前記ColHコラーゲン結合アンカードメインが配列番号3のアミノ酸配列を含み、かつ/または、
前記HSアンカードメインが配列番号5のアミノ酸配列を含む、
請求項1から6のいずれか一項に記載の融合タンパク質。 - アンカー結合ドメインと治療用ドメインとの間のリンカーをさらに含む、請求項1から7のいずれか一項に記載の融合タンパク質。
- リンカーが配列番号9または配列番号19のアミノ酸配列を有する、請求項8に記載の融合タンパク質。
- 標識、溶解度増進配列、精製タグ、またはその組合せをさらに含む、請求項1から9のいずれか一項に記載の融合タンパク質。
- 前記アンカードメイン、治療用ペプチドまたはその組合せが、ベンジル化、グリコシル化、アセチル化、リン酸化、アミド化、ペグ化、およびその組合せを受けている、請求項1から10のいずれか一項に記載の融合タンパク質。
- 炎症性または免疫障害の治療において使用するための、請求項1から11のいずれか一項に記載の融合タンパク質。
- 被験体の口、膀胱、鼻腔、胃腸管、肺、関節、目、または生殖系における組織に投与される、請求項12に記載の融合タンパク質。
- 前記炎症性または免疫障害が、慢性閉塞性肺疾患、喘息、気管支炎、鼻副鼻腔炎、粘膜炎、左側潰瘍性大腸炎、炎症性腸疾患、歯周疾患、インプラント周囲炎、間質性膀胱炎、萎縮性膣炎、または関節炎を含む、請求項12または請求項13に記載の融合タンパク質。
- 炎症性または免疫障害の治療において使用するための、請求項1から14のいずれか一項に記載の融合タンパク質をコードする単離された核酸分子。
- 異種プロモーターに作動可能に連結した、請求項15に記載の単離された核酸分子。
- 炎症性障害の治療において使用するための、請求項16に記載の単離された核酸分子を含む発現ベクター。
- 被験体中の組織の炎症を治療するための方法であって、前記被験体の前記組織に治療有効量の請求項1から14のいずれか一項に記載の融合タンパク質を投与することを含む、方法。
- 治療用タンパク質が免疫グロブリン結合(Ig)ポリペプチドまたはその断片を含み、前記方法が、前記Ig結合ポリペプチドまたはその断片に特異的に結合する抗体を投与することをさらに含む、請求項18に記載の方法。
- 前記組織が、被験体の口、鼻腔、胃腸管、肺、関節、目、または生殖系中にある、請求項19に記載の方法。
- 前記被験体が、慢性閉塞性肺疾患、喘息、気管支炎、鼻副鼻腔炎、粘膜炎、左側潰瘍性大腸炎、炎症性腸疾患、歯周疾患、インプラント周囲炎、間質性膀胱炎、萎縮性膣炎、または関節炎を有する、請求項19または請求項20に記載の方法。
- 前記被験体が、目に影響する炎症を有し、かつ、治療用ポリペプチドが、IL−17AまたはIL−23に特異的に結合する抗体を含む、請求項19または請求項20に記載の方法。
- 前記被験体がドライアイを有する、請求項22に記載の方法。
- 前記被験体がシェーグレン症候群を有する、請求項22または請求項23に記載の方法。
- 組織への外部および/または外用投与のために製剤化されている、治療有効量の請求項1から14のいずれか一項に記載の融合タンパク質および薬学的に許容される担体を含む医薬組成物。
- 請求項25に記載の医薬組成物を炎症組織に局所的に分配するための、単位用量ディスペンサー。
- ゲル、クリーム、ローション、または軟膏として製剤化されている、請求項25または26に記載の医薬組成物。
- 請求項1から14のいずれか一項に記載の融合タンパク質を含む、炎症性または免疫障害において使用するための融合タンパク質。
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