JP2018515072A - 単鎖cd40受容体アゴニストタンパク質 - Google Patents
単鎖cd40受容体アゴニストタンパク質 Download PDFInfo
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- JP2018515072A JP2018515072A JP2017555643A JP2017555643A JP2018515072A JP 2018515072 A JP2018515072 A JP 2018515072A JP 2017555643 A JP2017555643 A JP 2017555643A JP 2017555643 A JP2017555643 A JP 2017555643A JP 2018515072 A JP2018515072 A JP 2018515072A
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- receptor agonist
- agonist protein
- protein
- cd40l
- seq
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Classifications
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- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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Abstract
Description
(a)Gln121またはIle122
(b)(Gly/Ser)121
から選択される。
1.1 ポリペプチド構造
A)アミノ酸Met1−Gly20
Ig−κ−シグナルペプチド、アミノ酸GIy20の後ろの仮定のシグナルペプチダーゼ切断部位。
B)アミノ酸Gln21−Leu161
ヒトCD40Lリガンドの第一の可溶性サイトカインドメイン(CD40L、配列番号1のアミノ酸121〜261)。
C)アミノ酸GIy162−Ser169
配列番号2の第一のペプチドリンカーエレメント。
D)アミノ酸Gln170−Leu310
ヒトCD40Lリガンドの第二の可溶性サイトカインドメイン(CD40L、配列番号1のアミノ酸121〜261)。
E)アミノ酸GIy311−Ser318
配列番号2の第二のペプチドリンカーエレメント。
F)アミノ酸Gln319−Leu459
ヒトCD40Lリガンドの第三の可溶性サイトカインドメイン(CD40L、配列番号1のアミノ酸121〜261)。
G)アミノ酸Gly460−Cys482
配列番号16のヒンジ−リンカーエレメント。
H)アミノ酸Pro483−Lys700
配列番号13の抗体Fcフラグメントドメイン。
合成遺伝子は、適切な宿主細胞、例えば昆虫細胞または哺乳類細胞における発現に関するそのコドン使用頻度を考慮して最適化され得る。好ましい核酸配列は、配列番号37に示される。
2.1 融合ポリペプチドのクローニング、発現および精製
前述の融合タンパク質を、2つの異なる真核生物宿主細胞において、組み換えによって発現した:
前述のCD40受容体アゴニスト融合タンパク質の初期解析のために、10%のFBS、100ユニット/mlのペニシリンおよび100[mu]g/mlのストレプトマイシンで補充されたDMEM+GlutaMAX(GibCo)中で増殖したHek293T細胞を、適切な選択マーカーおよび融合ポリペプチドに関する発現カセット、例えば、ブラスチサイジン、ピューロマイシンまたはハイグロマイシン耐性遺伝子を含む機能性発現カセットを含む、プラスミドを用いて一時的にトランスフェクトした。最終産物を得るために複数のポリペプチド鎖が必要な場合では、トランスフェクションの間、発現カセットは、1つのプラスミド上に組み合わせるか、または、異なるプラスミド上に配置した。組み換え融合ポリペプチドを含む細胞培養上清を、トランスフェクションの3日後に採取し、300×gでの遠心分離によって浄化して、0.22μm滅菌フィルターを通した濾過を続けた。
PROTEIN A、B、およびCを発現して、実施例1および2に従って精製した。3つの精製されたタンパク質を、非還元(レーン1、4、および7)またはジチオスレイトールによって還元し(レーン2、5、8)、4〜12%のbis−tris中でSDS−Pageゲル電気泳動を行なった。結果を図6に示す。レーン1は、非還元条件下では、PROTEIN Aを発現したタンパク質は、単量体(85kDa)および二量体(170kDa)のバンドの両方を有することを示し、ポリペプチド自体に存在する内因性のフリーのチオールによる鎖間ヒンジジスルフィドの自己還元を示す。それにひきかえ、レーン4および7は、非還元条件下では、PROTEIN BおよびPROTEIN Cを発現したタンパク質は、二量体(170kDa)バンドのみを有することを示し、ヒンジ領域の鎖間ジスルフィド架橋が損なわれないままで、ポリペプチド自体の自己還元特性が無いことを示す。
六価CD40受容体アゴニスト融合タンパク質およびバクテリオファージRB69−FOLDONによって安定化された三価CD40の間の相対的結合を比較するために、PROTEIN X(配列番号38)をCHO−S細胞内で発現して、前のセクションで説明したとおりに精製した。SEC−精製したタンパク質を、以下の実施例においてコントロールとして使用した。PROTEIN Xの配列(配列番号38)を表7に示す。PROTEIN Xのアミノ酸1〜20はシグナルペプチドを示し、成熟タンパク質はアミノ酸Gln21でスタートする。このタンパク質は、1つの可溶性CD40Lドメイン(配列番号1のQ121〜L261)をそれぞれ含む3つの同一のポリペプチドからなり;この集合体は、フレキシブルリンカーによってCD40LのC末に融合されたバクテリオファージRB69フィブリチンの三量体化ドメインによって安定化される。
5A. Ramos B細胞の表面上での、CD40受容体アゴニストのそれらの生来の受容体CD40への結合を示すための、細胞結合アッセイ
水晶振動子マイクロバランス(QCM)を用いて得られたCD40受容体アゴニストに関する我々のアフィニティデータを完成させるために、我々は、我々のCD40受容体アゴニストが、細胞の表面上のそれらの生来の受容体に結合することができるかどうかを調べたかった。B細胞は完全な活性化のためにCD40シグナリングに依拠するので、我々は、このアッセイにヒトB細胞株Ramosを用いた。Ramos細胞は、それらの表面上にCD40を発現することが知られていて、CD40受容体アゴニストによるインキュベーション後、抗体によって、我々のCD40受容体アゴニストに結合したC末StrepTag IIを、検出することが可能であると想像することができた。それから、この抗体は、順々に、蛍光抗体を用いて検出することができ、および細胞をフローサイトメーター上で分析することができた。
CD86は、ヒトB細胞上の活性化マーカーであり、T細胞上のCTLA4およびCD28のリガンドである。CD86表面発現は、しばしば、B細胞の活性化状態を説明する手段として用いられる。B細胞は、B細胞受容体およびCD40ライゲーションを含む完全な活性化のためにいくつかのシグナルを必要とするので、我々は、CD40受容体アゴニストがCD86表面発現の上方制御をもたらすことができるのかどうか考えた。
CD40Lの三価構築物(例えば:PROTEIN X)およびCD40Lの六価構築物(例えばPROTEIN A、PROTEIN B、およびPROTEIN C)の、CD40に対する平衡結合定数(KD)を、自動化バイオセンサーシステム(Attana A100)を用いて決定された動態学的結合データ(konおよびkoff)に基づいて計算した。A100は、水晶振動子マイクロバランス(QCM)技術に基づいて、リアルタイムで、分子相互作用を調べるのを可能にする。
分子PROTEIN A/PROTEIN B/PROTEIN Cは、それぞれ、3つの鎖間ジスルフィド結合によって共有結合された2つのポリペプチドで構成され、全て、Fc領域の297位にN297S突然変異を含み(EUインデックスに従う)、CH2ドメインのアグリコシル化をもたらす。可溶性CD40Lドメインの外側表面システインはセリンに突然変異されて(配列番号1に示されるCD40LのC194等価位置)、配列番号15(PROTEIN A)と比較してC94S、C243S、C392Sを有する配列番号31(PROTEIN B)をもたらした。あるいは、可溶性CD40Lドメインの外側表面システインはアラニンに突然変異されて(配列番号1に示されるCD40LのC194等価位置)、配列番号15(PROTEIN A)と比較してC94A、C243A、C392Aを有する配列番号35(PROTEIN C)をもたらした。生じたFC−融合タンパク質の半減期を、これらの変更によって導入された効果について評価した。
単量体および凝集体の含有量は、実施例2に記載の分析SECによって決定される。この特定の目的のために、分析は、生理学的pHで生理学的塩濃度を含むバッファー中で行なわれる(例えば0.9% NaCl、pH7.4;PBS pH7.4)。典型的な凝集分析は、Superdex200カラム(GE Healthcare)で行われる。このカラムは、10〜800kDaの範囲内のタンパク質を分離する。
単量体含有量[%]=[ピーク面積単量体タンパク質]/[ピーク面積全体]×100)
M2様マクロファージは、活性化マーカー/T細胞活性化分子、例えばCD83、CD86およびHLAの低発現、およびIL−10のような免疫調節分子の高発現によって特徴付けられる。このため、M2様マクロファージは、「抗−腫瘍」M1様マクロファージとは対照的に、腫瘍促進性としばしば呼ばれる。我々は、PROTEIN−B(配列番号31)を用いた治療が、通常M2−極性化する条件において、M1様マクロファージの発達を増大させることができるかどうか試験することにした。これを達成するために、ヒト末梢血単核細胞(PBMC)を単離して、製造元の説明書に従って、Ficoll−Hypaque(Sigma)を用いて、健常者から得られたバフィーコートから精製した。培地(RPMI)中で、12ウェルプレート中で、2時間37℃でPBMCを培養することによって、単球を単離した。単球を、M2極性化条件で、IL−4(50ng/ml)およびIL−10(50ng/ml)、または培地のみで、3日間インキュベートした。このインキュベーション期間のあいだ、PROTEIN−B(50ng/ml)または培地コントロールをウェルの半分に加えた。3日目に、細胞懸濁液を、CD206、CD163、CD86、CD83、HLA−DRおよびCD4(BioLegend,eBioscienceまたはBD Biosciences)を含むモノクローナル抗体のカクテルを用いて染色した。DAPI(4’,6−ジアミジノ−2−フェニルインドール、ジヒドロクロリド)(ThermoFisher)を製造元の説明書に従って用いて、死んだ細胞を分析から取り除いた。Guava easyCyte 12フローサイトメーター(Merck Millipore)を用いて細胞を解析した。抗体の質をチェックして、アイソタイプコントロールを用いてゲーティングを行なった。Tree Star FlowJoおよびGuava InCyteソフトウェアを、フローサイトメトリーデータの分析のために用いた。ゲートおよびメジアン蛍光強度(MFI)を用いて発現を定量化した。IL−4およびIL−10(M2−極性化マクロファージ)を用いた処理は、CD206およびCD163(M2様マクロファージの古典的マーカー)の単球上の発現を増大させた(表10参照)。対照的に、PROTEIN−Bを用いた同時的な処理は、CD206およびCD163発現を37%から22%に低下させた。CD86(B7.2)は、古典的なT細胞共刺激分子であり、CD28の結合パートナーであり、一方で、CD83は、抗原提示細胞の成熟のマーカーである。重要なことに、PROTEIN−Bの処理は、IL−4/IL−10のみと比較して、CD86およびCD83の共発現を5%から20%に増大させた。加えて、HLA−DR、DPの発現は、IL−4/IL−10のみと比較して、PROTEIN−B処理後により高かった、94〜162(MFI)。これらの結果は、PROTEIN−B処理が、M2−極性化マクロファージの活性化状態を増大させることを示し、それらをより強力な抗原提示細胞にさせる。
M2様マクロファージは、HLAおよび共刺激分子(例えば、CD86)の低発現に起因して、T細胞応答を刺激する低い能力によって特徴付けられる。我々は、PROTEIN−Bによる処理が、M2様マクロファージの効能を増大させることができるかどうか試験したかった。これを試験するために、M2様マクロファージを、IL−10およびIL−4(それぞれ50ng/ml)を用いて上述のように生産した。製造元の説明書に従って、ナイーブCD4+T細胞単離キットII(Miltenyi)を用いて、第二の(アロジェニック)ドナー由来のPBMCからナイーブCD4+T細胞を単離した。製造元の説明書に従って、CellTrace CFSE Cell Proliferation Kit(ThermoFisher)を用いて、T細胞を標識化した。3日間処理された単球を、1単球に対して10リンパ球の比でナイーブCD4+T細胞に添加した。T細胞の増殖およびブラスティング(細胞***前の増殖)を、CFSEおよびForward Scatter(FSC)をそれぞれ用いて、3日後に測定した。培地のみでインキュベートしたT細胞のたった2%が、増殖(CFSEの希釈)またはブラスティング(FSCの増大)の証拠を示した(表11を参照)。対照的に、刺激無しのアロジェニック単球とインキュベートしたT細胞の23%が、活性化の証拠を示した。M2−極性化マクロファージとのT細胞のインキュベーションは、T細胞応答を16%まで低下させた。興味深いことに、M2−極性化状態へのPROTEIN−Bの添加は、アロジェニックマクロファージの効能を増大させて、T細胞の31%が応答した。このデータは、AGP1233を用いた単球の処理は、通常M2−極性化する条件において(in with AGP1233 normally M2−polarization conditions)、より強力な抗原提示細胞をもたらすことを示す。
下流シグナリングおよび受容体クラスタリングの効率を試験するために、我々は、本発明の六価アゴニストPROTEIN−Bを、当技術分野で知られている共通の工学概念を表わす2つのホモ三量体の三価CD40受容体アゴニストと比較した。PROTEIN−X2(配列番号39)は、ホモ三量体の安定化されていないCD40L−RBD自体を表わし、PROTEIN−X(配列番号38)は、バクテリオファージRB69に由来するC末融合された三量体化足場によって安定化されたホモ三量体のCD40L−RBDを表わす。我々は、生産的なCD40受容体シグナリングが、活性化マーカーの上方制御およびM1様マクロファージ発達の増大をもたらすことを示しているので、我々は、ヒト単球をバフィーコートから上述のように精製した。精製された単球を、3つの異なる濃度(10、100および1000ng/mL)の3つの異なる構築物(表12参照)で補充された培地中で3日間インキュベートして、活性化および表現型マーカーの発現について、フローサイトメトリーによって細胞を解析した。全ての3つの濃度の六価PROTEIN−Bによる処理は、コントロールと比較して用量依存的なCD86発現の増加を生じさせた(MFIおよび陽性パーセンテージの両方として)。対照的に、三価PROTEIN−X2のいずれの濃度も、コントロールと比較して違いを示さなかった。RB69−足場安定化三価PROTEIN Xの場合、最も高い濃度のみが、CD86発現のわずかな増大を生じさせた。加えて、同一の化合物および投与量の効果が、HLA−DR、DP発現で見られた(それは、六価構築物は低い投与量でさえ受容体クラスタリングおよび生産的シグナリングに十分であるが、三価構築物は、非常に高い濃度において活性を示さないまたは低い活性を示すことを確認する)。最後に、培地中の単球のおよそ20%は、一般に、3日でCD206およびCD163発現を上方制御し、それは、M2様マクロファージ発達を示す。全ての3つの濃度の六価PROTEIN−Bを用いた処理は、これを3%未満に低減させた。活性化マーカーデータと一致して、高濃度の三価タンパク質−Xのみが、M2様マクロファージ発達の任意の低減を示した。まとめると、データは、本発明のPROTEIN Bの優れた生物学的活性を示す。
1.配列番号15、および25〜35からなる群より選択されるアミノ酸配列を有するポリペプチドを含む、CD40受容体アゴニストタンパク質。
2.配列番号27、28、29、30、32、または34に示されるアミノ酸配列をそれぞれ有する2つのポリペプチドを含む、CD40受容体アゴニストタンパク質。
3.項目2のCD40受容体アゴニストタンパク質であって、2つのポリペプチドは、それぞれのポリペプチドのシステイン残基453、459、および462の間に形成された3つの鎖間ジスルフィド結合を通して共有結合される。
4.項目2または3のCD40受容体アゴニストタンパク質であって、ポリペプチド(単数または複数)の147位および296位のアスパラギン残基の1つまたは複数は、Nグリコシル化される。
5.項目2または3のCD40受容体アゴニストタンパク質であって、ポリペプチド(単数または複数)の147位および296位の両方のアスパラギン残基は、N−グリコシル化される。
6.項目1〜5のCD40受容体アゴニストタンパク質であって、ポリペプチド(単数または複数)は、さらに翻訳後修飾される。
7.項目6のCD40受容体アゴニストタンパク質であって、翻訳後修飾は、N末グルタミンの、ピログルタミン酸への改変を含む。
8.項目1〜7のいずれか1つのCD40受容体アゴニストタンパク質、および、1つまたは複数の薬学的に許容できる担体、希釈剤、賦形剤、および/またはアジュバントを含む、医薬組成物。
9.項目1のCD40受容体アゴニストタンパク質をコードする、核酸分子。
10.項目9の核酸分子を含む、発現ベクター。
11.項目9の核酸分子を含む、細胞。
12.真核生物細胞である、項目11の細胞。
13.項目11の細胞であって、細胞は哺乳類細胞である。
14.項目11の細胞であって、細胞はチャイニーズハムスター卵巣(CHO)細胞である。
15.CD40L関連の疾患または障害を有する対象を治療する方法であって、当該方法は、有効量の項目1〜7のいずれか1つのCD40受容体アゴニストタンパク質を対象に投与するステップを含む。
16.項目15の方法であって、疾患または障害は:腫瘍、感染性疾患、炎症性疾患、代謝疾患、自己免疫疾患、変性疾患、アポトーシス関連疾患、および移植拒絶反応からなる群より選択される。
17.項目16の方法であって、腫瘍は固形腫瘍である。
18.項目16の方法であって、腫瘍はリンパ系腫瘍である。
19.項目16の方法であって、自己免疫疾患は、リウマチ疾患、関節疾患、またはリウマチおよび関節の疾患である。
20.項目16の方法であって、疾患または障害は、関節リウマチである。
21.項目16の方法であって、変性疾患は神経変性疾患である。
22.項目21の方法であって、神経変性疾患は多発性硬化症である。
Claims (27)
- 単鎖融合ポリペプチドを含むCD40受容体アゴニストタンパク質であって、
(i)第一の可溶性CD40Lドメイン、
(ii)第一のペプチドリンカー、
(iii)第二の可溶性CD40Lドメイン、
(iv)第二のペプチドリンカー、および
(v)第三の可溶性CD40Lドメイン、および
(vi)抗体Fcフラグメント(好ましくは、配列番号13または14に示されるアミノ酸配列または配列番号13または14のアミノ酸1〜217からなる)、
を含む、
CD40受容体アゴニストタンパク質。 - 請求項1のCD40受容体アゴニストタンパク質であって、
前記抗体Fcフラグメント(vi)は、前記の第一のCD40Lドメイン(i)のN末および/または前記の第三のCD40Lドメイン(v)のC末に位置する、
CD40受容体アゴニストタンパク質。 - 請求項1または2のCD40受容体アゴニストタンパク質であって、
前記の抗体Fcフラグメントは、前記の第三のCD40Lドメイン(v)のC末に位置する、
CD40受容体アゴニストタンパク質。 - 請求項1から3のいずれか一項のCD40受容体アゴニストタンパク質であって、
実質的に非凝集性である、
CD40受容体アゴニストタンパク質。 - 請求項1から4のいずれか一項のCD40受容体アゴニストタンパク質であって、
前記の第二および/または第三の可溶性CD40Lドメインは、N末が短縮されたドメインであり、場合により、アミノ酸配列突然変異を含む、
CD40受容体アゴニストタンパク質。 - 請求項1から4のいずれか一項のCD40受容体アゴニストタンパク質であって、
前記可溶性CD40Lドメインの少なくとも1つ、具体的には、前記可溶性CD40Lドメイン(iii)および(v)の少なくとも1つは、配列番号1に係るヒトCD40Lのアミノ酸Gln121またはIle122で始まるN末配列を有する可溶性CD40Lドメインであり、ここで、Gln121は、SerまたはGIyのような中性アミノ酸によって置換され得る、
CD40受容体アゴニストタンパク質。 - 請求項6のCD40受容体アゴニストタンパク質であって、
前記可溶性CD40Lドメインの少なくとも1つ、具体的には、前記可溶性CD40Lドメイン(iii)および(v)の少なくとも1つは、
(a)Gln121またはIle122、および
(b)(Gly/Ser)121
から選択されるN末配列を有する可溶性CD40Lドメインである、
CD40受容体アゴニストタンパク質。 - 請求項6または7のCD40受容体アゴニストタンパク質であって、
前記可溶性CD40Lドメインは、配列番号1に係るヒトCD40Lのアミノ酸Leu261で終わり、および/または、場合により、E129位、A130位、S132位、K133位、T134位、E142位、Y145位、Y146位、C178位、C194位、R200位、F201位、C218位、Q220位またはN240位に突然変異を含む、
CD40受容体アゴニストタンパク質。 - 請求項6から8のいずれか一項のCD40受容体アゴニストタンパク質であって、
前記可溶性CD40Lドメイン(i)、(iii)および(v)は、配列番号1に係るヒトCD40Lのアミノ酸121〜261からなる、
CD40受容体アゴニストタンパク質。 - 請求項1から9のいずれか一項のCD40受容体アゴニストタンパク質であって、
前記の第一および第二のペプチドリンカー(ii)および(iv)は、独立に、3〜8個のアミノ酸の長さ、具体的には、3、4、5、6、7または8個のアミノ酸の長さを有し、好ましくは、グリシン/セリンリンカーであり、場合により、グリコシル化されてよいアスパラギン残基を含む、
CD40受容体アゴニストタンパク質。 - 請求項10のCD40受容体アゴニストタンパク質であって、
前記の第一および前記の第二のペプチドリンカー(ii)および(iv)は、配列番号2に係るアミノ酸配列からなる、
CD40受容体アゴニストタンパク質。 - 請求項1から11のいずれか一項のCD40受容体アゴニストタンパク質であって、
例えば配列番号17のN末シグナルペプチドドメインをさらに含み、それはプロテアーゼ切断部位を含んでよく、および/または、認識/精製ドメイン、例えば配列番号18に係るStrep−tagを含み得るおよび/または結合し得るC末エレメントをさらに含む、
CD40受容体アゴニストタンパク質。 - 請求項1から12のいずれか一項のCD40受容体アゴニストタンパク質であって、
前記抗体Fcフラグメント(vi)は、ヒンジリンカー、好ましくは、配列番号16および19〜24のいずれか1つを介して、前記可溶性CD40Lドメイン(i)および/または(v)に融合される、
CD40受容体アゴニストタンパク質。 - 請求項1から13のいずれか一項のCD40受容体アゴニストタンパク質であって、
前記抗体Fcフラグメント(vi)は、配列番号13または14に示されるアミノ酸配列または配列番号13または14のアミノ酸1〜217からなる、
CD40受容体アゴニストタンパク質。 - 請求項1から14のいずれか一項のCD40受容体アゴニストタンパク質であって、
配列番号15および25〜35のいずれか1つのアミノ酸配列を含む、
CD40受容体アゴニストタンパク質。 - 請求項1から15のいずれか一項のCD40受容体アゴニストタンパク質であって、
配列番号27、28、29、30、32または34に記載のアミノ酸配列をそれぞれ有する2つのポリペプチドを含む、
CD40受容体アゴニストタンパク質 - 請求項16のCD40受容体アゴニストタンパク質であって、
配列番号27、28、29、30、32または34に記載のアミノ酸配列をそれぞれ含む前記の2つのポリペプチドは、それぞれのポリペプチドのシステイン残基453、459および462の間に形成される3つの鎖間ジスルフィド結合を通して共有結合される、
CD40受容体アゴニストタンパク質。 - 請求項16または17のCD40受容体アゴニストタンパク質であって、
前記ポリペプチドの147位および296位のアスパラギン残基の1つまたは複数は、Nグリコシル化される、
CD40受容体アゴニストタンパク質。 - 請求項18のCD40受容体アゴニストタンパク質であって、
前記ポリペプチドの147位および296位の両方の前記アスパラギン残基は、Nグリコシル化される、
CD40受容体アゴニストタンパク質。 - 請求項1から19のいずれか一項のCD40受容体アゴニストタンパク質であって、
前記ポリペプチド(単数または複数)は、さらに翻訳後修飾される、
CD40受容体アゴニストタンパク質。 - 請求項20のCD40受容体アゴニストタンパク質であって、
前記の翻訳後修飾は、前記N末グルタミンの、ピログルタミン酸への改変を含む、
CD40受容体アゴニストタンパク質。 - 請求項1から21のいずれか一項のCD40受容体アゴニストタンパク質をコードする核酸分子であって、
好ましくは、発現制御配列と作動可能に連結している、
核酸分子。 - 請求項22の核酸分子を含む、
発現ベクター。 - 請求項22の核酸分子または請求項23のベクターで形質転換またはトランスフェクトされた、細胞または非ヒト生物であって、
前記細胞は、例えば、原核生物細胞または真核生物細胞、好ましくは哺乳類細胞、または、より好ましくは、ヒト細胞またはチャイニーズハムスター卵巣(CHO)細胞である、
細胞または非ヒト生物。 - 医薬組成物または診断組成物であって、
活性剤として、請求項1から21のいずれか一項のCD40受容体アゴニストタンパク質、請求項22の核酸分子、または、請求項23のベクターを含む、
医薬組成物または診断組成物。 - 請求項25に記載の医薬組成物または診断組成物であって、
1つまたは複数の薬学的に許容できる担体、希釈剤、賦形剤および/またはアジュバントをさらに含む、
医薬組成物または診断組成物。 - 医薬組成物であって、
治療での使用のための、より具体的には、CD40Lの機能障害、具体的には増殖性疾患、例えば、固形またはリンパ系腫瘍のような腫瘍;感染性疾患;炎症性疾患;代謝疾患;リウマチおよび/または関節疾患のような自己免疫疾患;変性疾患、例えば、多発性硬化症のような神経変性疾患;アポトーシス関連疾患または移植拒絶反応に起因する、関連する、および/または、伴う障害の、予防および/または治療での使用のための、
請求項25または26に記載の医薬組成物。
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