JP6681834B2 - 融合タンパク質 - Google Patents
融合タンパク質 Download PDFInfo
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- JP6681834B2 JP6681834B2 JP2016543457A JP2016543457A JP6681834B2 JP 6681834 B2 JP6681834 B2 JP 6681834B2 JP 2016543457 A JP2016543457 A JP 2016543457A JP 2016543457 A JP2016543457 A JP 2016543457A JP 6681834 B2 JP6681834 B2 JP 6681834B2
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- p75ntr
- nbp
- fusion protein
- pain
- vector
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- AGDSCTQQXMDDCV-UHFFFAOYSA-M sodium;2-iodoacetate Chemical compound [Na+].[O-]C(=O)CI AGDSCTQQXMDDCV-UHFFFAOYSA-M 0.000 description 1
- 229960003855 solifenacin Drugs 0.000 description 1
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- 239000012453 solvate Substances 0.000 description 1
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- 238000010254 subcutaneous injection Methods 0.000 description 1
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- 229960001940 sulfasalazine Drugs 0.000 description 1
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- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 1
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- 229960003386 triazolam Drugs 0.000 description 1
- JOFWLTCLBGQGBO-UHFFFAOYSA-N triazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl JOFWLTCLBGQGBO-UHFFFAOYSA-N 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
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- ZEWQUBUPAILYHI-UHFFFAOYSA-N trifluoperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 ZEWQUBUPAILYHI-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
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- 230000004614 tumor growth Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- IYFNEFQTYQPVOC-UHFFFAOYSA-N udenafil Chemical compound C1=C(C=2NC=3C(CCC)=NN(C)C=3C(=O)N=2)C(OCCC)=CC=C1S(=O)(=O)NCCC1CCCN1C IYFNEFQTYQPVOC-UHFFFAOYSA-N 0.000 description 1
- 229960002004 valdecoxib Drugs 0.000 description 1
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- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 1
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- 229960003414 zomepirac Drugs 0.000 description 1
- ZXVNMYWKKDOREA-UHFFFAOYSA-N zomepirac Chemical compound C1=C(CC(O)=O)N(C)C(C(=O)C=2C=CC(Cl)=CC=2)=C1C ZXVNMYWKKDOREA-UHFFFAOYSA-N 0.000 description 1
- 229960004496 zotepine Drugs 0.000 description 1
- HDOZVRUNCMBHFH-UHFFFAOYSA-N zotepine Chemical compound CN(C)CCOC1=CC2=CC=CC=C2SC2=CC=C(Cl)C=C12 HDOZVRUNCMBHFH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70578—NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/28—Neurological disorders
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/28—Neurological disorders
- G01N2800/2807—Headache; Migraine
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/28—Neurological disorders
- G01N2800/2842—Pain, e.g. neuropathic pain, psychogenic pain
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Cell Biology (AREA)
- Immunology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Toxicology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Pain & Pain Management (AREA)
- General Chemical & Material Sciences (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Epidemiology (AREA)
Description
(a)p75NTR(NBP)部分;および
(b)免疫グロブリンFc部分。
(b)疼痛および/または疼痛の症状の予防または治療の任意の1または複数のための、または、疼痛および/または疼痛の症状の発達または進行を改善する、制御する、発生を低減させる、または、遅らせるための、有効量の前記p75NTR(NBP)−Fc融合タンパク質、核酸分子、ベクターまたは医薬組成物の、個体への投与に関する説明書。
(a)p75NTR(NBP)部分;および
(b)免疫グロブリンFc部分。
(b)約0.1nM〜約50nMの間の結合親和性での、NGF、BDNF、NT3またはNT4/5のいずれかに対する結合親和性、
(c)ニューロトロフィンNGF、NT3、BDNFおよびNT4/5、好ましくはヒトNGF、NT3、BDNFおよびNT4/5のそれぞれに対する結合能力。
(a)急性疼痛および/または自発痛、
(b)慢性疼痛およびまたは進行中の疼痛、
(c)関節痛、変形性関節症または関節リウマチから生じる疼痛、炎症性腸疾患、乾癬および湿疹から生じる疼痛のいずれかを含む炎症性疼痛、
(d)侵害受容性疼痛、
(e)有痛性糖尿病性神経障害または帯状疱疹後神経痛と関連する疼痛を含む、神経障害性疼痛
(f)痛覚過敏、
(g)アロディニア、
(h)中枢痛、中枢性卒中後痛、多発性硬化症から生じる疼痛、脊髄損傷から生じる疼痛、またはパーキンソン病またはてんかんから生じる疼痛、
(i)癌性疼痛、
(j)術後疼痛、
(k)消化性内臓痛および非消化性内臓痛を含む内臓痛、胃腸(GI)障害に起因する疼痛、機能性腸疾患(FBD)から生じる疼痛、炎症性腸疾患(IBD)から生じる疼痛、月経困難、骨盤痛、膀胱炎、間質性膀胱炎または膵炎から生じる疼痛、
(l)筋骨格痛、筋肉痛、線維筋痛、脊椎炎、血清陰性(非リウマチ性)関節障害、関節外リウマチ、ジストロフィン異常症、グリコーゲン分解、多発性筋炎、化膿性筋炎、
(m)心臓または血管性疼痛、狭心症、心筋梗塞、僧帽弁狭窄、心膜炎、レイノー現象、浮腫性硬化症(scleredoma)、浮腫性硬化症または骨格筋虚血に起因する疼痛、
(n)片頭痛、前兆を伴う片頭痛、前兆を伴わない片頭痛、群発頭痛、緊張型頭痛を含む、頭痛、
(o)歯痛、顎関節筋膜痛または耳鳴りを含む、口腔顔面痛、または、
(p)背痛、滑液包炎、月経痛、片頭痛、関連痛、三叉神経痛、超増感、脊椎の外傷および/または変性または脳卒中から生じる疼痛
・オピオイド鎮痛薬、例えばモルヒネ、ヘロイン、ヒドロモルフォン、オキシモルフォン、レボルファノール、レバロルファン、メタドン、メペリジン、フェンタニル、コカイン、コデイン、ジヒドロコデイン、オキシコドン、ヒドロコドン、プロポキシフェン、ナルメフェン、ナロルフィン、ナロキソン、ナルトレキソン、ブプレノルフィン、ブトルファノール、ナルブフィンまたはペンタゾシン;
・非ステロイド性抗炎症薬(NSAID)、例えばアスピリン、ジクロフェナク、ジフルシナル(diflusinal)、エトドラク、フェンブフェン、フェノプロフェン、フルフェニサル、フルルビプロフェン、イブプロフェン、インドメタシン、ケトプロフェン、ケトロラック、メクロフェナム酸、メフェナム酸、メロキシカム、ナブメトン、ナプロキセン、ニメスリド、ニトロフルルビプロフェン、オルサラジン、オキサプロジン、フェニルブタゾン、ピロキシカム、スルファサラジン、スリンダク、トルメチンまたはゾメピラック;
・バルビツレート鎮静剤、例えばアモバルビタール、アプロバルビタール、ブタバルビタール、ブタルビタール(butabital)、メホバルビタール、メタルビタール、メトヘキシタール、ペントバルビタール、フェノバルビタール(phenobartital)、セコバルビタール、タルブタール、チアミラール(theamylal)またはチオペンタール;
・鎮静作用を有するベンゾジアゼピン、例えばクロルジアゼポキシド、クロラゼペート、ジアゼパム、フルラゼパム、ロラゼパム、オキサゼパム、テマゼパムまたはトリアゾラム;
・鎮静作用を有するH1拮抗薬、例えばジフェンヒドラミン、ピリラミン、プロメタジン、クロルフェニラミンまたはクロルシクリジン;
・鎮静剤、例えばグルテチミド、メプロバメート、メタカロンまたはジクロラルフェナゾン;
・骨格筋弛緩薬、例えばバクロフェン、カリソプロドール、クロルゾキサゾン、シクロベンザプリン、メトカルバモールまたはオルフレナジン;
・NMDA受容体拮抗薬、例えばデキストロメトルファン((+)−3−ヒドロキシ−N−メチルモルフィナン)またはその代謝物デキストロルファン((+)−3−ヒドロキシ−N−メチルモルフィナン)、ケタミン、メマンチン、ピロロキノリンキニン、シス−4−(ホスホノメチル)−2−ピペリジンカルボン酸、ブジピン、EN−3231(MorphiDex(登録商標)、モルヒネおよびデキストロメトルファンの組み合わせ製剤)、トピラマート、ネラメキサン、または、NR2B拮抗薬を含むペルジンホテル、例えばイフェンプロジル、トラキソプロジルまたは(−)−(R)−6−{2−[4−(3−フルオロフェニル)−4−ヒドロキシ−1−ピペリジニル]−1−ヒドロキシエチル−3,4−ジヒドロ−2(1H)−キノリノン;
・α−アドレナリン作用薬、例えばドキサゾシン、タムスロシン、クロニジン、グアンファシン、デキスメタトミジン(dexmetatomidine)、モダフィニル、または4−アミノ−6,7−ジメトキシ−2−(5−メタン−スルホンアミド−1,2,3,4−テトラヒドロイソキノール−2−イル)−5−(2−ピリジル)キナゾリン;
・三環系抗うつ薬、例えばデシプラミン、イミプラミン、アミトリプチリンまたはノルトリプチリン;
・抗痙攣薬、例えばカルバマゼピン、ラモトリジン、トピラマート(topiratmate)またはバルプロエート;
・タキキニン(NK)拮抗薬、特にNK−3、NK−2またはNK−1拮抗薬、例えば(αR,9R)−7−[3,5−ビス(トリフルオロメチル)ベンジル]−8,9,10,11−テトラヒドロ−9−メチル−5−(4−メチルフェニル)−7H−[1,4]ジアゾシノ[2,1−g][1,7]−ナフチリジン−6−13−ジオン(TAK−637)、5−[[(2R,3S)−2−[(1R)−1−[3,5−ビス(トリフルオロメチル)フェニル]エトキシ−3−(4−フルオロフェニル)−4−モルホリニル]−メチル]−1,2−ジヒドロ−3H−1,2,4−トリアゾル−3−オン(MK−869)、アプレピタント、ラネピタント、ダピタントまたは3−[[2−メトキシ−5−(トリフルオロメトキシ)フェニル]−メチルアミノ]−2−フェニルピペリジン(2S,3S);
・ムスカリン拮抗薬、例えばオキシブチニン、トルテロジン、プロピベリン、塩化トロスピウム(tropsium chloride)、ダリフェナシン、ソリフェナシン、テミベリンおよびイプラトロピウム;
・COX−2選択的阻害剤、例えばセレコキシブ、ロフェコキシブ、パレコキシブ、バルデコキシブ、デラコキシブ、エトリコキシブ、またはルミラコキシブ;
・コールタール鎮痛剤、特にパラセタモール;
・神経遮断薬、例えばドロペリドール、クロルプロマジン、ハロペリドール、ペルフェナジン、チオリダジン、メソリダジン、トリフルオペラジン、フルフェナジン、クロザピン、オランザピン、リスペリドン、ジプラシドン、クエチアピン、セルチンドール、アリピプラゾール、ソネピプラゾール、ブロナンセリン、イロペリドン、ペロスピロン、ラクロプリド、ゾテピン、ビフェプルノックス、アセナピン、ルラシドン、アミスルプリド、バラペリドン、パリンドール、エプリバンセリン、オサネタント、リモナバン、メクリネルタント、Miraxion(登録商標)またはサリゾタン;
・バニロイド受容体アゴニスト(例えばレシニフェラトキシン)または拮抗薬(例えばカプサゼピン);
・β−アドレナリン作用薬、例えばプロプラノロール;
・局部麻酔薬、例えばメキシレチン;
・コルチコステロイド、例えばデキサメタゾン;
・5−HT受容体アゴニストまたは拮抗薬、特に5−HT1B/1Dアゴニスト、例えばエレトリプタン、スマトリプタン、ナラトリプタン、ゾルミトリプタンまたはリザトリプタン;
・5−HT2A受容体拮抗薬、例えばR(+)−α−(2,3−ジメトキシ−フェニル)−1−[2−(4−フルオロフェニルエチル)]−4−ピペリジンメタノール(MDL−100907);
・コリン作用性(ニコチン性)鎮痛剤、例えばイスプロニクリン(TC−1734)、(E)−N−メチル−4−(3−ピリジニル)−3−ブテン−1−アミン(RJR−2403)、(R)−5−(2−アゼチジニルメトキシ)−2−クロロピリジン(ABT−594)またはニコチン;
・トラマドール(登録商標);
・PDEV阻害剤、例えば5−[2−エトキシ−5−(4−メチル−1−ピペラジニル−スルホニル)フェニル]−1−メチル−3−n−プロピル−1,6−ジヒドロ−7H−ピラゾロ[4,3−d]ピリミジン−7−オン(シルデナフィル)、(6R,12aR)−2,3,6,7,12,12a−ヘキサヒドロ−2−メチル−6−(3,4−メチレンジオキシフェニル)−ピラジノ[2’,1’:6,1]−ピリド[3,4−b]インドール−1,4−ジオン(IC−351またはタダラフィル)、2−[2−エトキシ−5−(4−エチル−ピペラジン−1−イル−1−スルホニル)−フェニル]−5−メチル−7−プロピル−3H−イミダゾ[5,1−f][1,2,4]トリアジン−4−オン(バルデナフィル)、5−(5−アセチル−2−ブトキシ−3−ピリジニル)−3−エチル−2−(1−エチル−3−アゼチジニル)−2,6−ジヒドロ−7H−ピラゾロ[4,3−d]ピリミジン−7−オン、5−(5−アセチル−2−プロポキシ−3−ピリジニル)−3−エチル−2−(1−イソプロピル−3−アゼチジニル)−2,6−ジヒドロ−7H−ピラゾロ[4,3−d]ピリミジン−7−オン、5−[2−エトキシ−5−(4−エチルピペラジン−1−イルスルホニル)ピリジン−3−イル]−3−エチル−2−[2−メトキシエチル]−2,6−ジヒドロ−7H−ピラゾロ[4,3−d]ピリミジン−7−オン、4−[(3−クロロ−4−メトキシベンジル)アミノ]−2−[(2S)−2−(ヒドロキシメチル)ピロリジン−1−イル]−N−(ピリミジン−2−イルメチル)ピリミジン−5−カルボキサミド、3−(1−メチル−7−オキソ−3−プロピル−6,7−ジヒドロ−1H−ピラゾロ[4,3−d]ピリミジン−5−イル)−N−[2−(1−メチルピロリジン−2−イル)エチル]−4−プロポキシベンゼンスルホンアミド;
・カンナビノイド;
・代謝型グルタミン酸受容体サブタイプ1(mGluR1)拮抗薬;
・セロトニン再取り込み阻害剤、例えばセルトラリン、セルトラリン代謝物デメチルセルトラリン、フルオキセチン、ノルフルオキセチン(フルオキセチンデスメチル代謝物)、フルボキサミン、パロキセチン、シタロプラム、シタロプラム代謝物デスメチルシタロプラム、エスシタロプラム、d,l−フェンフルラミン、フェモキセチン、イフォキセチン、シアノドチエピン、リトキセチン、ダポキセチン、ネファゾドン、セリクラミンおよびトラゾドン;
・ノルアドレナリン(ノルエピネフリン)再取り込み阻害剤、例えばマプロチリン、ロフェプラミン、ミルタザピン(mirtazepine)、オキサプロチリン、フェゾラミン、トモキセチン、ミアンセリン、ブプロプリオン、ブプロプリオン代謝物ヒドロキシブプロプリオン、ノミフェンシンおよびビロキサジン(Vivalan(登録商標))、特に選択的ノルアドレナリン再取り込み阻害剤、例えばレボキセチン、特に(S,S)−レボキセチン;
・二重セロトニン−ノルアドレナリン再取り込み阻害剤、例えばベンラファキシン、ベンラファキシン代謝物O−デスメチルベンラファキシン、クロミプラミン、クロミプラミン代謝物デスメチルクロミプラミン、デュロキセチン、ミルナシプランおよびイミプラミン;
・誘導型一酸化窒素合成酵素(iNOS)阻害剤、例えばS−[2−[(1−イミノエチル)アミノ]エチル]−L−ホモシステイン、S−[2−[(1−イミノエチル)−アミノ]エチル]−4,4−ジオキソ−L−システイン、S−[2−[(1−イミノエチル)アミノ]エチル]−2−メチル−L−システイン、(2S,5Z)−2−アミノ−2−メチル−7−[(1−イミノエチル)アミノ]−5−ヘプテン酸、2−[[(1R,3S)−3−アミノ−4−ヒドロキシ−1−(5−チアゾリル)−ブチル]チオ]−5−クロロ−3−ピリジンカルボニトリル;2−[[(1R,3S)−3−アミノ−4−ヒドロキシ−1−(5−チアゾリル)ブチル]チオ]−4−クロロベンゾニトリル、(2S,4R)−2−アミノ−4−[[2−クロロ−5−(トリフルオロメチル)フェニル]チオ]−5−チアゾールブタノール、2−[[(1R,3S)−3−アミノ−4−ヒドロキシ−1−(5−チアゾリル)ブチル]チオ]−6−(トリフルオロメチル)−3ピリジンカルボニトリル、2−[[(1R,3S)−3−アミノ−4−ヒドロキシ−1−(5−チアゾリル)ブチル]チオ]−5−クロロベンゾニトリル、N−[4−[2−(3−クロロベンジルアミノ)エチル]フェニル]チオフェン−2−カルボキサミジン、またはグアニジノエチルジスルフィド;
・アセチルコリンエステラーゼ阻害剤、例えばドネペジル;
・プロスタグランジンE2サブタイプ4(EP4)拮抗薬、例えばN−[({2−[4−(2−エチル−4,6−ジメチル−1H−イミダゾ[4,5−c]ピリジン−1−イル)フェニル]エチル}アミノ)−カルボニル]−4−メチルベンゼンスルホンアミドまたは4−[(1S)−1−({[5−クロロ−2−(3−フルオロフェノキシ)ピリジン−3−イル]カルボニル}アミノ)エチル]安息香酸;
・ロイコトリエンB4拮抗薬;例えば1−(3−ビフェニル−4−イルメチル−4−ヒドロキシ−クロマン−7−イル)−シクロペンタンカルボン酸(CP−105696)、5−[2−(2−カルボキシエチル)−3−[6−(4−メトキシフェニル)−5E−ヘキセニル]オキシフェノキシ]−吉草酸(ONO−4057)またはDPC−11870、
・5−リポキシゲナーゼ阻害剤、例えばジレウトン、6−[(3−フルオロ−5−[4−メトキシ−3,4,5,6−テトラヒドロ−2H−ピラン−4−イル])フェノキシ−メチル]−1−メチル−2−キノロン(ZD−2138)、または2,3,5−トリメチル−6−(3−ピリジルメチル)、1,4−ベンゾキノン(CV−6504);
・ナトリウムチャンネルブロッカー、例えばリドカイン;または
・5−HT3拮抗薬、例えばオンダンセトロン;
および、それらの薬学的に許容できる塩および溶媒和物。
(a)第一または第二の態様またはそれらの好ましい実施態様に係るp75NTR(NBP)−Fc融合タンパク質、または、第三および第四の態様に係る核酸分子またはベクター、または第八の態様の医薬組成物;および
(b)疼痛および/または疼痛の症状の予防または治療の任意の1または複数のための、または、疼痛および/または疼痛の症状の発達または進行を改善する、制御する、発生を低減させる、または、遅らせるための、有効量の前記p75NTR(NBP)−Fc融合タンパク質、核酸分子、ベクターまたは医薬組成物の、個体への投与に関する説明書。
p75−NTR Fc−融合タンパク質のFc部分の特異的なアロタイプは、IgG pConベクターIgGzaであった(上記参照)。
現在のところ利用可能な治療的Fc−融合タンパク質13個に関するタンパク質配列を、United States Adopted Names(USAN)ウェブサイト(http://www.ama−assn.org/ama/pub/physician−resources/medical−science/)から取得した。可能な場合は、タンパク質配列を相互参照し、オンラインの特許情報ウェブサイトのような他のオンラインリソースに対して確認した。研究グレードのFc−融合タンパク質に関するタンパク質配列を、オンラインリソースを用いて他の市販の供給元から得た。
Epibase(商標)免疫プロファイリングを、Globalセット中の85のHLAクラスIIアロタイプを用いて、Fc−融合タンパク質変異に関して行なった。
提案されるp75−NTR Fc−融合タンパク質の構造モデルは、Lonzaのモデリングプラットフォームを用いて生産した。p75−NTRおよびFc部分に関する候補の構造テンプレート断片は、社内の抗体データベースの塩基およびProtein Data Bank(PDB)の両方から、それらの配列同一性、および、分解能(Angstrom(A))のようなテンプレート構造の定性的結晶学的方法に関して、スコアを付け、ランクを付け、選択した。
p75−NTR Fc−融合タンパク質の3つのリンカー変異を設計した。最終のFc−融合タンパク質内のp75−NTR領域における可動性を維持する試み、および、αおよびγセクレターゼに関する不要な切断部位を避ける望みの、設計制約を考慮して、細胞外p75−NTR配列をG237位でトランケートした。元のp75NTR−Fc配列1(配列番号1)を、A250位でトランケートした。αセクレターゼ切断部位は、241−242位と244−245位との間のp75−NTRの細胞外部分に同定されていて(Zampieri et al.2005 J Biol Chem.280,14563−71)、推定のγセクレターゼ切断部位は、282位の領域内の配列ホモロジーにより推測されている。配列1のPK/PDから、配列1(配列番号1)のPKおよび生物学的活性は、配列3(配列番号3)と比較して有意に低下していることが明らかである。これらの実験から、αおよびγセクレターゼの位置(sties)は、インビボ活性の低下に寄与することが結論付けられた。
・Gx−可動性
・A(EAAAK)XA−剛性(配列番号14)
・(PA)x−剛性
実験ではBiacoreチップを調製し、フローセル1および2にプロテインAをアミン結合した。捕捉されたp75−Fcに結合するNGFの1サイクルのカイネティクスを測定した。
融合タンパク質−NGF結合データを、Biacore T200評価ソフトウェアv1を用いて以下の方法で分析した:
両方の融合タンパク質に関する、NGFへの結合プロファイルは、400pM(配列番号1)および360pM(配列番号3)であった。これらの試験から、配列3(配列番号3)は、配列1(配列番号1)よりも、NGFに関して高い親和性を有することが明らかであった。
体重120〜150g(到着時)の雄Wistarラット(Charles River UK)を、この試験に用いた。各動物は、到着時に検査し、外見上健康であるようであった。それらを2つのケージに無作為に割り当て、各ラットは、尾に押した入れ墨により固有の識別番号が割り当てられた。0日目の試験開始前に少なくとも10日間、動物を動物ユニットに慣れさせた。
ラットを38℃に設定された加温ボックス内に、最低5分間だが10分よりも長くない時間置いて、尾静脈の血管拡張を誘導して出血を促進させた。ラットを適切なサイズの保定器(restrainer)内に監禁し、滅菌23Gニードルを用いて尾静脈を刺し、CB300マイクロベットチューブ(Sarstedt 16.444)へ血液を流し入れた。最低100μlおよび最高300μlの血液を、全ての時点において各ラットから回収した。繰り返しのサンプリングのために異なる部位を選択し、ラットは手順全体を通じて落ち着いていた。ラットは、繰り返しの血液サンプリングに良好に耐容し、傷の所見はなかった。回収した血液を用いて血漿を調製した。
末端血液サンプルを、テルモ1mlシリンジおよび23Gニードルを用いたイソフルラン麻酔薬の下で、心臓穿刺により採取した。それから動物を頚椎脱臼により殺した。回収した血液を用いて血清を調製した。
尾静脈由来の血液を含むマイクロベットを穏やかに数回反転させて、抗凝固剤(カリウム−EDTA)との良好な混合を確実にした。それから、2700×gで10分間遠心分離する前にチューブを氷上に置き、血漿をポリプロピレンチューブ中に等分した(1アリコートのみ調製された2日目を除き、各時点について動物あたり2アリコート)。全ての血漿サンプルを直ちに凍らせて、必要になるまで−80℃で保管した。
15日目に心臓穿刺により回収した血液を、ポリプロピレンチューブ内で室温にて2〜3時間(最大3時間)凝固させた。それから、凝固血液を4000×gで5分間遠心分離し、血清をポリプロピレンチューブ中に等分した(動物あたり2アリコート)。血清サンプルを直ちに凍らせて、−80℃で保管した。
無傷のp75NTR−Fcの全血漿濃度を決定する手段として、p75NTR(R and D systems)およびIgG1 Fc ELISA(R and D systems)に関して改変ELISAを用いて、血漿p75NTR−Fcを測定した。
配列1(配列番号1)p75NTR−Fcのαおよびγセクレターゼ切断部位を取り除くことにより、配列3(配列番号3)と比較して、これはp75NTR−FcのPKを有意に改善し、続いて、慢性の治療後の疼痛スコアにより評価される有効性を改善した。配列1(配列番号1)p75NTR−Fcのαおよびγセクレターゼ切断部位は、この化合物を、疼痛およびニューロトロフィン生物学に関連する他の病理(例えば呼吸器疾患)の治療のためのインビボ薬として不適切にさせた。
この試験の目的は、ラットでの、ヨード酢酸一ナトリウム(MIA)で誘導される変形性関節症(OA)における、p75NTR−Fc(配列番号3)の慢性暴露の、疼痛有効性に対する効果を調べることであった。
MIAを0.3mg/50μlのETF−PBS(それぞれの関節内注入に用いられる容量)で調製した(6mg/mlストック溶液と同等である)。302mgのMIAを量り取り、50.3mlのETF−PBS中に溶解させた。MIAを1日前もって調製し、必要になるまで暗所にて4℃で保管した。
体重110〜130g(到着時)の44匹の雄Wistarラット(Charles River UK)を、この試験に用いた。各動物は、到着時に検査し、外見上健康であるようであった。それらを2つのケージに無作為に割り当て、各ラットは、尾に押した入れ墨により固有の識別番号が割り当てられた。
試験設計は、5グループの動物が存在するようにした:コントロールヒト抗体(n=6)、0.3mg/kgのp75NTR−Fc(配列番号3)、1mg/kgのp75NTR−Fc(配列番号3)、3mg/kgのp75NTR−Fc(配列番号3)および3mg/kgのPG−007(ファイザーのタネズマブのバイオシミラー抗−NGF抗体)。
試験の開始前にラットを計量し、各群内の動物の平均体重がほぼ等しくなるように、2つの各ケージのラットを無作為に処置群に割り当てた。特定の処置群に割り当てられた各ラットに加え、各ラットの左右いずれかの膝にMIAを注入するように(各ラットの逆側の膝はETFPBSを注入した)、さらなる無作為化も行なった。処置群の割り当ておよび各ラットに関してどちらの膝が治療を受けるかは、MacのMicrosoft Excel(Version 14.1.1)の乱数発生器を用いて出した。動物と接触のない職員が、無作為化手順および割り当てを行なった。
膝の関節内注入
全てのラットを、Boyles Apparatusを用いたイソフルランの吸入により麻酔した。各動物の両膝上の毛をクリップで留めて、両膝をエタノールで拭いた。27Gニードルを付けた0.5ml滅菌Becton Dickinson Micro−Fineインスリンシリンジを用いて、ETF−PBS中0.3mgのMIAまたはETF−PBSのみのいずれかを50μl、膝蓋下靭帯を通して各膝に注入した。
各動物に関して、無能力試験器(Linton Instruments,U.K.)を用いて左右後肢の荷重負荷を測定することにより自発痛を判定した。ラットを、それらの後脚が別々のセンサー上に座るように、無能力試験器上の適切なサイズのパースペックス動物ボックス中に置いた。ボックスのサイズは、ラットが押し潰されずに快適に座ることを可能にしたが、同様に、方向転換する十分な空間を与えなかった。ラットが安定して落ち着いた時点で、各肢の荷重負荷を5秒にわたり記録し、両後肢によってもたらされる力(グラム)の平均を記録した。後足の荷重配分を各時点で各ラットに関して5回判定し(その妥当性を以前に我々は示している)、5回の測定値の平均を計算した。右肢の荷重を両後肢に関する合計荷重で割ることにより、個々の荷重負荷データを荷重配分に変換した。
無能力試験器を用いて自発痛を評価して、後肢を通じた荷重の配分を測定した。評価はベースラインで、MIAでの処置の3週後に行なった。
文献および従来技術から、低親和性p75ニューロトロフィン受容体は、約1nMの全てのニューロトロフィンに関して同様の親和性を有することが一般に認められている(Ichim etal.,2012 Exp Cell Res 318(11):1221−8)。さらに、Apollo Life Sciences(Molecules and chimeric molecules thereof US 20090232808 A1)の従来技術は、個々のニューロトロフィンに関するp75ニューロトロフィン受容体の親和性の類似性をさらに挙げている。「NGFRは、28アミノ酸のシグナルペプチドからなる427アミノ酸の糖タンパク質として合成されるI型膜タンパク質である。NGFRは、全てのニューロトロフィンに同等の親和性で結合する。」
Claims (13)
- p75NTRニューロトロフィン結合タンパク質(NBP)−Fc融合タンパク質であって:
(a)p75NTR(NBP)部分;および
(b)免疫グロブリンFc部分、
含み、
ここで、
前記p75NTR(NBP)−Fc融合タンパク質は、配列番号3に示すアミノ酸配列を含むか、またはそれからなる、または、
前記p75NTR(NBP)−Fc融合タンパク質は、配列番号15に示すアミノ酸配列を含むか、またはそれからなる、
p75NTR(NBP)−Fc融合タンパク質。 - 請求項1に記載のp75NTR(NBP)−Fc融合タンパク質であって、
前記p75NTR(NBP)はヒトp75NTR(NBP)である、
p75NTR(NBP)−Fc融合タンパク質。 - 請求項1または2に記載のp75NTR(NBP)−Fc融合タンパク質であって、
前記FcはヒトFcである、
p75NTR(NBP)−Fc融合タンパク質。 - 請求項1から3のいずれか一項に記載のp75NTR(NBP)−Fc融合タンパク質であって、
前記p75NTR(NBP)は、NGF、BDNF、NT3またはNT4/5のいずれかに、20℃での表面プラズモン共鳴により測定すると、0.01nM〜50nMの結合親和性(Kd)で結合する、
p75NTR(NBP)−Fc融合タンパク質。 - 請求項1から4のいずれか一項に記載のp75NTR(NBP)−Fc融合タンパク質であって、
疼痛の治療での使用のための、
p75NTR(NBP)−Fc融合タンパク質。 - 請求項1から5のいずれかに記載のp75NTR(NBP)−Fc融合タンパク質をコードする核酸分子であって、
場合により、シグナル配列をコードするものをさらに含む、
核酸分子。 - 細胞(場合により哺乳類の細胞)をトランスフェクトするための複製可能な発現ベクターであって、
前記ベクターは請求項6の核酸分子を含む、
複製可能な発現ベクター。 - 請求項7の複製可能な発現ベクターであって、
前記ベクターはウイルスベクターである、
複製可能な発現ベクター。 - 請求項6の核酸分子を保有する、
宿主細胞。 - 請求項6に記載の核酸分子、または、請求項7または8のいずれかに記載のベクターであって、
疼痛の治療での使用のための、
核酸分子またはベクター。 - 請求項1から4または請求項5のいずれか一項に記載のp75NTR(NBP)−Fc融合タンパク質、または、請求項6から8のいずれか一項に記載の核酸またはベクターであって、
前記のp75NTR(NBP)−Fc融合タンパク質、または、核酸分子またはベクターは、第二の薬理学的に活性の化合物と組み合わせて、別々に、連続して、または同時に併用するためのものである、
p75NTR(NBP)−Fc融合タンパク質、または、核酸またはベクター。 - 医薬組成物であって、
請求項1から4または請求項5のいずれか一項に記載のp75NTR(NBP)−Fc融合タンパク質または請求項7から10に記載の核酸分子またはベクター、および、薬学的に許容できる担体および/または賦形剤を含む、
医薬組成物。 - (a)請求項1から4または請求項5のいずれか一項に記載のp75NTR(NBP)−Fc融合タンパク質、または、請求項6から10に記載の核酸分子またはベクター、;および
(b)疼痛の予防または治療の任意の1または複数のための、または、疼痛の発達または進行を改善する、制御する、発生を低減させる、または、遅らせるための、有効量の前記p75NTR(NBP)−Fc融合タンパク質、核酸分子、ベクターまたは医薬組成物の、個体への投与に関する説明書
を含む、
キット。
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