TW200526246A - Medicament comprising inhibitors of long pentraxin PTX3 - Google Patents

Medicament comprising inhibitors of long pentraxin PTX3 Download PDF

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TW200526246A
TW200526246A TW093137054A TW93137054A TW200526246A TW 200526246 A TW200526246 A TW 200526246A TW 093137054 A TW093137054 A TW 093137054A TW 93137054 A TW93137054 A TW 93137054A TW 200526246 A TW200526246 A TW 200526246A
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arthritis
ptx3
patent application
disease
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Barbara Bottazzi
Paolo Carminati
Cecilia Garlanda
Alberto Mantovani
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Defiante Farmaceutica Lda
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Description

200526246 (1) 九、發明說明 【發明所屬之技術領域】 本文所述本發明係有關長賓特辛PTX3的抑制劑對於 製備治療自體免疫性疾病與骨骼和軟骨的退化疾病所用藥 •劑之用途。 【先前技術】 PTX3爲一種糖蛋白，能夠自然地自己組織或由二硫 化橋聯維持在一起的同元十體物結構（homodecameric structure )，其可在多種細胞類型內表現（Bottazzi，et al·，J. Biol. Chem·，1997; 272: 32817-32823)，特別是 在暴露於炎性細胞介質間白素1 b e t a ( I L — 1 b e t a )與腫 瘤壞死因子a ( TNF — a )之後於單核型吞噬物細胞和內 皮細胞內表現。 PTX3包括二個結構功能部位，一爲與任何已知分子 不相關的N -端，及另一爲類似於短賓特辛例如C -反應 性蛋白（CRP )的C 一端。於人類PTX3 ( hPTX3 )與動物 PTX3之間有實質的相似性存在。 有關賓特辛的總評，可參看 H. Gewurz， et al.， Current Opinion in Immunology, 1995，7 ： 54 — 64 o 重組型PTX3與由初級細胞（如纖維母細胞，內皮細 胞和天賦免疫細胞）所表現的PTX3兩者之間都是主要組 織成爲由二硫化橋聯所穩定化的十體物結構體。PTX 3的 單一單體物具有約4 5 k D a的分子量，可從該十體物型蛋白 200526246 (2) 質透過二硫化橋聯的還原接著單體物間交互作用中涉及的 經還原本胱胺酸烷基化而得而得或透過彼等的部位特異性 突變生成而得（Battazzi，et al·，J· Biol. Chem” 1997; 272 :3 2 8 1 7 - 3 2823 ) ° 對於患有風濕性關節炎的病人所作的最近硏究顯示出 在滑液內 PTX3表現水平有明顯的增力日。此增加的 PTX3 表現關聯於此疾病特性中的炎性程序（Lucchetti, et al·， Clin. Exp. Immunol. 2000; 1 1 9: 1 96-202 ) 0 WO 0 3 /0 8 63 8 0述及PTX3基因表現抑制劑對於自體免 疫性疾病，包括風濕性關節炎的治療之用途。 WO 0 3 /0 863 8 0與本發明不同之處在於其所面對者爲 相對於本發明中所述化合物和抑制方法爲完全不同的化合 物與完全不同的抑制方法之用途。 事實上，於本專利申請中，係述及能夠直接抑制蛋白 質（PTX3 )生物學活性物的PTX3拮抗齊U。 諳於此技者都熟悉下述事實，亦即用小分子來調節（ 以選擇性方式）基因表現，例如不改變發炎所涉及的其他 基因之表現者，如在WO 03 /0 8 63 8 0中所槪述者，可能爲 困難者。再者，對於在重要生物學功能上起基本作用的蛋 白質之表現，在基因層次上給予抑制也可能促成非所欲之 效應，例如，對於感染和生殖力的敏感性之增加。 於醫學領域中，因而對於能夠作爲P TX 3拮抗劑的其 他抑制劑（彼等可用來根據本發明治療疾病）之可取得性 保持著強烈感知之需求。 -6- 200526246 (3) 【發明內容】 頃發現PTX3的抑制劑或拮抗劑可用來預防和治療自 體免疫性疾病與骼和軟骨的退化性疾病。 本發明PTX3抑制劑的一非限制性例子爲單株或多株 抗一 PTX3抗體，而本發明PTX3拮抗劑的一非限制性例子 爲單體型PTX3或其肽或肽模擬性衍生物。 本發明的目標因而爲能夠阻抗長賓特辛P TX 3所具生 物學活性的長寡特辛PTX3之抑制劑或拮抗劑對於因爲製 備治療選自下列所構成的群組中之自體免疫性疾病所用藥 劑之用途：系統性紅斑狼瘡（S LE )、多發性硬化（MS ) 、關節炎、糖尿病、甲狀腺炎、溶血性貧血、萎縮性睪九 炎、Good pasture氏病、自體免疫性視網膜病、自體免疫 性血小板減少症、重症肌無力、原發性膽硬化、慢性攻擊 性肝炎、漬瘍性結腸炎、皮炎、慢性血管球性腎炎、 SjSgren氏徵候群、Reiter氏徵候群、肌炎、系統性硬化 及多關節炎；及用爲製備治療選自下列所構成的群組中之 退化性骨骼和軟骨所用藥劑之用途：骨關節炎；骨關節病 ;關節退化病；膠原缺乏；具有軟骨內軟化的特徵之軟骨 或骨骼疾病；原發性關節炎，包括，例如，風濕性關節炎 '幼年型關節炎、未分化型慢性關節炎；和多關節炎；自 體免疫源的繼發性關節炎，包括，例如，系統性紅斑狼瘡 、牛皮癬性關節炎、Crohn氏病關節炎；代謝不全性來源 之關節炎，包括，例如，尿酸一鈉關節病、焦磷酸鹽關節 >7- 200526246 (4) 病、草酸鈣關節病；傳染性關節炎、因骨質疏鬆所致關節 炎、無菌性骨壞死、良性和惡性骨腫瘤。 【實施方式】 發明詳細說明 ”長賓特辛PTX3抑制劑”意指不論其天然（人類或動 物），重組或合成來源爲何，能夠結合P TX 3且阻抗其生 物學活性的任何單株或多株抗體。 本發明單株抗體製備之一例子爲Godine, J. W., 1986, 在 Monoclonal Antibodies: Principle and Practice.
Academic Press，San Diego中所述及者，而本發明多株抗 體製備之一例子爲 Harlow E. and Lane D·，在 Antibodies: A Laboratory Manual. Cold Spring Harbor Laboratory， 1988; Cold Spring Harbor，NY 中所述者。 ’’單體物型賓特辛”意指不論其天然（人類或動物）， 重組合成來源的任何單體物型賓特辛。 ’’單體物型賓特辛的衍生物”意指該單體物型賓特辛的 載有至少一突變且保持著選擇性抑制P TX 3活性的官能能 力之官能類似物’或指能夠模擬p TX 3所具線型或構型功 能部位且保持著選擇性抑制PTX3活性的官能能力之肽或 肽模擬性類似物。 較佳的單體物型賓特辛之類型爲人類單體物型賓特辛 ，其序列載於WO 99/32516之中。 與PTX3異常性活化相關的自體免疫性疾病爲包括在 -8 - 200526246 (5) 下列所構成的群組之中者：系統性紅斑狼瘡（SLE )、多 發性硬化（M S )、關節炎、糖尿病、甲狀腺炎、溶血性 貧血、萎縮性睪九炎、Good pasture氏病、自體免疫性視 網膜病、自體免疫性血小板減少症、重症肌無力、原發性 膽硬化、慢性攻擊性肝炎、潰瘍性結腸炎、皮炎、慢性血 管球性腎炎、Sj0gren氏徵候群、Reiter氏徵候群、肌炎 、系統性硬化及多關節炎。 與P T X 3異當性活化相關的退化性骨和軟骨疾病爲包 括在下列所構成的群組之中者：骨關節炎；骨關節病；關 節退化病；膠原缺乏；具有軟骨內軟化的特徵之軟骨或骨 黯疾病；原發性關節炎，包括，例如，風濕性關節炎、幼 年型關節炎、未分化型慢性關節炎；和多關節炎；自體免 疫源的繼發性關節炎，包括，例如，系統性紅斑狼，瘡、牛 皮癬性關節炎、Crohn氏病關節炎；代謝不全性來源之關 節炎’包括，例如，尿酸—鈉關節病、焦磷酸鹽關節病、 草酸錦關節病；傳染性關節炎、因骨質疏鬆所致關節炎、 無菌性骨壞死、良性和惡性骨腫瘤。 下面的實施例進一步闡述本發明。 實施例1 於一膠原誘發關節炎（CIA)小鼠模型中使用ρτΧ3 — 缺乏性小鼠（Campbell，et al·，Eur. j. Immunol，2〇〇〇; 30 1 5 6 8 7 5 )。貫驗的目標爲評估p τ χ 3 — / 一小鼠對於關 節炎表現型的透導之敏感性。 200526246 (6) 對129sv χ C57BL/6 P T X 3 - / -小鼠使用1 〇 〇微克雞第 Π型膠原（SIGMA)在完全Freund’s佐劑中且加入250微 克經熱抑活化的結核分枝桿菌（M. tuberculosis)，總體 積1 0 0微體，經由在接近尾巴區的多次皮下注射予以處理 ， 〇 於2 1天後重複相同的處理。 於給藥期結束時，使用計及發炎關節的存在及彼等的 大小之隨意計分系統評估關節炎的發生率及嚴重性。所得 φ 結果呈現於表1之中。 於表1中所報告的在PTX 3 +/ +小鼠體內之較大疾病發 生率提供出PTX3 -/•小鼠對膠原誘導關節炎的發展爲較小 敏感之證據。此發現亦由顯示出在PTX3 +/ +小鼠體內的關 節炎比在PTX3 小鼠體內者有較大嚴重性之臨床評分所 確定。 所得結果表明P T X 3或其抑制的不存在可用來預防和 治療骨骼和軟骨的炎性及/或退化性疾病。 g 表1 在 PTX3+/ +和 PTX3-/-小 鼠體內的膠原誘發關節炎 動物 發生率* 臨床計分 PTX3+/ + 3/5 1 0 PX3-/- 3/7 3.6 於實驗結束的發生率（第一次免疫化的6 0天後）。 在實驗結束時有關節炎的動物之平均臨床評分。 -10- 200526246 (7) 附註：於第二次免疫化後，四肢關節炎臨床微像的# 在係每一星期評估二次。每一肢係以從1至4評分；每— 動物因而可得最大評分値1 6。 有關工業應用性方面，單體物型賓特辛PTX3或其月太 或肽模擬衍生物或抗-賓特辛PTX3抗體都可呈藥學,組成 物形式’其中係以藥學可接受之賦形劑及/或稀釋劑，例 如無菌水、羧甲基纖維素或此領域中的專業者所知的其他 賦形劑將活性成分溶解化及/或賦形化。 可用於單體物型賓特辛的藥學組成物之例子爲與在 WO 99/3 25 1 6中對長賓特辛PTX3所述者相同。 根據本發明的化合物可經腸或非經腸途徑給用，特別 較佳的藥學形式爲慢釋放性植體或關節內注射形式。 每曰劑量係決定於主治醫師的判斷，病人的體重，年 齡和一般狀況。 必須提及者’該等藥學組成物，包括慢釋放性形式， 其製備可以使用藥劑師及藥學技術專家所熟知的例行性技 術和設備予以完成。

Claims (1)

  1. 200526246 (1) 十、申請專利範圍 1· 一種長賓特辛（pentraxin) PTX3的抑制劑或拮抗 劑對於製備預防和治療骨骼和軟骨退化疾病所用藥劑之用 途。 、 2 ·如申請專利範圍第1項之用途，其中該長賓特辛 _ PTX3抑制劑爲能夠結合ΡΊΓΧ3的任何單株或多株抗體。 3 ·如申請專利範圍第2項之用途，其中該抗體爲天 然（人類或動物），重組或合成來源者。 C 4 ·如申請專利範圍第1項之用途，其中該拮抗劑爲 保有選擇性抑制ΡΤΧ3活性的能力之單體物型ΡΤΧ3，或其 肽或肽模擬性衍生物之一者。 5 ·如申請專利範圍第4項之用途，其中該拮抗劑爲 天然（人類或動物），重組或合成來源者。 6 ·如申請專利範圍第4項之用途，其中該單體物型 賓特辛爲人類來源者。 7.如申請專利範圍第1項之用途，其中該自體免疫 · 性疾病爲選自下列所構成的群組之中者：系統性紅斑狼瘡 (S LE )、多發性硬化（M S )、關節炎、糖尿病、甲狀腺 、 炎、溶血性貧血、萎縮性睪九炎、Good pasture氏病、自 體免疫性視網膜病、自體免疫性血小板減少症、重症肌無 力、原發性膽硬化、慢性攻擊性肝炎、漬瘍性結腸炎、皮 炎、慢性血管球性腎炎、Sj0gren氏徵候群、Reiter氏徵 候群、肌炎、系統性硬化及多關節炎。 8 .如申請專利範圍第1項之用途，其中該退化性骨 -12 - 200526246 (2) 縣或軟骨疾病係選自下列所構成的群組之中者：骨關節炎 •’骨關節病；關節退化病；膠原缺乏；具有軟骨內軟化的 特徵之軟骨或骨骼疾病；原發性關節炎，包括，例如，風 濕性關節炎、幼年型關節炎、未分化型慢性關節炎；和多 · 關節炎；自體免疫源的繼發性關節炎，包括，例如，系統 丨生紅斑狼瘡、牛皮癣性關節炎、Crohn氏病關節炎；代謝 不全性來源之關節炎，包括，例如，尿酸一鈉關節病、焦 碟酸鹽關節病、草酸鈣關節病；傳染性關節炎、因骨質疏 ^ 鬆所致關節炎、無菌性骨壞死、良性和惡性骨腫瘤。 -13 - 200526246 七 定 無 明 說 單 簡 號 符 為代 圖件 表元 代之 定圖 指表 案代 本本 八、本案若有化學式時，請揭示最能顯示發明特徵的化學 式：無
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