九、發明說明： 【發明所屬之技術領域】 本發明疋有關於一種藉由將作用劑之組合投予有需要 的患者而治療多發性硬化（MS)之方法，該作用劑之組合 的特徵在於具有減少淋巴球數目的藥理活性之第一作用 劑，以及可阻斷單核球及白血球附著至内皮細胞之第二作 用劑。 【先前技術】 夕發f生硬化（MS )是一種漸進的神經性自體免疫疾病， 早在美國就影f 25G，GGG i 350，GGG A。它S腦部及脊髓 髓鞘脫失的結果。它是最廣為人知的人類中枢神經系統 (CNS )之慢性發炎髓鞘脫失疾病。這個疾病的發作通常 是在二十至四十歲的年齡間發生，女性受影響是比男性多 兩倍。多發性硬化的發作是以中樞神經系統官能障礙的第 -入神經性症狀之發生而定義。導源於這個髓鞘脫失的症 狀包括虛弱、視覺損傷、不協調 '刺痛（異常刺痛）、中 樞神經系統發炎、腦部萎縮以及認知損傷。也觀察到性慾 才貝傷及括約肌官能障礙《這個疾病的進程是不可預料的， 但通常經由症狀的惡化接著緩解的循環而進行。緩解的長 度呈多樣化，並可持續數年，但不經常是永久性的。腦脊 髓液（CSF)分析及磁共振造影（MRI)的進展，已簡化 診斷的過程以及促進早期的診斷（N〇SeW〇rthy等人，Λ^， 2000，343(13) : 938-952 )。 多發性硬化可分類成四種疾病的進程：復發緩解型 1373337 (RR)、次發-漸進型（SP)、首發·漸進型（pp)以及漸 發-緩解型（pr )多發性硬化。超過8〇%的患者一開始將 顯示具有神經性症狀的臨床惡化之復發_緩解型進程，接著 是可能完全或可能不完全的復原（Lublin及Reing〇ld， 叹少，ι996，46 : 9〇7·9η )。在復發·緩解型多發性 硬化期間’殘疾的累積係導源於從復發的不完全復原。大 約一半具有復發-緩解型多發性硬化的患者，在疾病發作後 約十年内轉變成次發_漸進型多發性硬化。在次發-漸進型 期間，殘疾的惡化性係導源於惡化之後殘留症狀的累積， 但也導源於惡化之間的隱伏進展（LubUn及Reing〇]d，上 述文獻）。10%的多發性硬化患者呈現首發_漸進型的疾病 進程，其特徵在於從疾病發作開始症狀的隱伏進展。少於 5%的患者具有漸發-緩解型多發性硬化，並且與首發-漸進 型多發性硬化患者共有相同的不良預後。 已有建議不同的病原機轉可能涉及不同的患者亞群， 並且對於疾病分類及治療具有廣泛的關連（Lassmann等 人，心从0/·从^·’ 7: 115·121; Lucchineui 等人，2〇〇ι， CiOph· TVwm/·，14 : 259_269 )。雖然並不知道多發 性硬化的病原學，但許多研究已將活化的單核球及巨噬細 胞’在活化的T細胞之存在下，牽連在多發性硬化的進展 及/或惡化之中（Fredrickson等人，1987， •S⑽汰，75 : 352-355 ; Huber 等人，1984，乂 脚心， 160 : 310-316)。在顯微鏡的水平’單核球、微神經膠細 胞（中樞神經系統的巨噬細胞）以及活化的τ細胞，是在 1373337 多發性硬化的惡化期間，於神經細胞的髓鞘脫失區域内被 發現（Ceci卜醫學教科書（1997)，Beeson等人编輯，W.B. Saunders公司，費城，賓州）。活化的淋巴球及巨噬細胞 • 已牵連到與多發性硬化相關的急性發炎性腦部損傷及血腦 屏障（BBB)破壞之病原發生（c〇Us等人，1999， A^wro/.，46(3) : 296-304)。 按照疾病進展與發炎細胞出現的關連性，目前用於多 發性硬化之修飾疾病的治療（亦即修飾多發性硬化進程） 之藥物’係藉由調節或抑制免疫系統而作用。有四種食品 及藥物管理局核准用於復發-緩解型多發性硬化的免疫調節 作用劑’二種冷干擾素（Betaseron™，Berlex ; Avonex™， B]ogen ; Rebif®，Ser〇no )以及格拉提姆（（31^1抓〇醋酸 .no. ( Copaxone ，Amgen )。也有一種食品及藥物管理局 核准用於惡化性多發性硬化的免疫抑制藥物：米托蒽醌 (Mit〇xantrone) (N〇vamr〇neTM，Amgen)。然而，仍不 φ 清楚是否這些藥物確實可預防疾病的進展，或者它們的優 點可持續一段時間。此外，部分患者也無法耐受副作用， 例如，類流感症狀，以及在部分的例子中，掉髮、血液細 皰異常及沮喪（Fillippini等人，在復發'緩解型多發性硬 化中的干擾素·系統性回顧，361 : 545-552，2003)。 a. 2-氣-2’·去氧腺穿： β午多其他的作用劑正在臨床試驗以用於治療多發性硬 在/、中 種氯化的嗓吟類似物2 -氯-2，-去氧腺穿 (2-CdA )已顯示可有效於治療多發性硬化（歐洲專利 7 丄川337 626853B1及美國專利第5,5()6,2i4號）。它的作用模式可 能是由於其藥理活性朝向活化的單核球及巨噬細胞所致。 許夕臨床研究已有說明肖2CdA以靜脈内及皮下投予至多 發)·生硬化的心者。用於治療多發性硬化的口服調配物之有 效劑量也已有說明（美國專利第55〇6,2M號）。 兩個利用2-CdA的雙盲、安慰劑對照之第^期研究， 分別是在治療漸進型的多發性硬化（Seiby等人，i998 Ci^ 乂 ，25 . 295-299 )及復發-緩解型多發性硬化 (Romine等人，1999,⑽，⑴⑴： 35 44 )中進行。在第一個試驗中，劑量是〇 1毫克/公斤 共7天，藉由連續靜脈注射四個月。在第二個試驗中，2_ CdA的劑量是〇.〇7毫克/公斤共5天，藉由皮下注射。安 慰劑對照之第III期研究是在具有首發_漸進型多發性硬化 及次發-漸進型多發性硬化的患者中進行。在這個研究中， 患者藉由皮下注射而接受0 07毫克/公斤劑量的2_cdA， 共二個月或六個月。 上述的臨床試驗顯示在多發性硬化患者中，2_CdA的 治療在Kuzke殘疾狀態擴展評分表（EDSS )、臨時神經症 狀測定量表（SNRS )及磁共振造影調查方面之功效（BeutIer 等人 ’ 1996，咖，93 : 1716-1720 ; R0mine 等人， 1 999,上述文獻第u期研究顯示2_CdA可顯著減少mri_ 測量的腦部損傷（Rice等人，2〇〇〇，上述文獻）^部分不 利的效果，例如，增加有關妥協的免疫功能或骨髓抑制之 感染發生率’也在最高的劑量時觀察到（Selby等人，1 998， δ 1373337 上述文獻；Beuler 等人 ’ 1994，，91 : i〇 l5 ) 在有效劑量及不利效果的發生之間有狹窄的安全性邊緣， 因此’ 2-CdA治療多發性硬化的口服途徑是被排除的 (Beutler 等人 ’ 1996，/« 价則M/‘，331(S1) : 45-52 ) b.抗-α -4整合素抗體： 另一個在臨床試驗中用於治療多發性硬化 -m , 是對整合素（integrin )超家族的α _4鏈具有特異性之人類 化單株抗體。a -4U整合素（VLA_4)是表現在活化的 淋巴球及單核球之細胞外表面上，其已牽連到與多發性硬 化相關的急性發炎性腦部損傷及血腦屏障（ΒΒΒ)破壞之 病原發生（Coles等人，上述文獻）。對抗整合素的 作用劑，已在活體外及活體内的動物模式中測試它們的抗 發炎潛力（Yednock 等人，1992，編，356 : 63_66 ; 美國專利第5,840,229號；美國專利第MG1，8()9號）。活 體外的實驗顯示，抗·α·4整合素抗體可阻斷淋巴球附著 至腦部内纟。在多發性硬化、實驗性自體免疫性腦脊髓炎 (㈣）的動物模式中之實驗，顯示投予抗心4整合素抗 體可預防腦部發炎以及後續在動物中的癱瘓。整體而言， 這些實驗將抗-α - 4作用劑鑑定為用於治療多發性硬化之 有潛力的有效治療作用齊卜因為它們可預防發炎細胞穿越 血腦屏障。 >第m期研究顯示，每月3〇〇毫克單一劑量的抗·α 4 MM |減少多發性硬化損傷。在這個研究中所觀察到 的不利效1，包括免疫球蛋白相關並且可能係因作用劑是 1373337 抗體的事實而導致之過敏型反應。雖然未被報導，但是蛋 白質治療劑（例如，抗體治療）的顯著爭議是誘發免疫反 應以及中和治療的抗體之後續發展，使得慢性投予變得因 難0 雖然在治療多發性硬化已有部分最新的進展，但仍需 要進一步的改善以促進罝右 退，、有改善有蚨性的治療作用劑之發 展’並且減少副作用。因此，在此技藝中對於改善多發性 硬化的治療，仍有需求。本發明完成這些需求，並且進一 步提供其他相關的優點。 【發明内容】 本發明是有關於利用作用劑之新賴組合以治療多發性 々更化0 本發明之方法包括將第—作用劑及第二作用劑投予有 耑要的患者，且中兮笙 理性質，以及：中：第一作 有減少淋巴球數目的藥 著至内皮細胞第二作用劑可阻斷單核球及白血球附 I發明的具體實你丨 兮第m 亥第―作用劑係2_CdA，以及 K乍用劑係抗^4整合素抗體。 本發明的另—且興 致劑量的減少，該^ ^提供任—或兩種作用劑之有 治療優點之所f:肖劑係提供治療多發性硬化的最大 本發明的另一且 醫藥組成物，复勺、體實例係提供用於治療多發性硬化之 -作用劑且有：Γ括第一作用劑及第二作用劑，其中該第 /、有减>、淋巴球數目的藥理性質，以及其中該第 ⑧ 1373337 二作用劑可阻斷單核球及白血球附著至内皮細胞。 【實施方式】 本發明是有關於一種治療多發性硬化之方法，其包括 將2 CdA及& · α _4整合素抗體投予有需要的患者。雖然 2-CdA及抗-α_4整合素抗體已各自分別用於治療多發性硬 化，但該等作用劑並未被組合地用於治療多發性硬化。將 2-CdA及抗-α -4整合素抗體組合，是比任一作用劑單獨投 予更有效於治療多發性硬化。此外，組合治療也提供產生 治療有利效果所需的一種或兩種作用劑的劑量之減少，或 提供產生治療有利效果所需的治療長度之減少。減少一種 或兩種作用劑的劑量，可減少與投予個別作用劑有關的不 利效果’例如’免疫球蛋白相關的過敏反應及/或對於抗-α -4整合素抗體的免疫反應。 不欲受限於理論，作用劑之組合可提供協同的效果。 作用劑的協同效果可能是由於個別作用劑各自不同的作用 機轉所致。2-CdA具有減少淋巴球數目的藥理效果，而抗· α -4整合素抗體則可阻斷單核球及白血球附著至内皮細 胞。特別涵蓋的是’本發明之方法包括使用除2_CdA以外 可減少淋巴球數目之作用劑，以及除抗-α ·4整合素抗體 以外可特異性結合至包括α _4次單元的整合素及抑制整合 素活性之作用劑。 卜定義： 此處所使用的“治療期間”是指從治療第一天到治療 結束’投予本發明的2-CdA及抗-α -4整合素抗體之期間。 11 1373337 :用於2-CdA ,组合抗_α_4整合素抗體的給藥療程之 内文％此處所使用的“有效量”是指2_cdA或抗· ^ μ 整合素抗體的量’如果以缺少另一種而提供時，將導致個 別作用劑都可達成效果的多發性硬化之最大治療如果以 單一作用劑提供的話。 當用於給藥療程的内文時，此處所使用的“功效，，是 指特定治療療程的有效性。功效可根據對於本發明給藥療 程反應的疾病進程之變化而測量。例如治療多發性硬化 的功效可藉由復發·緩解型多發性硬化中的復發頻率，以及 如利用例如磁共振造影的方法偵測中樞神經系統中存在或 不存在新損傷而測量。 此處所使用的“誘發免疫反應”是指當導入作用劑之 後，在個體中產生對於抗―^：“整合素抗體的免疫反應。 在個體中的免疫反應，其特徵可在於與抗_α4整合素抗 體的血清反應性，其至少是未治療個體的兩倍，更佳是未 冶療個體的反應性之三倍，以及還要更佳是未治療個體的 反應性之至少四倍。 此處所使用的“治療結束”是指患者變得無須2_CdA 及/'或抗-α -4整合素抗體之日。 當用於說明4又予2-CdA及抗- α-4整合素抗體時，此 處所使用的“組合”是指2-CdA可在抗-α -4整合素抗體 之前、同時或之後投予。 此處所使用的“病理發炎，，是指與多發性硬化相關的 不適當及fe性發炎（特別是指抑制進一步的髓鞘脫失）。 12 ⑧ 1373337 這樣的發炎’其特徵在於發炎細胞（包括浸潤白血球）之 增加的反應。經過一段時間，該等病理發炎通常會導致對 於不適當發炎區域中的組織之傷害’也就是中樞神經系統 的組織。 此處所使用的緩解，是指在多發性硬化漸進的進程 期間，其中患者經歷了疾病症狀的縮小或穩定。這可以是 一段部分治癒中框神經系統損傷及/或減少中樞神經系統 發炎的期間。 此處所使用的“特異性結合”是指其中特異性結合配 對的一個成員將不會顯示與除了其特異性結合伙伴以外的 分子之任何顯著結合的狀況（例如，對其特異性結合伙伴 約1000X或更多的親和力）。 當用於2-CdA組合抗整合素抗體的給藥療程的 内文時，此處所使用的“次適劑量”是指2_CdA或抗-口 _4 整合素抗體少於上述定義的有效量之劑量。 此處所使用的“實質同源”是指在序列中具有一個改 k的任何多肽，使得功能相等的胺基酸取代在多肽中的一 個或多個胺基酸，藉此產生對於多肽的結合性質沒有影響 或相富少影響的改變。例如，在序列内的一個或多個胺基 酸殘基，可藉由相似極性的其他胺基酸而取代。 此處所使用的治療”及類似用詞，一般是指獲得所 要的藥理及生理效果。該效果在預防或部分預防疾病、症 狀或其病症方面可以是預防性的，及/或在部分或完全治 療疾病、病症、症狀或歸因於疾病的不利影響方面可以是 13 ⑧ 137333/ 治療性的。此處所使用的名肖“治療，’涵蓋哺乳動物的疾 病之任何治療，特別是人類，並且包括：⑺預防疾病在 個體中發纟’該個體可能容易感染該疾病，但尚未被診斷 為患有該疾病；（b)抑制疾病’也就是阻止其發展； 或減緩疾病’也就是’致使該疾病及/或其症狀或病症復原。 2.組合： 根據本發明，2-CdA係組合抗-α·4整合素抗體而投 予。作用劑的劑量可各自是有效的量。較佳地，個別作用 劑的劑量是如次適量。 兩個作用劑可同時投予或彼此連續投予。當同時投予 =可將作用劑調配在相同的組成物或不同的組成物中。 當兩個作用劑不是以部分相同的調配物而投予時，兩個作 用劑可藉由相同或不同的投予途徑而投予。2_CdA及抗 ·4整合素抗體的相對投予，可取決於特定的投予途徑及/或 個別成分的調配物而定^ 2_CdA及抗_ α ·4整合素抗體的相 '寸才又予，可根據患者是否經歷症狀的復原或惡化而不同。 作用劑的Μ合可對於一種或多種治療週期而投予。每 固化療週期都可具有任何的期間，包括但並不限於，從約 兩個月至六個月，其中2_CdA是每天提供約12次，每月 为5-7天，以及抗· α _4整合素抗體是每月週期投予約一 人或每月週期約1 -4次或每週約一次。每月週期的次數 也可從約6次至約12次，或可超過12次。每月週期的次 數可根據多發性硬化的進程（例如，患者是否經歷復發_緩 解J或次發-漸進型多發性硬化）及患者是否經歷症狀的復 14 ⑧ 1373337 原或惡化而改變。 3. 2-CdA ： 2-CdA及其藥理上可接受的鹽可用於實施本發明.。製 -備2_CdA的方法是在此技藝中熟知的》例如，2-CdA的製 備是說明於歐洲專利申請案第173,〇59 A2號，以及Robins 等人，·/· Jw. CAe/n.心匕，1984，106: 6379、W0 04/028462、 美國專利第5,208,327號及WO 00/64918。另一選擇為，2-IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD The present invention relates to a method for treating multiple sclerosis (MS) by administering a combination of agents to a patient in need thereof, the combination of which is characterized by A first agent having a pharmacological activity for reducing the number of lymphocytes, and a second agent capable of blocking the attachment of mononuclear cells and white blood cells to endothelial cells. [Prior Art] Xifa f-hardening (MS) is a progressive neurological autoimmune disease, as early as in the United States, f 25G, GGG i 350, GGG A. It results in the loss of myelin in the brain and spinal cord. It is the most widely known chronic inflamed myelin loss disease in the human central nervous system (CNS). The onset of this disease usually occurs between the ages of 20 and 40, and women are twice as affected as men. The onset of multiple sclerosis is defined by the occurrence of a first-introduced neurological disorder of the central nervous system dysfunction. Symptoms derived from this myelin loss include weakness, visual impairment, incoordination 'stinging (abnormal tingling), central nervous system inflammation, brain atrophy, and cognitive impairment. Sexual desires and sphincter dysfunction have also been observed. The progression of this disease is unpredictable, but is usually done through a cycle of worsening symptoms followed by relief. The length of remission is diverse and can last for years, but not always permanent. The analysis of cerebrospinal fluid (CSF) and the progress of magnetic resonance imaging (MRI) have simplified the diagnosis process and promoted early diagnosis (N〇SeW〇rthy et al., Λ^, 2000, 343(13): 938-952) . Multiple sclerosis can be classified into four disease processes: relapsing-remitting 1373337 (RR), secondary-progressive (SP), first-initial (pp), and progressive-remission (pr) multiple sclerosis. More than 8% of patients will initially show a relapsing-remitting process with clinical signs of neurological symptoms, followed by a complete or possibly incomplete recovery (Lublin and Reing〇ld, Sigh less, ι996, 46: 9〇) 7·9η ). The accumulation of disability during relapsing-remitting multiple sclerosis is due to incomplete recovery from relapse. About half of patients with relapsing-remitting multiple sclerosis are converted to secondary gradual multiple sclerosis within about ten years after the onset of the disease. During the secondary-progressive period, the deterioration of disability is due to the accumulation of residual symptoms after deterioration, but also from the insidious progression between the deterioration (LubUn and Reing〇), the above literature). 10% of patients with multiple sclerosis present a first-progressive disease progression characterized by an insidious progression of symptoms from the onset of the disease. Less than 5% of patients have progressive-remission multiple sclerosis and share the same poor prognosis as patients with first-progressive multiple sclerosis. It has been suggested that different pathogens may involve different patient subgroups and have a broad relationship with disease classification and treatment (Lassmann et al., from 0/· from ^·' 7: 115·121; Lucchineui et al. 2〇〇ι, CiOph· TVwm/·, 14 : 259_269 ). Although the etiology of multiple sclerosis is unknown, many studies have linked activated mononuclear and macrophage 'in the presence of activated T cells to the progression and/or progression of multiple sclerosis (Fredrickson Et al., 1987, • S(10), 75: 352-355; Huber et al., 1984, Pepsi, 160: 310-316). At the level of the microscope, 'mononuclear spheres, microglial cells (macrophage of the central nervous system), and activated tau cells were found in the demyelination area of nerve cells during the deterioration of 1373337 multiple sclerosis. (Ceci Bu Medical Textbook (1997), edited by Beeson et al., WB Saunders, Philadelphia, Pennsylvania). Activated lymphocytes and macrophages • have been implicated in the pathogenesis of acute inflammatory brain damage associated with multiple sclerosis and blood-brain barrier (BBB) destruction (c〇Us et al., 1999, A^wro/., 46(3): 296-304). Therapeutic drugs currently used for the treatment of modified diseases of multiple sclerosis (i.e., modifying the process of multiple sclerosis) act by regulating or suppressing the immune system, depending on the association of disease progression with the appearance of inflammatory cells. There are four FDA-approved immunomodulatory agents for relapsing-remitting multiple sclerosis's two cold interferons (BetaseronTM, Berlex; AvonexTM, B]ogen; Rebif®, Ser〇no) and Gratim ((31^1 grabs acetic acid.no. (Copaxone, Amgen). There is also an immunosuppressive drug approved by the Food and Drug Administration for degenerative multiple sclerosis: Mittxantrone (Mit〇xantrone) ( N〇vamr〇neTM, Amgen. However, it is still not clear whether these drugs can prevent the progression of the disease, or their advantages can last for a while. In addition, some patients are unable to tolerate side effects, such as flu-like symptoms, And in some examples, hair loss, blood blistering abnormalities and depression (Fillippini et al., Systematic Review of Interferon in Relapsing Relapsing Multiple Sclerosis, 361: 545-552, 2003). a. 2 -Gas-2'·Deoxygland gland: β-Morning other agents are being tested in clinical trials for the treatment of multiple hard, medium-chlorinated guanidine analogues 2-chloro-2,-deoxygen glands Wear (2-CdA) has been shown to be effective in treatment Multiple sclerosis (European Patent No. 7 丄 337 626 853 B1 and US Patent No. 5, 5 (6, 2, 2 i4). Its mode of action may be due to its pharmacological activity towards activated mononuclear spheres and macrophages. Xi'an clinical studies have shown that Xiao 2CdA is administered intravenously and subcutaneously to the heart of the sclerosing heart. The effective dosage of oral formulations for the treatment of multiple sclerosis has also been described (U.S. Patent No. 5,56, 2M). Two double-blind, placebo-controlled, phase 2 studies using 2-CdA were performed in the treatment of progressive multiple sclerosis (Seiby et al., i998 Ci^ 乂, 25. 295-299) and Relapsing-remitting multiple sclerosis (Romine et al., 1999, (10), (1) (1): 35 44). In the first trial, the dose was 〇1 mg/kg for 7 days, with continuous intravenous injection for four months. In the second trial, the dose of 2_CdA was 〇.〇7 mg/kg for 5 days by subcutaneous injection. The placebo-controlled Phase III study had a first-onset progressive multiple sclerosis and secondary - Progressive multiple sclerosis in patients. In this study, patients borrowed A subcutaneous injection of 2_cdA at a dose of 0 07 mg/kg for two months or six months. The above clinical trial showed that in patients with multiple sclerosis, treatment of 2_CdA was performed on the Kuzke Disability Status Extended Score (EDSS), temporary Neurological Symptoms Scale (SNRS) and the efficacy of magnetic resonance imaging studies (Beut Ier et al. 1996, café, 93: 1716-1720; R0mine et al., 1 999, the second study of the above literature shows that 2_CdA can significantly reduce mri_ Measurement of brain damage (Rice et al., 2 pp., above)) Partial adverse effects, for example, increased incidence of infection with compromised immune function or myelosuppression' also observed at the highest dose (Selby Et al., 1 998, δ 1373337 above; Beuler et al '1994, 91: i〇l5) have a narrow margin of safety between the effective dose and the onset of adverse effects, so '2-CdA treatment of multiple sclerosis The oral route was excluded (Beutler et al. '1996, /« valence M/', 331 (S1): 45-52) b. Anti-α -4 integrin antibody: another used in clinical trials Treatment of multiple Of -m, is α _4 superfamily chain having specificity for the human monoclonal antibody of integrins (integrin). a -4U integrin (VLA_4) is expressed on the extracellular surface of activated lymphocytes and mononuclear cells, which has been implicated in acute inflammatory brain damage associated with multiple sclerosis and blood-brain barrier (ΒΒΒ) destruction. Pathogens occur (Coles et al., supra). Agents against integrins have been tested for their anti-inflammatory potential in both in vitro and in vivo animal models (Yednock et al., 1992, ed., 356: 63-66; U.S. Patent No. 5,840,229; U.S. Patent No. MG1,8 ( )No.9). In vitro experiments have shown that anti-α·4 integrin antibodies block the attachment of lymphocytes to the brain's internal hemorrhoids. In an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis ((iv)), it was shown that administration of an anti-cardiac 4 integrin antibody can prevent inflammation of the brain and subsequent convulsions in animals. Overall, these experiments identified anti-α-4 agents as potential and effective therapeutic agents for the treatment of multiple sclerosis because they prevent inflammatory cells from crossing the blood-brain barrier. > The m-th study showed that a single dose of anti-α 4 MM |3 mg per month was used to reduce multiple sclerosis injury. The adverse effects 1 observed in this study included immunoglobulin-related and possibly allergic reactions due to the fact that the agent was 1373337 antibody. Although not reported, a significant controversy over protein therapeutics (eg, antibody therapy) is the subsequent development of antibodies that induce immune responses and neutralizing treatments, making chronic administration difficult because of the fact that there are already parts in the treatment of multiple sclerosis. Recent advances, but further improvements are needed to promote sputum retreat, improve the development of aggressive therapeutic agents, and reduce side effects. Therefore, there is still a need in the art for improving the treatment of multiple sclerosis. The present invention fulfills these needs and further provides other related advantages. SUMMARY OF THE INVENTION The present invention relates to the use of a new combination of agents for the treatment of multiple sputum. The method of the present invention comprises administering a first agent and a second agent to a patient having a significant effect, and The nature of the phlegm, and: in the first: the first to reduce the number of lymphocytes to the endothelium, the second agent can block the mononuclear ball and white blood cells attached to the invention of the specific 丨兮 m hai ─ ─ agent The system is a 2_CdA, and the K is an anti-4 integrin antibody. The additional and preferred dosage reduction of the present invention provides a therapeutic advantage of any or both agents: the diabolic agent provides the greatest additional pharmaceutical composition of the present invention for treating multiple sclerosis, The scooping and body examples provide an agent for treating multiple sclerosis and include: a first agent and a second agent, wherein the /, minus >, the pharmacological properties of the number of lymphocytes, and Among them, the 8th 1373337 two-agent can block the attachment of mononuclear cells and white blood cells to endothelial cells. [Embodiment] The present invention relates to a method for treating multiple sclerosis comprising administering a 2 CdA and & α_4 integrin antibody to a patient in need thereof. Although 2-CdA and anti-α_4 integrin antibodies have each been used to treat multiple sclerosis, respectively, these agents have not been used in combination to treat multiple sclerosis. The combination of 2-CdA and anti-α-4 integrin antibodies is more effective than single agent in the treatment of multiple sclerosis. In addition, combination therapy also provides a reduction in the dosage of one or both of the agents required to produce a therapeutically beneficial effect, or a reduction in the length of treatment required to produce a therapeutically beneficial effect. Reducing the dose of one or both agents reduces the adverse effects associated with administration of the individual agents, e.g., 'immunoglobulin-related allergic reactions, and/or immune responses to anti-α-4 integrin antibodies. Without wishing to be bound by theory, the combination of agents may provide a synergistic effect. The synergistic effect of the agent may be due to the different effects of the individual agents. 2-CdA has a pharmacological effect of reducing the number of lymphocytes, while anti-α-4 integrin antibodies block the attachment of mononuclear and white blood cells to endothelial cells. It is specifically contemplated that the method of the present invention includes the use of an agent which reduces the number of lymphocytes other than 2_CdA, and specifically binds to integrin including α_4 subunits and inhibits integration in addition to anti-α·4 integrin antibodies. An active agent. Definitions: As used herein, "treatment period" means the period during which the 2-CdA and anti-α-4 integrin antibodies of the present invention are administered from the first day of treatment to the end of treatment. 11 1373337: For the administration of 2-CdA, a combination of anti-α_4 integrin antibodies, the "effective amount" as used herein refers to the amount of 2_cdA or anti-^ μ integrin antibody 'if in the absence of another One provides the greatest treatment for multiple sclerosis that will result in an effect on individual agents if provided as a single agent. As used herein, the term "efficacy" refers to the effectiveness of a particular course of treatment. The efficacy can be measured in response to changes in the course of the disease in response to the course of administration of the present invention. For example, treatment of multiple The efficacy of sclerosis can be measured by the frequency of recurrence in relapsing-remitting multiple sclerosis and by detecting, for example, the presence or absence of new lesions in the central nervous system using, for example, magnetic resonance imaging. "This means that an immune response against an anti-":" integrin antibody is produced in an individual when the agent is introduced. An immune response in an individual characterized by a serum reactivity with an anti-α4 integrin antibody that is at least twice as high as that of an untreated individual, more preferably three times less reactive than an untreated individual, and More preferably, the untreated individual is at least four times more reactive. As used herein, "end of treatment" refers to the day on which a patient becomes free of 2_CdA and/or or anti-a-4 integrin antibodies. As used in the description of 4 and 2-CdA and anti-α-4 integrin antibodies, the term "combination" as used herein means that 2-CdA can be administered before, simultaneously or after the anti-α-4 integrin antibody. . As used herein, "pathological inflammation refers to inappropriate and feline inflammation associated with multiple sclerosis (especially inhibition of further myelination). 12 8 1373337 Such inflammation is characterized by inflammatory cells (including The increased response of infiltrating white blood cells. Over time, these pathological inflammations often cause damage to tissues in inappropriately inflamed areas 'that is the tissues of the central nervous system. The relief used here refers to multiple sclerosis During the gradual progression, the patient experiences a reduction or stabilization of the disease symptoms. This may be a period of partial healing of the mesenteric nervous system injury and/or reduction of inflammation of the central nervous system. As used herein, "specific binding" refers to A member of a specific binding pair will not display any significant binding status to a molecule other than its specific binding partner (eg, an affinity for its specific binding partner of about 1000X or more). When the CdA combination anti-integrin antibody is administered in the context of the treatment, the "secondary dose" used herein "" means that the 2_CdA or anti-mouth-4 integrin antibody is less than the effective amount of the above defined dose. As used herein, "substantially homologous" refers to any polypeptide having a k in the sequence that renders an equivalent amine. The base acid replaces one or more amino acids in the polypeptide, thereby producing an alteration that has no or little effect on the binding properties of the polypeptide. For example, one or more amino acid residues within the sequence may be Substitution by other amino acids of similar polarity. The treatments and similar terms used herein generally refer to obtaining the desired pharmacological and physiological effects. The effect may be prophylactic in preventing or partially preventing the disease, symptom or condition thereof, and/or may be 13 8 137333 / therapeutic in terms of partial or complete treatment of the disease, condition, symptom or adverse effect due to the disease. of. As used herein, the term "treating," encompasses any treatment of a disease in a mammal, particularly a human, and includes: (7) preventing the disease from developing in the individual 'the individual may be susceptible to the disease but has not been diagnosed with the disease (b) inhibiting the disease 'that is, preventing it from developing; or slowing down the disease', that is, causing the disease and/or its symptoms or conditions to be restored. 2. Combination: According to the present invention, the 2-CdA combination anti-α· 4 Integrin antibodies are administered. The doses of the agents may each be a effective amount. Preferably, the doses of the individual agents are as appropriate. The two agents may be administered simultaneously or continuously with each other. The agent can be formulated in the same composition or in different compositions. When the two agents are not administered in a partially identical formulation, the two agents can be administered by the same or different routes of administration. In contrast, the relative administration of 2_CdA and anti-integrin antibodies may depend on the specific route of administration and/or the formulation of the individual components, depending on the formulation of the 2_CdA and anti-α·4 integrin antibodies. Only give it again, Depending on whether the patient experiences recovery or worsening of the symptoms. The combination of agents can be administered for one or more treatment cycles. Each curing cycle can have any period, including but not limited to, from about two months. Up to six months, of which 2_CdA is provided about 12 times a day for 5-7 days per month, and anti-α_4 integrin antibody is administered monthly for about one person or monthly cycle of about 1-4 times or weekly. Once. The number of monthly cycles can also be from about 6 to about 12, or more than 12. The number of monthly cycles can be based on the course of multiple sclerosis (for example, whether the patient experienced relapse _ relieve J or secondary - Progressive multiple sclerosis) and whether the patient experienced a change in the original or worsening of the symptoms. 3. 2-CdA: 2-CdA and its pharmacologically acceptable salts can be used in the practice of the present invention. Preparation - 2_CdA The method is well known in the art. For example, the preparation of 2-CdA is described in European Patent Application No. 173, 〇 59 A2, and Robins et al., J. CAe/n. 匕, 1984 , 106: 6379, W0 04/028462, US Patent No. 5,208,327 and WO 00 /64918. Another option is, 2-
CdA的醫藥製備物可購自貝德福實驗室（貝德福，俄亥俄 譬州）。 一般而言，2-CdA的劑量可在相當廣泛的範圍改變， 以達成並且較佳地維持所要的血漿濃度。2_CdA的劑量可 以是足以提供在患者血漿中約〇 5 nM至約5 0 nM的濃度， 較佳是約1 nM至約10 nM。2-CdA的有效每日劑量可以是 約0_04至約ΐ·〇毫克/公斤體重，更佳是約〇 〇4至約〇 2〇 毫克/公斤/曰’以及最佳是約0.1毫克/公斤體重。2_cdA 的其他劑量是說明於美國專利第5,5〇6,214號，其内容以 •引用方式納入本文中。 4. 抗-〇： -4整合素抗體： 抗-α -4整合素抗體可特異性結合至包括α ·4次單元 的整合素，並可抑制整合素的活性。抗體也可結合至包括 α _4整合素的二聚體’例如，α _4·石-1或α -4-沒-7。抗-« -4整合素抗體可能無法顯示與除了 α_4整合素或包括α •4整合素的受體以外的任何多肽明顯結合。抗體可以1 〇7 莫耳/公升或更多的結合親和力而結合至α _4整合素，較佳 15 ⑤ 1373337 是ίο8莫耳/公升或更多。 一般而言，抗-α -4整合素抗體的劑量可在相當廣泛 的範圍改變，以達成並且較佳地維持所要的血漿濃度。抗_ α -4整合素抗體的有效劑量是其提供在腦部磁共振造影偵 測的損傷之最大減少及/或抑制的劑量。抗體的劑量可以少 於每月投予約300毫克，至少6個月的期間，更佳是i 2 個月，以及或許可超過數年的期間。另一種較佳的給藥療 程是每個月3毫克/公斤的患者體重。抗整合素抗體 的其他劑量是說明於美國專利公開案2〇〇4/〇〇〇9169，其内 容以引用方式納入本文中。 本發明的抗體包括IgG、IgM、IgA、及型抗Pharmaceutical preparations of CdA are commercially available from Bedford Laboratories (Bedford, Ohio). In general, the dose of 2-CdA can be varied over a wide range to achieve and preferably maintain the desired plasma concentration. The dose of 2_CdA may be sufficient to provide a concentration of from about 5 nM to about 50 nM in the patient's plasma, preferably from about 1 nM to about 10 nM. The effective daily dose of 2-CdA may be from about 0. 04 to about ΐ·〇 mg/kg body weight, more preferably from about 4 to about 2 mg/kg/kg, and most preferably about 0.1 mg/kg body weight. . The other doses of 2_cdA are described in U.S. Patent No. 5,5,6,214, the disclosure of which is incorporated herein by reference. 4. Anti-〇: -4 integrin antibody: The anti-α -4 integrin antibody specifically binds to integrin including α·4th unit and inhibits integrin activity. The antibody may also bind to a dimer comprising, for example, α_4 integrin, e.g., α _4· stone-1 or α -4- -7. Anti-«-4 integrin antibodies may not show significant binding to any polypeptide other than α_4 integrin or a receptor including α•4 integrin. The antibody may bind to α_4 integrin at a binding affinity of 1 〇7 mol/liter or more, preferably 15 5 1373337 is ίο8 mol/liter or more. In general, the dosage of the anti-α-4 integrin antibody can be varied over a wide range to achieve and preferably maintain the desired plasma concentration. An effective dose of an anti-[alpha]-4 integrin antibody is one that provides the greatest reduction and/or inhibition of damage detected by brain magnetic resonance imaging. The dose of the antibody may be less than about 300 mg administered per month for a period of at least 6 months, more preferably i 2 months, and or for a period of more than a few years. Another preferred administration regimen is a patient weight of 3 mg/kg per month. Other dosages of anti-integrin antibodies are described in U.S. Patent Publication No. 2/4/9,169, the disclosure of which is incorporated herein by reference. Antibodies of the invention include IgG, IgM, IgA, and type antibodies
體及其片段及衍生物’包括Fab及F(ab，）2t>抗體也可以是 重組抗體產物，包括但並不限於，單鏈抗體、嵌合型抗體 產物、人類抗體、“人類化”的抗體產物及“靈長類化” 的抗體產物、CDR-移植的抗體產物。本發明的抗體包括單 株抗體、多株抗體、親和力純化的抗體或其對於抗_α_4 整合素抗體顯示足夠結合特異性的混合物。抗體也可以是 抗體/段。抗體可利用標準技術而製造，包括如W〇 01/5)210所說明的技術，其内容以引用方式納入本文中。 仏°』連恕在標籤上。標籤可以是產生訊息的酵 素、抗原、其他抗體、外源凝集素、碳水化合物、生物素、 杬生物素蛋白、放射性同位素、毒素、重金屬以及其他在 此技蟄中已知的組成物。連結技術也是在此技藝中所熟知 的0 、And fragments and derivatives thereof, including Fab and F(ab,)2t> antibodies, may also be recombinant antibody products including, but not limited to, single chain antibodies, chimeric antibody products, human antibodies, "humanized" Antibody products and "primatized" antibody products, CDR-grafted antibody products. The antibody of the present invention includes a monoclonal antibody, a polyclonal antibody, an affinity-purified antibody, or a mixture thereof exhibiting sufficient binding specificity for an anti-α_4 integrin antibody. The antibody can also be an antibody/segment. Antibodies can be made using standard techniques, including those described in WO 01/5) 210, the contents of which are incorporated herein by reference.仏°" forgiveness on the label. The label can be a message-generating enzyme, an antigen, other antibodies, lectins, carbohydrates, biotin, avidin, radioisotopes, toxins, heavy metals, and other compositions known in the art. Linking techniques are also well known in the art.
16 Ϊ373337 其他的抗體可利用在此技藝中可用的技術而鑑定。例 如，本發明的單株抗體可利用噬菌體顯示技術而製造。接 著可選擇性結合至α-4整合素或包括α-4整合素的二聚體 之抗體片段。藉由噬菌體顯示而製造該等抗體的示範性較 佳方法，是說明於美國專利第6,225,447 ; 6，180,336 ; 6,172,197 ； 6,140,471 ； 5,969,108 ； 5,885,793 ； 5,872,215 ； 5,871，907 ; 5,858,657 ; 5,837,242 ; 5,733,743 及 5,565,332 號，其内容以引用方式納入本文中。 才/l體可藉由將編碼完整或部分抗體（例如，單鏈Fv ) 的多核苷酸投予患者而提供。多核苷酸是在適當的載體中 投予個體，以使抗體以治療有效的量而在個體中表現。 5.組成物： 本發明的組成物更可包括一種或多種醫藥上可接受的 八他成刀，例如，明礬、穩定劑、抗微生物劑、緩衝劑、 色劑、香味劑、佐劑等等。 本發明的組成物可以是以傳統方式調配的片劑或旋劑 形式° ^"用於口服投予的片劑或膠囊可包含傳統的賦 形劑，包括但並不限於，點結劑、填充劑、润滑劑、崩散 劑及濕潤劑。黏結劑包括但並不限於，糖I阿拉伯膠樹、 ㈣ '山梨糖醇、㈣加康斯膠1粉及聚乙稀料貌酮 的黏液。填充劑包括但並不限於，乳糖、嚴糖、微晶體纖 維素、玉米濺粉、鱗酸弼及山梨糖醇。潤滑劑包括但並不 ，於，硬脂酸鎮、硬脂酸、滑石、聚乙二醇及二氧化石夕。 朋包括但並不限於’馬鈴薯澱粉及乙醇酸納澱粉。濕 ⑧ 17 1373337 潤劑包括但並不限於’硫酸月桂酯鈉。片劑可根據在此技 藝中熟知的方法而包膜。 本發明的組成物也可以是液體調配物，包括但並不限 於’水溶液或油性懸浮液、溶液、乳液、糖漿及萬能藥。 組成物也可調配成乾燥產物’以在使用前以水或其他適合 的載劑溶解。該等液體製備物可包含添加劑，包括但並不 限於，懸浮劑、乳化劑、非水性載劑及防腐劑。懸浮劑包 括但並不限於，山梨糖醇糖漿、甲基纖維素、葡萄糖/簾糖 糖漿、明膠、羥乙基纖維素、羧甲基纖維素、硬脂酸鋁膠 及氫化的可食用脂肪。乳化劑包括但並不限於，卵磷脂、 單油酸山梨聚糖及阿拉伯膠。非水性載劑包括但並不限 於’可食用油脂、杏仁油、分餾的椰子油、油性酯、丙二 醇及乙醇。防腐劑包括但並不限於，對_羥基苯甲酸甲酯或 對·羥基苯曱酸丙酯以及山梨酸。 本發明的組成物也可調配成栓劑，其可包含拴劑基 底，包括但並不限於’可可油或甘油◊本發明的組成物也 可調配成吸入劑，其可以是以下的形式，包括但並不限於， 可以乾粉投予的溶液、懸浮液或乳液，或是利用推進劑（例 如’二氣二氟甲烷或三氣氟甲烷）的氣溶膠形式。本發明 的組成物也可調配成經皮調配物，其包括水溶性或非水溶 性載劑，包括但並不限於，乳霜、油膏、洗劑、糊劑、藥 用石膏、貼片或薄膜。 本發明的組成物也可調配用於非腸胃道投予，包括但 亚不限於，注射或連續灌輸。用於注射的調配物可以是懸 ⑧ 1373337 浮液、溶液或在油性或水溶性載劑中的乳液之形式，並可 包含調配劑，包括但並不限於，懸浮劑、穩定劑及分散劑。 組成物也可以粉末形式而提供，用於以適合的载劑再溶 • 解，載劑包括但並不限於，無菌、無熱源的水。 本發明的組成物也可調配成儲存（depot )製備物，其 可藉由移植或藉由肌肉内注射而投予。組成物可與適合的 聚合或疏水性材料（例如，調配成在可接受的油中之乳 液）、離子交換樹脂而調配，或調配成微溶性衍生物（例 •如，調配成微溶性鹽）。 本發明的組成物也可調配成微脂粒製備物。微脂粒製 備物可包括微脂粒，其可穿透有興趣的細胞或角質層，並 且與細胞膜融合，導致將微脂粒的内含物傳遞至細胞中。 例如，可使用例如Yarosh的美國專利第5,〇77,211號、 Redziniak等人的美國專利第4,621〇23號或Redziniak等 人的美國專利第4,508,703號所說明的微脂粒。其他適合 的調配物可使用脂質體（ni〇somes)。脂質體是類似於微 脂粒的脂質載體，具有大部分由非離子性脂質所組成的 膜’其部为形式是有效於將化合物運送穿過角質層。 2-CdA的代表性調配物是說明於美國專利第6，194,395 號及美國專利第5,506,214號、W〇 96/1923〇、w〇 96/19229、W0 04/087100 及 W0 〇4/〇871〇1，其内容以引 用方式納入本文中。 6.投予： 本發明的組成物可以任何方式投予，包括但並不限16 Ϊ 373337 Other antibodies can be identified using techniques available in this art. For example, the monoclonal antibodies of the present invention can be produced using phage display technology. An antibody fragment that selectively binds to alpha-4 integrin or a dimer comprising alpha-4 integrin. Exemplary preferred methods of making such antibodies by phage display are described in U.S. Patent Nos. 6,225,447; 6,180,336; 6,172,197; 6,140,471; 5,969,108; 5,885,793; 5,872,215; 5,871,907; 5,858,657; 5,837,242; 5,733,743 and 5,565,332 , the content of which is incorporated herein by reference. The vector can be provided by administering a polynucleotide encoding a complete or partial antibody (e.g., a single chain Fv) to a patient. The polynucleotide is administered to the individual in a suitable carrier such that the antibody behaves in the individual in a therapeutically effective amount. 5. Composition: The composition of the present invention may further comprise one or more pharmaceutically acceptable octahedral knives, for example, alum, stabilizer, antimicrobial agent, buffer, colorant, fragrance, adjuvant, etc. . The composition of the present invention may be in the form of a tablet or a blister in a conventional manner. The tablets or capsules for oral administration may contain conventional excipients including, but not limited to, sticking agents, Fillers, lubricants, disintegrating agents and wetting agents. Adhesives include, but are not limited to, mucus of sugar I gum arabic, (iv) 'sorbitol, (iv) plus Kangsi gel 1 powder and polyethylene ketone. Fillers include, but are not limited to, lactose, Yan sugar, microcrystalline cellulose, corn splash powder, bismuth citrate, and sorbitol. Lubricants include, but are not, in, stearic acid, stearic acid, talc, polyethylene glycol, and dioxide. Friend includes, but is not limited to, 'potato starch and sodium glycolate. Wet 8 17 1373337 emollients include, but are not limited to, sodium lauryl sulfate. Tablets may be coated according to methods well known in the art. The compositions of the present invention may also be liquid formulations including, but not limited to, aqueous solutions or oily suspensions, solutions, emulsions, syrups, and panacea. The composition may also be formulated as a dry product' to dissolve with water or other suitable carrier prior to use. Such liquid preparations may contain additives including, but not limited to, suspending agents, emulsifying agents, non-aqueous vehicles, and preservatives. Suspending agents include, but are not limited to, sorbitol syrup, methylcellulose, glucose/silica syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate, and hydrogenated edible fats. Emulsifiers include, but are not limited to, lecithin, sorbitan monooleate, and gum arabic. Non-aqueous vehicles include, but are not limited to, 'edible oils, almond oil, fractionated coconut oil, oily esters, propylene glycol, and ethanol. Preservatives include, but are not limited to, methyl p-hydroxybenzoate or propyl p-hydroxybenzoate and sorbic acid. The compositions of the present invention may also be formulated as a suppository, which may comprise an elixir base, including but not limited to 'cocoa butter or glycerin oxime. The compositions of the present invention may also be formulated as inhalants, which may be in the form of, but It is not limited to a solution, suspension or emulsion which can be administered as a dry powder, or in the form of an aerosol using a propellant such as 'difluorodifluoromethane or trifluoromethane. The compositions of the present invention may also be formulated as a transdermal formulation comprising a water-soluble or water-insoluble carrier including, but not limited to, creams, ointments, lotions, pastes, medicinal plasters, patches or film. The compositions of the present invention may also be formulated for parenteral administration, including, but not limited to, injection or continuous infusion. The formulation for injection may be in the form of a suspension, solution or emulsion in an oily or water-soluble carrier, and may contain formulating agents including, but not limited to, suspending, stabilizing and dispersing agents. The composition may also be provided in powder form for reconstitution with a suitable carrier including, but not limited to, sterile, pyrogen-free water. The compositions of the present invention may also be formulated as a depot preparation which can be administered by transplantation or by intramuscular injection. The composition may be formulated with a suitable polymeric or hydrophobic material (for example, formulated as an emulsion in an acceptable oil), an ion exchange resin, or formulated as a sparingly soluble derivative (eg, formulated as a sparingly soluble salt) . The compositions of the present invention can also be formulated as a preparation of vesicles. The liposome preparation may comprise a vesicle that penetrates the cell or stratum corneum of interest and fuses with the cell membrane, resulting in the delivery of the contents of the vesicle into the cell. For example, the aliquots described in U.S. Patent No. 5, No. 4, 621, No. 4, the entire disclosure of which is incorporated herein by reference. Other suitable formulations may use ni〇somes. Liposomes are lipid carriers similar to vesicles, with a majority of membranes composed of nonionic lipids in the form of a portion effective to transport the compound across the stratum corneum. Representative formulations of 2-CdA are described in U.S. Patent No. 6,194,395 and U.S. Patent Nos. 5,506,214, W〇96/1923〇, w〇96/19229, W0 04/087100 and W0 〇4/〇871〇 1, the content of which is incorporated herein by reference. 6. Administration: The composition of the present invention can be administered in any manner, including but not limited to
19 1373337 於，口服、非腸胃道、舌下、經皮、直腸、經黏膜、局部、 經由吸入、經頰投予或其組合。非腸胃道投予包括但並不 限於，靜脈内、動脈内、腹膜内、皮下、肌肉内、顱内及 關節内。本發明的組成物也可以植入物的形式而投予，其 可提供組成物的缓慢釋放以及緩慢控制的靜脈内輸液。 本發明藉由以下實施例而進一步說明，這些實施例並 非要以任何方式限制本發明的範疇。 實施例1 :多發性硬化之治療 對於六十位患有慢性多發性硬化的患者進行研究。每 一位患者都首先檢查正常肝臟、腎臟及骨髓功能，以建立 基線數值。將患者隨機分配至表1所列之治療組之一。 表1 組別 2-CdA 那他珠單抗 (natalizumab ) 1 一 — 2 0.25毫克/公斤 3 0.5毫克/公斤 — 4 1毫克/公斤 1 5 一 1毫克/公斤 6 一 3毫克/公弄 7 — 6毫克/0 ' 8 0.25毫克/公斤 1毫克/公斤 9 〇·5毫克/公斤 3毫克/公斤 10 1毫克/公斤 ό毫克' 在第2-4及8_10組中的每一位患者，都以溶解於無菌 無防腐劑的等張鹽溶液中< 2，CdA而治療，而在第】及5_ 7組中的患者則接受安慰劑（鹽溶液）。2-CdA是靜脈内 投予總共七天，每月一次總共一年。在第51〇組的每位患 ⑧ 20 1373337 =都以那他珠單抗治療，而f卜4組則接受安慰劑（鹽溶 =)。那料單抗是靜脈内投予總共七天，每月_次總共 年’與2-CdA治療在相同的天數治療。 dt、者W測^是否有與多發性硬化進展相關的腦部 展或改善。所有的患者都在·12月具有基 置）及磁八振造影研究（腦部或脊椎神經，根據損傷的位19 1373337, orally, parenterally, sublingually, transdermally, rectally, transmucosally, topically, by inhalation, buccal administration, or a combination thereof. Parenteral administration includes, but is not limited to, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intracranial, and intra-articular. The compositions of the present invention may also be administered in the form of an implant which provides for slow release of the composition and slow controlled intravenous infusion. The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention in any way. Example 1: Treatment of multiple sclerosis Sixty patients with chronic multiple sclerosis were studied. Each patient was first examined for normal liver, kidney, and bone marrow function to establish baseline values. Patients were randomly assigned to one of the treatment groups listed in Table 1. Table 1 Group 2-CdA Natalizumab 1 - 2 0.25 mg / kg 3 0.5 mg / kg - 4 1 mg / kg 1 5 - 1 mg / kg 6 - 3 mg / kg 7 - 6 mg / 0 ' 8 0.25 mg / kg 1 mg / kg 9 〇 · 5 mg / kg 3 mg / kg 10 1 mg / kg ό mg ' in each of the patients in groups 2-4 and 8_10, The patients were treated with < 2, CdA dissolved in a sterile preservative-free isotonic saline solution, while patients in the groups 5 and 7 received a placebo (salt solution). 2-CdA is administered intravenously for a total of seven days, once a month for a total of one year. In the 51st group, each patient suffered from 8 20 1373337 = all were treated with natalizumab, while the group b was given placebo (salt solution =). Nambab was administered intravenously for a total of seven days, and monthly _ times total years were treated on the same day as 2-CdA treatment. Dt, W test whether there is brain development or improvement related to the progression of multiple sclerosis. All patients have a base in December and magnetic eight-enhanced angiography (brain or spinal nerve, depending on the location of the injury)
在第1_…組中的患者具有增加的腦部損傷。在第 4及6-10組中的*去且古沾卜认_ Α #在第 〜者”有減少的腦部損傷。重要的是，在 第1〇組中的患者顯示最大減少的腦部損傷。此外，在第8 組中的患者具有減少的腦部損傷’相似於第4卩6組中的 患者。這個數據㈣2儒及那他珠單抗的組 投：t 一作I，效。此外，數據也顯示2_⑽及那他 的在早獨投予2德或那他珠單抗是無效的 劑量時是有效的。 【圖式簡單說明] 無 【主要元件符號說明】 無 21Patients in the group 1_... have increased brain damage. In the 4th and 6th-10 groups, the group of patients in the group 1 and 6-10 have reduced brain damage. It is important that the patients in the group 1 show the largest reduction in the brain. In addition, patients in Group 8 had reduced brain damage 'similar to those in Group 4-6. This data (4) 2 Groups of Confucian and Natalizumab: t for I, effect. The data also shows that 2_(10) and that is effective when it is administered to 2D or Natalizumab at an early dose. [Simplified illustration] No [Main component symbol description] No 21