TWI242444B - Combination therapies for B-cell lymphomas comprising administration of anti-CD20 antibody - Google Patents
Combination therapies for B-cell lymphomas comprising administration of anti-CD20 antibody Download PDFInfo
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- TWI242444B TWI242444B TW088113738A TW88113738A TWI242444B TW I242444 B TWI242444 B TW I242444B TW 088113738 A TW088113738 A TW 088113738A TW 88113738 A TW88113738 A TW 88113738A TW I242444 B TWI242444 B TW I242444B
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Description
1242444 五、發明說明（4) 抗-CD20抗體。 同時，本發明之方法可使闬任何的抗-CD20抗體，較佳 的喪合型抗體為C2B8(IDEC Pharmaceuticals，Rituximab® )。較佳的放射性標示之抗體為Y 2 B 8，其為以紀—9 0(9(3 Y )標 示之老鼠抗體。然而，亦可使用帶有其他放射性標記的拆 體’尤其疋以卢或α同位素標不的那些’亦可使用抗-C D1 9抗體。 熟諳此藝者將知道選擇特定類型之抗-C D 2 0抗體的變數 。例如，喪合型和人類化的抗體，在減少免疫原性上是有 利的，並經由人類恆定區功能部位而有助於抗體效應物調 節的免疫反應。老鼠和其他哺乳動物的抗體，相反地有剎 於遞送放射性標記至腫瘤細胞中，並使得這類抗體在活艘 内通常具有減少的半衰期。 一'開始對難以醫治或已經復發之患者進行抗體處理，町 包括最初利用嵌合型抗體或哺乳動物抗體的處理。亦包抬 利用其他抗體的最初處理，包括抗—CD19抗體和抗—Lym抗 體，以及利用以胞毒部份標示的抗體處理，像是毒素和放 射性標記，例如Oncolym®(Technicl〇ne)或Bexxar (Coulter) 〇 應該很清楚可同時提供該治療，來進行本發明之混合的 治療攝生法，也就是同時或是在相同的時間架構内（也就 是同時進行治療’但並非在猜確相同的時間内投予製劑） ，投予抗-CD20抗體。亦可在其他治療之前或之後，投予 本發明之抗-C D 2 0抗體。無論患者對第一種治療是否有反
1242444 五、發明說明（5) 應’均可進行後續的投藥，以便減少緩和或復發的可能性 〇 本發明之混合治療包括處理β—細胞淋巴瘤的方法，包括 投予至少一種嵌合型抗—CD2()抗體和至少一種細胞分裂素.. 。特定而言’本發明包括處理8 —細胞淋巴瘤的方法，包括 投予協同的治療組合，其包括至少一種抗— CD2〇抗體和至 少一種細胞分裂素，其中治療效果比單獨投予治療劑的相 加效果更佳。較佳的細胞分裂素，選自包括α干擾素、7 干擾素、IL-2、GM-CSF和G-CSF。再者，可分別按順序或 混合投予抗-CD20抗體和細胞分裂素（們）。 本發明亦包括處理B -細胞淋巴瘤的方法，包括在化學 治療的攝生法之别、期間或之後，對患者投予具有療效之 含量的嵌合型抗-CD20抗體。這類化學治療的攝生法至少 可選自包括CHOP、ICE、米托沙酮、阿糖胞普、dvp、ATRA 、伊達比星、Hoe lzer化學治療攝生法、La La化學治療攝 生法、ABVD、CE0P、2-CdA、FLAG & IDA(有或無後續的G-CSF 處理）、VAD、M&P、C - Weekly、ABCM、M0PP 和 DHAP。 亦包括處理B -細胞淋巴瘤的方法’包括在骨髓或周圍幹 細胞移植之前、期間或之後，對患者投予有療效之含量的 嵌合型抗-CD20抗體。這類骨髓移植亦可伴隨有其他治療 性的攝生法，像是化學治療。亦可藉著對患者投予鼓合型 抗- C D 2 0抗體，在骨髓分離治療之前或之後的減少骨髓或 幹細胞中殘餘之C D 2 0 +腫瘤細胞的方法中，使用本發明之 抗體。亦有可能在活體外使用這類抗體，以便在將骨髓戒
1242444
五、發明說明（6)
幹細胞製品輸回至該患者體内之前，誘發腫瘤細胞的細胞 程式死亡，並減少或革除在該製品中殘餘的腫瘤細胞。匕 應該明瞭該幹細胞移植物可以是同種的或自體的。如 果該移植物是同種的，也就是得自其他個體，則所揭示 治療性攝生法可包括在投予抗_CD20抗體之前，利兩免1"疫之 抑制藥物來處理。亦企圖設計可促進移植物的接受，並^ 激免疫細胞之產生和分化的其他藥物的共同投藥。例如， 已經顯不對骨隨移植之接受者投予GM — CSF，促進了特定骨 髓細胞的發育，其轉而產生循環中與感染交戰的嗜中 血球’並增加骨髓移植物接受者的存活率。 亦可使用本發明之方法來處理各種B-細胞淋巴瘤，包括 低級/濾泡性非-霍奇金氏淋巴瘤（NHL)、小琳巴細胞（sl) 之NHL三中級/濾泡性NHL、中級擴散性〇1、高級免疫胚性 NHL、'、南級琳巴母細胞性NH]L、高級小的非-印裂細胞性nhl 、容積性疾病圓[和瓦耳登斯壯氏（^1(1611311>〇111，3)巨球蛋 白血症。热諸此藝者應該很清楚這些淋巴瘤通常有不同的 名稱’係因為多變化之系統的分類，而罹患在不同名稱下 分類之淋巴瘤的患者，亦可從本發明之混合的治療性攝生 法中獲益。 例如’由歐洲和美國病理學家提出之目前的分類系統， 稱為修3丁的歐洲美國淋巴瘤（Revised £ur〇peari American
Lymphoma) (REAL)之分類。該分類系統承認包膜細胞淋巴 瘤和邊緣的細胞棘巴瘤，在其他周圍的β _細胞贅生物中， 並以細胞學為基礎將一些分類再分等级，也就是小細胞、
第9頁 1242444 五、發明說明 ----〜- !! ί ί胞和大細胞。將明瞭所有這些經過分類的淋巴瘤， 句°」自本發明之混合治療中獲益。 =家癌症協會(NCI)再將某些舰分類 l床用途之"不活動性"或"侵略性,，的淋巴瘤命名。 :::?瘤包括濾泡性細胞淋巴瘤，分成細胞學"等級"， 獷政U小祙巴細胞的淋巴瘤/慢性淋巴細胞性白， :”巴I細胞瘤/瓦耳登斯壯氏巨球蛋白血症皿： =和毛uairy)細胞白血病。侵略性麻 性此。的或大細胞淋巴瘤、柏 ^岵擴政 亦可自本發明之混合治療性攝生法 只。°二淋巴瘤 亦按"等級"，以其他疾病之二二 氏淋巴瘤分類，包括低_級、= ’將非-霍奇金 級的淋巴瘤通常呈現結節的疾：：二的淋巴瘤。低- 慢生長的。中_和高_級的^吊=活動性或缓 ，並有大的、結節外的巨大腫；：；_:極和具^略性w 以及低-級的NHL·，均可自本$ 问級的疾病， 益。 本&明之混合治療性攝生法中獲 對於罹患NHL的患者，亦常使 Μ 該系統中，可依據患者具有充 +、η ^ 〇r分類系統。在 無⑴1成人的工^ ^義之概括性徵候⑻或 名為B之患者具有下列的徵候·在、二階段分成A和6類。命 法解釋之1〇%以上的體重喪失：^斷之前6個月内’有無 灾天，無法解釋的發燒，溫度在
1242444
量處理來治療。 >9 5%在細胞I ^ ^氏林巴瘤為β_細胞惡性’且這些中 興趣的標靶，' =出CD20抗體。該抗體為免疫治療感 細胞、前-B %胞：正a '細胞上找到，而不能在造血的幹 它也不會從έ±吊的漿細胞或其他正常組織中找到。 (i)。曰、'，田胞衣面上脫落，而不會調節抗體的結合作用 & 髟是一種新產生的單株抗體’發展出來克服走 遇到的限制’其包括短半衰期、刺激人類效應 物功旎的有限能力，及免疫原性（2,3)。
Ritux:imab®是以遺傳方式，利用老鼠輕一和重—鏈可變區 ，和亡類r I重-鍵和卡巴輕-鍵恆定區來設計的單株抗體 。該嵌合型抗體包括兩個具有451個胺基酸之重鏈，和兩 個具有213個胺基酸之輕鏈，並具有大約的分子量。 R i ΐ u X 1 m a #在固定補體和調節a ο C C上，比其老鼠親代更有 效，且其在人類補體出現時調節CDC(4)。該抗體在6—細胞 株FL-18、Ramos和Raji中抑制細胞生長，使化學抗藥性之
人類淋巴瘤細胞株對白喉毒素、蓖麻蛋白、CDDP、阿黴素 和鬼臼乙叉武（etoposide)敏感化，並以劑量依賴性之方 式’在D H L - 4人類B -細胞淋巴瘤細胞株中誘發細胞程式死 亡（5 )。在人類中，在第一次輸液之後，抗體的半衰期.為 大約6 0小時，並在第四次輸液之後，隨著每次投藥增加至 1 7 4小時。抗體的免疫原性很低，在七個臨床研究的3 5 5個 患者中，僅有三個（< 1 % )具有可檢測到之抗-嵌合性抗體
第12頁 1242444 五、發明說明（10) (MCA)的反應。 使用老乳2 B 8抗體，·以遺傳方式來設計r丨t u x i m a b 。為 I和治療之目的，亦已經將2B8抗體與不同的放射性 標圯結合。為了這個目的，同在申請中之申請案連續第 08/475,813 號、〇8/475,815 號，和08/478,967號，將其合 併於此以作為參考，揭示了以放射性標示之抗_CD2〇共軛 物’可在投予治療性抗體之前，用於β—細胞淋巴瘤腫瘤之 #斷呈像。’’ I n2B8”共軛物包括老鼠的單株抗體，2B8， 對人類CD20抗體有特異性，經由雙重功能的螯合劑將其 銦[111 ](luIn)附接，也就是mx —DTpA (二亞乙基三胺五乙 酸），其包括1-異硫氰基基〜3-甲基-DTPA和1 一曱基一3 - 異硫氰基基—DTPA的1 ·· 1混合物。選擇銦_[丨丨丨]做為診 斷放射性核素，是因為其放出τ幅射，並在用來做為呈像 劑之前發硯。 與螯合劑和螯合劑共軛物有關之專利，是此項技藝中已 熟知的。、例如〇3113(^的美國專利第4,831，175號，其^十對 多重取代之二亞乙基三胺五乙酸螯合劑，和含有相同物的 蛋白質共軛物，以及其製備方法。Gans〇w的美國專利 5, 0 9 9, 0 6 9 號、5, 2 46, 69 2 號、5, 286, 8 5 〇 號和 5, 1 24 47 1 亦關於多重取代的DTPA螯|。以其完整内容將這些專， 併於此以作為參考。 一 。 按照對三價金屬具有高親和力 1刀’亚挺供增加的腫瘤-對一 非-腫瘤比例、降低骨骼攝入，计 ^ 4 亚在標靶部位，也就是 細胞淋巴瘤腫瘤部位處，使放& w t 义叹射性核素在活體内的停留更
1242444 五、發明說明（1U 久，來選擇在MX-DTPA中使用，可促進螯合作用的特定雙 重功能之螯合劑。然而，其他的雙重功能整合劑是此項技 藝中已知的，亦可有利於腫瘤之治療。 在美國專利第5, 7 3 6, 1 37號中亦揭示了為了瞄準並破壞· β〜細胞淋巴瘤和腫瘤細胞，以放射性標示之治療性抗體。 特別是Υ2Β8共軛物，其包括相同的抗-人類CD2〇老鼠單株 抗體，2 B 8，經由相同的雙重功能螯合劑與釔—[9 〇 ] (^ γ )附 接。為了數個理由選擇該放射性核素用於治療。9〇γ的6 4小 % ^之半衰期，長得足以容許使抗體堆積在腫瘤中，不像例 如131Ϊ ’其為純的高能量/3發射體，在其衰變時並未伴隨 有r輕射，範圍在1 〇 〇到1 〇 〇 〇的細胞直徑。最低含量的貫 穿輻射容許對門診病人投予標示之抗體。此外，為了 殺死細胞並不需要内化的放射性標示之抗體，而離子幅射 的局部放出，對於缺乏標耙抗原的鄰近之腫瘤細胞應該是 致命的。 口為使用相同的雙重功能螯合劑分子Μ —DTP A，將9(3γ放 射性核素與2Β8抗體附接，該Υ2Β8共軛物具有與上文討論 相同的優點，例如增加放射性核素在標靶部位（腫瘤）處的 停留。然而，不像⑴Ιη，，其無法用來呈像，因為其缺乏相 關的二輻射。因此，可在本發明之混合攝生法中，投予治 ，療c/生^ 〇型或9GY''標示之抗體之前及/或之後，使用診斷性 ”呈像”的放射性核素，如min，來決定腫瘤的位置和相對 大I此外，亦可製造能夠以計量器評估的以銦-標示之 抗體。
1242444 五、發明說明（14) 並不認為 療。在15 之研究’證實尚未達到最大的容忍劑量；然而， 以最高劑量輸液的時間長度通用於門診病人的“ 個患者中的ORR為13%(表1 )(6)。 表1
Rituximab® :效力結杲的概述
研究說明 適應症 0RR CR PR 中間值 DR(月） 中間值 TIP(月） 參考 文獻 階段Ι/Π， 單次投藥， 單一製劑 復發的B-細胞淋 巴瘤 15 2(13%) 0(0%) 2(13%) NA+ 8.1 6 階段I/II， 多次投藥， 有劑量範圍 復發的低-、中-和南-級淋巴瘤 34 17(50%) 3(9%) 14(41%) 8.6 10.2 7 階段π;與 CHOP混合 的多次投藥 新近診斷或復發 的低級或渡泡 性B-細胞淋巴瘤 38 38(100%) 22(58%) 16(42%) 35.3+ 36.7+ 21， 22 階段ΠΙ，多 次投藥，單 一製劑 復發的低-級或 渡泡性B-細胞淋 巴瘤 151 76(50%) 9(6%) 67(44%) 11.6 13.2 8, 9 階段π，多 次投藥，單 一製劑 復發的低-級或 渡泡性B -細胞淋 巴瘤 35 21(60%) 5(14%) 16(46%) 13.牡 19.4+ 13 階段π，與 干擾素混合 的多次投藥 復發的低-級或 渡泡性B-細胞淋 巴瘤 38 17(45%) 4(11%) 13(34%) 22.3+ 25.2+ 29 階段n，多 次投藥，單 一製劑 復發的低級或濾 泡性B-細胞琳巴 瘤，容積性疾病 28 12(43%) 1(4%) 11(39%) 5.9 8.1 14
第17頁 1242444
階段II，多 次投藥，單 一製劑 復發的低-級或濾 泡性B-細胞淋巴 瘤，再度處理 57 23(40%) 6(11%) 17(29%) 15.0+ 16.7+ 19, 20 階段Π，與 CHOP混合 的多次投藥 先月彳未處理的中-或高-級淋巴瘤 30 29(96%) 19(63%) 10(33%) 11+ 17+ 34 階段Π，另 一種的多次 投藥 中-或高-級的B-細 胞淋巴瘤 54 17(32%) 5(9%) 12(22%) NA卞 8.2+ 33 可評怙之患者的數目 +無法利甩
在階段I / Π之劑量-範圍研究的第I階段中，患者接受四 次的每週125-375毫克/平方公尺之輸液。並未證實與劑量 有關之毒性’並選擇3 7 5毫克/平方公尺做為第π階段的劑 1。在3 7個接受該劑量之患者的1 7個（4 6 %中觀察到腫瘤的 退化’包括3個（8%)完全的反應（CR)和14個（38%)部分的反 應（PR)(7)。 在1 6 6個罹患復發的或難以醫治之低-級或濾泡性⑽乙 (International Working Formulation[IWF]類型A — D，以 及R E A L分類，小淋巴球淋巴瘤、濾泡性癌症，濾泡等級I 、Π、ΙΠ (8))的患者中，經營四次以3 7 5毫克/平方公尺， 每週輸液之Rituximab®的後續單-臂樞軸研究。從該研究 中排除腫瘤團塊> 1 0公分，或在周圍血液中> 5 0 0 〇個淋巴球 /微升的患者。中間年齡為5 8歲（1 〇 5個男性和6 1個女性）， 且先前處理之中間數為三。評估骨髓的涉入，在1 4 9個患
第18頁 1242444 五'發明說明（16) ' "— --- 者中有5 6 %。4 5 %具有-2的結節外部位而4 1 %有容積性疾病 (-5公分）。 、
立完全反應需要證實在至少問隔28天的兩次之中，在顯 部、胸部、腹部和骨盤CT掃貓時，所有的淋巴結退化至 < 1 X 1平方公分，並解除所有淋巴瘤的徵候和症狀，和骨體 、肝臟和脾臟的正常化。部分反應需要在至少2 8天内，在 垂直測量病變產物的總和上有2 5 〇 %的降低，而無任何進 行性疾病的證據。並未達到CR4PR的患者，被視為是未一 反應者’即使觀察到可測量之疾病的淨降低（〉5 〇 %。從第 一次輸液開始測量進行的時間，直到進行為止。 全面性的反應率（ORR)為48%，有6%CR和42%PR率（8)。進 行時間的中間值（TTP )為1 3. 2個月，反應期間的中間值 (DR)為11·6個月。80個反應者中有22個（28%)在20.9 +至 3 2 · 9 +個月中維持持續進行的緩和（9 )。 投予Rituximab®，結果迅速並持續地耗盡卜細胞。在前 二次投藥中耗盡循環中的B -細胞，並在處理後，在8 3 %患
者中有南達6至9個月中持續耗盡。在處理之後個月，b-細胞含量的中間值回復至正常。雖然NK細胞計數之中間值 維持不變，但在基準線處較高之絕對NK細胞計數和對 R i t ux i mab®的反應之間，觀察到正性相關（丨〇 )。 分析數個基準線預兆因子，定出其對反應的相關性。重 要的是，23個在ABMT或PBSC之後復發的患者，ORR為78%， 對之前未經歷高劑量處理之患者中為43°/Q (p<〇. 01 )。在多 變$分析中’與小淋巴球·淋巴瘤的患者相比較，在罹
第19頁 1242444 五、發明說明（17) ~ ' -----一》- 患濾泡性NHL的患者中是較高的（58%對丨2% =學敏感性愎發的患者中，比在化學抗藥性之·者中更 问（534對36%，p = 〇.〇6)。與下列因素之關連，並ς 反應速率：年齡〉㈤歲，結節外的㈣，"不會;^ Τ之處理，或骨髓的涉入。 的氣回％ 1放 在處理和追縱調查期間的多個時間點，，、 之中間值和反應之間，發現在統計學上的顯虹/辰度 與罹患小淋巴球淋巴瘤之患者相比較，在妨^ ( 1 1 )。 NHL的患者中有較高的抗體血清含量。平均▲惟濾泡性 瘤大小的測量值和在基準線處之循環中B〜細於青抗*體與腫 相反關係。較低血清抗體濃度與較高數量 ^ η數目亦有 胞，以及較大之腫瘤大小的關聯，暗示抗體1 =中NHL細 的主要模式。較高血清抗體濃度與反應，以:二腫瘤細胞 大小或循環中細胞的關聯，·暗示在一些患者的乂】、之腫瘤 如罹患容積性疾病的那些，誘發反應可能需i f、、且中’諸 更多次投予RHunmab®。 而要較高劑量或 暗示以 這是令 儘管如此，在4 3 %腫瘤> 5公分的患者中，以及 > 7公分的患者中，利用R i t u X i m a b®所見到的反應在Μ %腫瘤 Ri tuximab⑧處理罹患容積性疾病的患者是可行^ 人意外的，因為認為它是長的，在整個抗體治療、 病的 $公尺 由於腫瘤之緻密性質而為不可傳導來處理容於二過程中 在曰本進行的研究中（12)，每週以250毫克/ _ 、 (Ν = 4)或 375 毫克/ 平方公尺（Ν = 8)的 Rituximab® w 復發之B -細胞淋巴瘤的患者四次。在11個接愛+處理罹 入砰估的患者 1242444 五、發明說明（18) 中，8個患有濾泡性NHL，2個患有擴散性大-細胞NHL，而 一個患有包膜_細胞淋巴瘤。1 1個中有兩個具有C R，5個具 有PR，ORR為6 4% ;所有的反應者均具有濾泡組織學。 因為在先前的研究中，Rituximab®的血清含量和反應為 正性相關的，在低-級或濾、泡性N H L患者中，經營八次每週 投予375毫克/平方公分之Rituximal#的第Π段研究。在可 評估的患者中，0RR·為6 0%，1 4%的C R和4 6 %的PR比例。在反 應者中，TTP和DR的中間值分別為13.4和19.4 + (13)。雖然 不易比較交叉研究，顯然由於使用更多次的投藥而改善了 TTP 和DR。 與早期關於僅適用於微量轉移之疾病的抗體治療之假定 相反，Rituximab®在高容積性疾病中是相當活躍的。在個 別的研究中，31個罹患復發的、大的低-級NHL的患者（單 一病變的直徑>10公分），以每週輸液375毫克/平方公分 Ri tux imab®，接受四次處理。在28個可評估的患者中，1 2 個（43%)證實 CR(1，4%)或 PR(11，39°/。）（14)。 瓦耳登斯壯氏巨玻I白血症 瓦耳登斯壯氏巨球蛋白血症（WM )是其中B淋巴球分泌過 里I gM抗體的惡性疾病。醫通常在六十歲以上的人身上發 生’但亦在三十出頭的成人身上檢測到。今天，認為WM是 罕見的、無法醫治的、不活動的惡性疾病，過去藉著血漿 除去法’降低血清黏性來處理之。通常開立諸如烷化劑之 類的化學治療劑和皮質類固醇的藥方。對WM最推薦的藥物 為留斯達丁（Leustatin)(2CdA)。
第21頁 1242444 五、發明說明（19) 對利用Rituximab®(每週375毫克/平方公尺，4次）處理 之七個罹患瓦耳登斯壯氏巨球蛋白血症的患者所做的報告 Ο 5 )，提及在四個（5 7% )患者中有反應。不前進發展之存 活的中間值為8個月（範圍從3 - 2 7 +個月）。因此，
Ri tux imab®對於混合治療之草案應該是有用的，特別是諸 如2CdA之類的化學治療劑。 慢性淋巴球白血病C.CLL) CLL是小淋巴球琳巴瘤（SLL)的液態（白血病性）相等物。 當以標準劑量之Ri tuximab⑧處理時與罹患其他低-級NHL亞 型的患者相比較，罹患SLL之患者有較低的血清含量和較 低的反應率。這或許是因為在患有CLL之患者中：有極高 含量的循環腫瘤細胞，並同為CLL中涉及之惡性細胞，被 認為在細胞表面上具有降低程度的CD20表現。 - 儘管如此，本發明仍揭示可利用Rituximab®來處理血液 學上的惡性疾病，如CLL。最近的臨床研究評估以較高劑 量的Rituximab®來處理CLL患者（16)。所有患者均接受375 毫克/立方公尺的第一個劑量，以便將輸液—復發的副作用 減至最低。之後每週的投藥次數（3)維持不變，但給予增 加的劑量。以5 0 0 - 1 5 0 0毫克/立方公尺之劑量處理個^ 者。年齡的中間值為66歲（範圍：·25 —7δ)。81%在第ffl—^ 階段疾病的末期’白血球計數之中間值為4 〇χ丨〇9公升（苑 圍：4 - 2 0 0 )、Hgb 11.6 克 / 毫微升（範圍：7·7 —14 了）、^血 小板75x10V公升（範圍·· 16-160)、化免疫球蛋白之中 值為4·5毫克/公升（範圍，先前治療之數目的
1242444 五、發明說明（21) 細胞之表面上的表現，藉此使CD20，或其他諸如CD1 9之類 的細胞表面標記，成為對免疫治療更具吸引力的標靶。已 經開始進行合作的研究，測試關於在活體内向上調節CD2 〇 的最佳細胞分裂素之劑量。該研究草案涉及一開始以2 5 0 微兄/平方公尺GM-CSF SQ QD x3，處理十個患者，以IL-4 微克/公斤SQ QD x3，處理十個患者，並以5微克/公斤G-CSF SQ QD X3，處理十個患者。關於細胞程式死亡之研究 藉著Ficon Hypaque離心法分離單核細胞，決定CD20轉
澤的向上調節，是否促進Rituxima b®殺死禮瘤細胞。 CLL的抗體處理，可與其他傳統的，已知可周來處理CLL 之化學治療性處理混合。CLL最常使用的單一製劑為苯丁 酸氮芬（留克偷（leukeran))，以每天0.1毫克/公斤或每四 週〇·4至1.0毫克/公斤提供。苯丁酸氮芥通常與口服的脫 氫皮甾醇（30至100毫克/平方公尺/天）混合，其在自體免 疫之血球細胞減少症的管理上是有兩的。環鱗醯胺是笨丁 酸氮芥以外的另一種選擇，常用的劑量為1 - 2克/平方公尺 ’每隔3- 4週，與長春新鹼（vincristine)和類固醇一起 (例如COP攝生法）。 CLL已經使用各種藥物之組合，包括c〇p(環璘醯胺、長4丨 春新鹼（oncovin)和脫氫皮<邊醇），以及CHOP(道三種藥物 加上阿黴素）。氟達拉濱（fludarabine)對CLL尤處理顯示 出效力，並在以2 5-3 0毫克/平方公尺/天，每3一4週處理的 患者組中，提供50%的〇RR。雖然有些患者對氟達拉濱顯示 疋難以醫治的。這類患者亦對2 - C d A有抗樂性’囚為通常
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1242444 五、發明說明（22) 氣達杈濱難以治癒的患者，對2-CDA而言亦是難以醫治的 (〇 Brien 等人，ν· Engl· J. Med .330:319-322 (1994)) 因此，對於在利用化學治療藥物處理之後，為難以醫治: 或又復發的患者而言，抗-CD20抗體之治療將是特別有用 的。在這些患者中，R i t u X i m a b®治療亦可與放射性治療混 合。對7 5至1 5 0厘戈瑞之總劑量，已經顯示具有1 5厘戈瑞 之低分級大小的T B I，在大約三分之一的患者中是有效的
目前在CLL患者中，藉著CALGB正在經營第Π階段的試驗 同時投予Rituximab⑧和氟達拉濱，接著在Rituximab®之 後合併Rituximab®對氟達拉濱的誘導作用。 與骨髓分離之治療
在不活動的淋巴瘤中，骨髓分離治療已經產生反應，然 而’不論如何高劑量之治療，仍有殘餘的腫瘤細胞，且 PBSC的再灌注可能含有腫瘤細胞。在幹細胞移動之前，和 移植之後使用Ri tuximab®，以便降低殘餘的CD2〇 +腫瘤細 胞’並收獲骨趙或幹細胞的污染物。暫時性的結果證實， 在所獲得的細胞中並未檢測到⑶“十細胞。24個患者中有 1 8個完成移植’並完全容忍該處理。進行pcR測試來評估 剩下的腫瘤細胞（1 8 )。 U 復發的低—級nhl 已、”二報σ «平估5 3個對r丨t u X丨瓜a 有反應，但猶後又復發 之患者的再度處理之試驗（丨9 )。5 6個可評估的患者中，有
第25、頁 1242444 五、發明說明（23) 7個（13%)得到CR，並有16個得到PR(29°/〇，ORR為42%。四 個患者有第二次的反應，接受第三次處理；其中3個有反 應。 在兩次連續的Ri tuximab㊆處理之後，一個患者的腫瘤， 最初分類為濾泡性、小的卵裂細胞NHL，不再表現CD20抗 體，並對Rituximab®無反應性，此時轉化為擴散的、大細 胞NHL(20)。 因此’對於先前以R i t u X i m a b®處理之後又再復發之患者 ，利用Rituximab®再次處理是有效的，在第二次處理之後 ’可能有增加的CD20-腫瘤細胞發生率。這項觀察支持上 述之混合治療處理攝生法的利用性。 避於低-級N H L ’混合R i t u X i m a b®和C Η〇P化學治療 暫於低-級或濾泡性NHL，以環磷醯胺、阿黴素、長春新 鹼和脫氫皮甾醇的化學治療（CHOP)，是有效的第一線治療 。雖然一開始的反應率很高，但最後出現復發，且後續的 化學治療攝生法在短的期間内使產生減輕。第]2階段的研 究’ 一開始評估在新近診斷出的，以及復發的低—級或濾 泡性NHL中，CHOP與Rituximab®的組合（21)，因為因為其 作用機制並不是交叉—對抗的，且Rituximab®與某些胞毒 % 藥物有協同作闬，包括阿徵素（5)。
在3 8個患者中，有2 9個之前未接受抗癌症的治療。以標 準劑量每三週一次，投予CHOP，進行六次循環，並六之輸 液以1：1^丨1^匕©(375毫克/平方公尺）。在第一次(：1{〇?循環之 雨第1和第6天時，投予第1和第2次，並在第8天開始CHOP
.第26頁 1242444 五、發明說明（24) 。在第3和第4次CHOP循環之前兩天，分別投卞第3和第4次 Rituximab®輸液，並在第6次CHOP循環之後第134和第141 天時，分別提供第5和第6次輸液。 在該組合的研究中，3 8個接受處理的患者1 〇 〇 %產生反應 (C R，5 8 % ; P R，4 2 % )。3 5個完成處理的町評估之患者中， 有63 % CR和37 % PR (21) 〇DR的中間值為35.3+個月，在觀 察期間的中間值3 6 · 7 +個月之後，未達到不進行之存活的 中間值。在3 6 +個月和5 3 · 4 +個月之後，2 0個患者仍得到緩 和（22)。第一線處理的DR是令人印象深刻的，且該試驗群 中有24%在化學治療後復發。 在藉著CALGB經營的研究中，4〇個患者低-級NHL的患者 將每週接受Rituxima#8次，並從第8天開始每天口服環罐 酿胺。20個患者將單獨接受8週劑量的以tuxi[nab(D。 在藉著£(：(^處理罹患低—級NHL的患者，與環磷醯胺和氟 k拉濱（A # )與標準c v p治療（β臂）的組合作比較，來經營 第Ε[階段的研究。在隨機的Α臂和Β臂中，藉著年齡、戶 重、.組織學和B徵候，脾电本八你 , ㈤ 將柄屛策一在兩臂中的反應者， 、.·工土 —一人蚣機的每週R i t u X i m a b®持崤、、厶瘩7 q古上/ 平方公尺）4次，每佃日i , 符、.另化療（ 3 75笔兄/ 受觀察（D臂）。 月再〜’持續2年（C臂），或僅接 分裂素的組合 可藉著；二：ί ?即免疫系統的細胞分裂素(23)。干擾素 機帘1來增加抗體的效力，包括抗原表現的能力
1242444 五、發明說明（26) 克/平方公尺χ4)。到目前為止，在9個接受評估的患者中 獲得的早期結果，產生67%的〇RR(44% CR，22% PR)，在9 個患者的8個中，有最小的毒性（3 3 )。最常見的不利事件 為發燒（4/8的患者）、鼻炎（4/8)、發冷（3/8)和頭痛（3/8) ’這與先鈾在單獨投予r i t u x丨m ab®時所觀察到的不利事件 可相比擬。已經開始第η階段部份的研究，將檢查G-CSF 和375毫克/平方公尺Rituximat^)x4i混合的效力。 R i tux i mab@加 I L- 2 已經使用利用自體周圍血液幹細胞（P；BSC)或骨髓（BM)解 救的高劑量治療來處理NHL，然而功效仍受制於復發的高 危險’其為50-80 %。努力去改善在移植之後持久的缓和， 許多處理中心已經從事利用〗L — 2，來誘發高劑量和低劑量 治療之免疫治療的研究。這類研究暗示I L - 2之治療，證實 在β植之後早期的抗-腫瘤活性。 最初在自體移植之後，展現延遲之免疫重建的患者，有 可能導致免疫-調節的腫瘤撲滅（4 3，4 4 )。確實，已經顯示 C D 8 + Τ細胞和胞毒c D 8 + Τ細胞受—抑制（4 5 - 4 9 )。在活體外 的測定，已經證實深深的壓抑Τ細胞的細胞溶解和增殖反 應’並降低了反映促細胞分裂劑和可溶性抗原之IL_2的產 生。然而，可溶性IL-2能夠使這些免疫反應復原，暗示在 自體移植之後在患者體内的免疫細胞，能夠對外源性I ^ 一 2 起反應（4 7 )。在B iM T之後，周圍血液N K活性亦維持比對照 值更低，並藉著加入外源性IL-2，亦增加NK的活性（49)。 這些資料暗示在幹細胞移植之後不久，馬上對患者投予
第29頁 1242444 五、發明說明（27) IL-2 ,可在決定期促進免疫的反應性，此時腫瘤的載重為 最少’而此時在缺少IL-2之下，缺乏免疫反應性。工 例如，Caligiuru等人已經顯示，以〇·45χ1〇6單位/平方 公尺/天，藉著24小時連續ιν來投予IL_2 (H〇ffman — LaRoche)，持續12週，能夠耗盡絕對數量的⑶“明亮的· 細胞（5 0 - 5 2 )。對門診病人中未移植的患者投予該攝生法 ，顯示有少量的毒性。
動物模式顯示非-LAK誘發之低劑量的IL_2，當與腫瘤一 特異性T效應物細胞一起投予時，戲劇化地促進了抗—腫瘤 的活性（53)。此外，Soiffer等人（54)對13個經歷復發之 白血病或淋巴瘤處理的自體BMT或T細胞耗盡之同種BMT接 受者’投予低劑量之IL-2。在實驗室中利用在循環中CD56 明，之CD16+ CD3-NK細胞的5 -至40 -倍增加，證實了增加 的免疫學反應性。再者，IL-2的低劑量攝生法導致在活體 外殺死NK標乾K562的增加。當s〇iffer等人（55)更新29個 接受低劑量IL-2之同種BMT患者的結果時，他們發現與組 織學的對照相比較（3 0 %，p = 〇 · 4 1 )，這些患者有令人驚訝 的存活（7 0 % )。
Laur ia等人（56)，在ABMT之後中間值為42天時，以 2χ10δ單位/平方公尺之劑量，每兩天一次wIL-2處理11個 罹患高級NHL的患者兩週，然後以3x1 〇s單位/平方公尺每 週兩次’持續處理一年。表現型的分析顯示，在總漭巴球 之絕對數量和比例上有持久和明顯地增加（p = 〇 . 〇 〇 1 )，且 特別是在治療6週之後的CD1 6和CD 56 NK細胞兩者之上。在
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開始 >台療之後’在22個月的追蹤調查中間值（範圍在丨〇 —42 ，月）内’沒有患者繼續進行。此外，兩個患者在ΑβΜΤ之 佼有殘餘的疾病，一個在肝臟，而第二個在淋巴結，在 I L 2治^療之後7和丨〇個月，獲得完全的反應。 ^Vey等人（57)利用低劑量的IL —2處理25個患者有難以醫 f或復發之HD(11個患者）和NHL(14個患者）的患者。48%的 患者在移植處有抵抗性疾病，且84%在ABMT之後達到CR。 在移植之後平均54天時開始几―2，並包括處理5天的第一 人循環’接著疋母隔一週處理2天的4次循環。患者接受平 均160x1 〇6單位/平方公尺的IL_2。在五年之後的追蹤調查 ’存活的可能性和DFS為72% (HD 73%和NHL 70%)，和45% (HD 36%和NHL 48%)。
Fred Hutchinson Cancer Research Center (FHCRC)中 有一組’目前發現低劑量的I L - 2治療，在門診病人中是完 全可容忍的，且在以低劑量I L- 2處理之患者中的緩和，有 比未經IL-2處理者更長的傾向。IL-2的治療與增加某些免 疫細胞族群的數量有關連，包括CD8+ CD69+細胞；CD16 + CD8+細胞；CD16+ CD69+細胞；CD16+ CD56+細胞；CD16 + CD122 +細胞；CD16+ Dr+細胞；以及CD8+ CD56+細胞。在 對抗腫瘤標乾K 5 6 2和D a u d i之溶解活性的表現上亦有增加 ，分別為中間值有5, 9 -倍和6 · 5 -倍的增加。當出現復發 時，在移植之後1 7. 8個月的中間值處出現，並報告其缓和 的特徵為，比在病歷上看到沒有I L - 2治療的移植接受者的 更長。
第31頁 1242444 五、發明說明（29) 從對ABMT移植之接受者利用I L - 2治療的研究中，收集到 令人鼓舞的資料，在移植之後將I L - 2治療與r丨t u X i m a b®混 合似乎是合理的，Rituximab⑥的生物活性顯然經由ADCC， 和補體-調節之溶解活性來調節。因此，已經與FHCRC合作· 開始第I階段的試驗，評估混合治療之攝生法的安全性和 可能效力。 亦進行個別的第.Π階段研究，來評估在接受低劑量之 IL-2和Rituxan⑧的患者中，HACA形成的效力和發生率。該 研究的特定目標為評估是否藉著在活體外内與IL-2接觸： 促進ADCC ’且ADCC之活性是否與臨床反應有相互關係。在 組織學上證實患者的標準涵蓋第Η — jy階段的低-級、渡泡 性Β-細胞或包膜細胞淋巴瘤。為了臨床的研究，藉著免疫 組織化學法將包膜細胞淋巴瘤定義為CD5+、CD23 —(如杲可 利角）’及/或b c 1 -1 +。在第一次以標準治療，也就是化學 治療、放射性治療、ABMT，及/或免疫治療處理之後，未 產生反應或再復發的患者是合格的。
Ri tux—i mab®加GM-CSF，來處理復發之低-級良_遽泡性B — 細胞淋巴瘤 亦已經開始兩個個別的第Π階段試驗，來測試 Rituximab®與GM-CSF之混合處理的效力。一個研究涉及4〇 個罹患復發之低級B-細胞淋巴瘤的患者，並包括每週投予 375 毫克 / 平方公尺 Rituximab®x4 (1，8，15，22)，並在第一 次设予Rituxima b®之如^一小時，開始每週三次皮下投予 2 5 0 微克的 GM-CSF (Leukine, Immunex)持續8 週。將使用
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該研究來評估混合治療之攝 a 速率（ORR)、完整的*八及库’ 、^床效力（完整的反應 敗的存、、m 應速率、進行的時間和免於失 双的存活率）’定出混合治療八 利辜件& & μ ^ π , ，、 文王性（定性、定量的，不 之二:)的特徵，並決定混合治療對相關' 細f分ί素的影馨。第二個研究亦計劃監 f Dq Γ ^文。平估咸死的機制（補體C3和C4，CH50， ⑶3、CD4、CD8、CD16、CD19 ^ 及ADCC測定）。 和咖6的流動細胞計數’以
R—ituximah®加 丫一千播音 為了處理患有低-級或高—級淋巴瘤的患者，亦可使用7 干擾素與Ri tuximab®混合治療。目前已經發現τ _干擾素 向上调希CD20在多種骨髓瘤（mm)患者的漿細胞、患者的β- 細胞上’以及在正常捐贈者β-細胞上的表現（Tre〇n等人，
Lugano ’1999)。事實上，Treon及同事已經顯示r -干擾 素增大f那些細胞與Ri tux i mab®的結合作用。以劑量依賴 之模式’在漿細胞上出現CD20表現的誘導作用，在像1單 位/毫升之r -干擾素這樣低之下，亦可見向上的調節作用
。在1 00單位/毫升48小時處出現高原區。因此，當τ -干 擾素與Ri tux i mab®混合投予時，亦可能是有利的。 中-級和高-級NHL j： 一製劑之研究 在歐洲和澳洲經營的研究中，在5 4個患有復發或難醫治 之中-或高-級NHL的患者中評估另一種投藥計劃（34)。每 週以375毫克/平方公尺輸液Rituximab®，投藥8次，或以
第33頁 1242444 五、發明說明（31) 375毫克/平方公尺一次，接著每週以500毫克/平方公尺’ 投藥7次。ORR為31%(CR 9%，PR 2 2%)，在劑量攝生法之間 並未觀察到顯著差異。患有擴散性大細胞淋巴瘤（N = 3 0 )的 患者有37%的ORR，而患有包膜細胞淋巴瘤的那些（N = l2)具 有33% 的ORR 。
Ri tuximab®和CHOP化學治療之組合
在其他的研究中，，使31個患有中-或高-級之NHL的患者 (1 9位女性，1 2位男性，中間年齡為4 9歲），在六次2 1 -天 <：11〇?循環中每次的第1天，接受1^1：1^：[11^1#)(35)。在30個 可評估的患者中，有19 CR(63%)，和10 PR(33%)，0RR為 96%。認為該攝生法是完全可容忍的，並可導致比單獨之 Rituximab®或CHOP更高的反應率。
Cancer Treatment and Diagnosis 的NC I 部严，與I DEC Pharmaceuticals Corporation合作，探討在其他適應症 上的Ri tuximab®處理。由ECOG、CALGB和SW0G在患有混合 、擴散的大細胞和免疫胚性大細胞組織學關1的較老患者 (>60歲）中’經營CHOP對CHOP和Rituximab®的第π階段試 驗（計劃進行N = 63 0 )。這些研究包括利用Ri tuximab®的第 二次隨機維持對未-維持。 在Dana Farber Institute亦在40個罹患先前未經處理 之包膜細胞淋巴瘤的患者中，進行撕和的第 瓜階段試驗。在每2 1天為一次循環的第}天時投予 Rxtuximab®，並在第卜3天時投予CH〇p ,進行6次循環。已 經完成該研究的增補。亦已經完成由sw〇G在新近診斷出之
第34頁 1242444 五、發明說明（32) 濾泡性淋巴瘤中’經營C Η Ο P接著R i t u X i m a b⑩的第Π階段的 試驗。正在分析這兩個試驗的結果。 由AIDS和Malignancy Consortium ，在HIV-相關之NHL 中 經營之CHOP和Ri tux imab®對單獨CHOP的第Π階段試驗正在 進行中，計劃進行1 2 0個患者。 骨髓分_墼治療復發之後的Rituximab®
Ri tuximab⑧在利用自體pbsC支撐物之高劑量治療之後， 患有復發的中-級N H L之患者中顯示出有希望的早期結果。 七個患者中有六個有反應（1個CR和5個pr)，而一個患者有 穩定的疾病；治療是完全可容忍的（3 6 )。 安全性體驗 混合得自在五個單一製劑美國研究中的3丨5個患者之不 利事件和臨床實驗資料’提供r i t u χ i m a砂在患有低—級或 濾泡性NHL的患者中的安全性特徵。大部份的不利事件是 與輸液有關的’並在第一次輸液之後有逐漸降低的發生 率。最常見與輸液有關之事件為發燒（49%)、發寒（32%)、 噁心（18%)、疲勞（16%)、頭痛（14%)、血管水腫（13%)”搔 癢（1 0%),以及偶爾發生的低血壓（1 〇%)和支氣管痙攣（8%) 。在處理期間（在最後一次投藥之後高達3〇天），1〇%的患 者體驗到第3或4級的不利事件，其主要是與輸液或血液學 有關的。在1· 3%的患者中發生血小板減少症（<5〇, 〇〇〇金小 板/立^毫米）’在1· 9%中發生嗜中性白血球減少症（<1〇〇〇 /立方*米），並在1 · 〇 %中發生貧血（〈8克/分升）。雖然 IMtuxwab®在70%-80%的患者中誘發B—細胞的耗盡，但在
第35頁 1242444 五、發明說明（33) $部份的患者中觀察到異常減少的血清免疫球蛋 染的發生率顯然並沒有增加。 白’而感 在10%的患者中發生需要中斷Rituxiinab(I^^ ，並在1 %中為第3或4級。在1 3%的患者中報告有血2血壓 ，並在一個患者中認為這是嚴重的。在8%的患者管水踵 氣管痙攣，2%以支氣管擴張劑處理。注意到^ 、發生支 支氣管炎的報告。大部份的患者並未體驗到藉著=閉鎖性 後續輪液，更進一步與輪液有關的毒性。在^理=二次和 產生不利事件之患者的百分比，與在第一次過^ &報告其 告類似（1 4 )。 狂之後的報 四個患者在Ri tux imab®輪液期間發展出節律不软 之中的一個中斷處理，因為心室性心搏過速和二丄四個 過速'。其他三個患者體驗三連脈（N = 1)和不規律的\室心搏 2)，但不需要中斷治療。在輸液期間報告有咽峽^ R/專U二 一位先前有心肌梗塞病史之個體中，在輸液之後二=在 心肌梗塞。 大务生 不利事件和第3和4級的不利事件，在容積性疾病之患土 中的全面發生率比在非-容積性疾病之患者中更高。眩u晕" 、嗜中性球減少症、血小板減少症、肌痛、貧血和胸痛的 發生率，在病變> 1 〇公分的患者中較高。第3或第4級嗜中 性球減少症、貧血、低血壓和呼吸困難的發生率，在患有 容積性疾病的患者中’亦比病變< 丨〇公分的患者更高（丨9 ) 因 為F D A在1 9 9 7年核准以rt u χ丨m a必處理復發或難以醫
第36頁 1242444 五、發明說明（34) 治之低-級或濾泡性NHL，推測已經處理了 1 7, 0 0 0個患者。 在1 9 9 8年5月，八個上市之後的報告說明，概述了與 R i t u X i m a b®的使用有關聯，應導致致命之結果的嚴重與輸 液有關之不利事件。在八個死亡案件中，七個在第一次 R i t u X i m a b®輸液期間發生嚴重的徵候。在八個案例中，有 兩個未報導死亡原因，或仍是未知的。嚴重的呼吸事件， 包括缺氧、肺的浸潤、或成人呼吸道緊迫徵候群促成八個
報告死亡其中的六個。一個患者具有600, 000 /立方毫米之 處理前的琳巴球計數；另一個，肌酸酐為8 ;第3個，呼吸 速率為4 0 ;而第4個，泛血球減少症。具有高腫瘤負重或 高數量之循環惡性細胞的患者，可能是高危險的，並在整 個每次輸液中應徹底監視這些患者。 先前在Rituximab®臨床研究中，觀察到最近描述到的大 部份'不利事件。一個值得注意的例外是與輸液有關，與快 速腫瘤溶解有關的徵候，在六個有高數量之循環中腫瘤細 胞的患者有報告（37，3 8 )。該徵候的特徵為發燒、惡寒、
與血氧過少有關的支氣管痙攣，周圍淋巴球的快速衰退， 腫瘤破壞的實驗室證據，以及暫時性嚴重的血小板減少症 。這些患者已診斷出B -前淋巴球白血病（N = 2 )，慢性妹巴 球白血病（N = 2)，包膜-細胞琳巴瘤（N二1)，或轉化之NHL (N=l);全部均有循環中淋巴球的升高，大量的腺病和器 官巨大化。雖然這六個患者中有五個需要住院治療，但解 除徵候並完全可容忍後續的Ri tux imab®處理；最後一個患 者拒絕進一步的治療，並在兩週之後死於進行性的疾病。 1242444
在七個患有CLL之患者和一個患有包膜—細胞淋巴瘤之患 者個別的報告中，在淋巴球計數> 1 〇χ1 〇9公升的那些患者 中，第一次Rituximab®輸液之後，觀察到腫瘤溶解的徵候 (39)。 、 .利角與Rituximat^混合之以μ釔—標示之抗_CD2〇抗體的 放射性免疫治療 其他在評估之中的NHL治療途徑，為與Ri tuximab(B)混合 放射性標示之抗- CD20 抗體（10£〇¥268)。10£(]-¥288(9(^-ibr i tumomab t iuxetan)是經由與抗體共價結合的螯合劑 }^-〇??人，將老鼠12〇1卡巴抗4〇20抗體與，結合。在 IDEC-Y2B8之前投予Rituximab®( 2 5 0毫克/平方公尺），耗 盡周圍的B淋巴球，並改善放射性標示之抗體的生物分布 在最近的報告中，第I / Π階段的研究（40-42 )，以 IDEC-Y2B8 處理患有低-級 NHL(N = 34)、中-級NHL(N 二 14)或 包膜-細胞淋巴瘤（N二3 )的患者。年齡的中間值為6 0，7 1 % 為男性而96%為白種人。在51個患有復發或難以醫治之NHL 的患者中，34 ( 67%)對單一劑量之0· 2、0· 3或0. 4毫居里/ 公斤的IDEC-Y2B8有反應。在患有低-級或濾泡性NHL的患 者中，0RR為82%( 28/34 )，而患有中-級淋巴瘤的患者為 4 3 % ( 6 / 1 4 )。沒有罹患包膜-細胞疾病的患者有反應。 第Π階段的隨機研究，正在進行IDEC-Y2B8與Rituximab必 (3 7 5毫克/平方公尺，每週一次，4次）處理低-級濾泡性或 轉化之NHL患者的比較。亦在患有R i tux i mab®難以醫治之
苐38頁 1242444
五、發明說明（36) 復發性NHL的患者中經營其他第瓜階段的試驗 總結 在缺乏NHL之醫療性治療時，治療的目標是在有意義， 期間内’完成對疾病的控制，並提供對與腫瘤有關之徵: =減’而沒有不當的毒性。利用Rituximab®的處理’象 簡紐的、2 2 -天的門診病人之治療，並在大部份的患者中 僅有有限的不利事件。在臨床研究中，5 〇%可評估之復發 的丄或化學治療難以醫治的，低-級或濾泡性MHL患者，達 到完全或部份的反應。這些反應是持久的，不需要支持療| 法；在搞軸研究中，反應者的TTP中間值為;[3. 2個月，DR 中間值為1 1 · 6個月。 認了R^tuximab⑨對於罹患低-級或濾泡性β〜細胞NHL之患 者’是安全和有效的處理。其具有明顯的臨床活性，新穎 的作用機制，並在反應速率和反應期間上，比其他治療更 二正在進行之，究的完成，將證實另—種Rjtuximab@ 攝生法-Ritmmab®，在處理其他CD20+ β—細胞承性疾病 上所扮演的角色。 〜、
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‘U. Wiseman G, White C，Witzig 丁，Gordon L, Emmanouilides C, Raubitschek: A, Janakiraman N, Spies S, Silverman D, Guthcil Schilder R, Parker E, Rosenberg J, Grillo-Lopcz A. IDEC-Y2B8 radioimxnunotherapy: Baseline bone marrow iuvolTeinent and platelet count are better predictors of hematologic toxicity than dosimctr>\ Blood 199S; 92:417a. 42. WitzigT, White C, Wiseman G, Gordon L, Emmanouilides C, Raubitschek A, Janakiraman N, Spies S, Silverman D, Gutheil J, Schilder R, Ding E, Shen D, Gnllo-L0pez A. IDEC-Y2BS Radioimmunotherapy: Responses in patients wixi\ splenomegaly. Blood 1998; 92:4l7(a), 43. Witherspoon RP, Lum LG, Storb R, Immunologic reconstitution after bone marrow grafting. Semin Hcmatol 21:27 1984. 小1. Antler^on, KC nl： nematologiosl cngrafhrient ptuI ummine reconstitution postlrarisplant with anti-Bl purged autologous bone marrow. Blood 69:597, 1987.
45. Lum LG. Kinetics of immune reconstitution after human marrow transplantation. Blood 69:369, 1987. 46. A2〇gni O., Gluckraan E., Fradelizi, D., Inhibition of IL-2 production after human allogeneic bone marrow transplantation. J. Immunol. 131:1205, 1983 47. Wcltc, K. et al, Defective Interleukm-2 production in patients after bone xnarrow transplantation and in vitro restoration of defective T lyraphocite proliferation by liighLy purified Interleukin. Blood 64:380, 1984.
第46頁 1242444 五、發明說明（44) 48· Cayeau, S. et al., T-cell ontogeny after bone marrow transplantation: failure to synthesize Interleukin-2 (IL-2) and lack of CD2- and CD3-mediated proliferation by botli CDE4-^- and CD8+ cells even in the presence of exogenous IL-2. Blood 74:2270, 1989. 49. Bosley, A. et al., Lnterleukin-2 as consolidative imrnuotherapy against minimal residual disease. Nouv Rev Fr Hematol 32:13, 1990. 50. Caligiuri, M.A. et al，Extended continuous infusion low-dose recombinant Interleukin-2 in advanced cancer. Prolonged immunomodulation without significant toxicity. J Clin Oncol 9;2110, 1991. 51· Caligiuri, M.A. et al, Selective immune modulation of NK cells following prolonged infusions of low dose recombinant IL-2. J Clin Invest 91:123, 1993. 52. Caligiuri, M.A., Low-dose reoembinant Intcrleukin-2 therapy; rationale and potential clinical applications. SEM in Oncol 20:3, 1993. 53· Klamct, J.P. et al, Antigen-driven T cell clones can proliferate in vivo, eradicate disseminated leukemia and provide specific immiinologic memory. J Immunol. 138:4012, 1987. 54. Soiffcr, RJ. et al, Clinical and immunologic effects of prolonged infusion of low-doc recombinant Intcrleukin-2 after autologous and T cell-depleted allogeneic bone mairow transplantation. Blood 79:517, 1992. 55. Soiffer, R J. et al, Effect of low-do$e Interleukiu-2 on disease relapse after T-cell depleted allogeneic bone marrow transplantation. Blood 84:964, 1994. 56· Lauria, F. et al, Immunologic aud clinical modifications following low-dose subcutaneous administration of rIL-2 in non-Hodgkin^s lymphoma patients after autologous bone marrenv transplantation. BMT 18:79, 1996. 1242444
五、發明說明（45) 57. Vcy, N. et al, A pilot study of autologous bone marrow transplantation followed by recombinant Interleukin-2 in malignant lymphomas. Leukemia & Lymphoma 21:107, 1996. 58· Venugopal, P. et al, Uprcgulation of CD20 expression in CLL cells by cytokines. Submitted to ASH Meeting, December 1998. mm 第48頁
Claims (1)
1242444 _案號 88113738_年月日_1±^_ 六、申請專利範圍 中之抗-CD20 抗體為 C2B8(Rituximab®)。 1 0.根據申請專利範圍第1至7項中任一項之醫藥組合 物，其中該B-細胞淋巴瘤係選自下列群組：低級/濾泡性 非-霍奇金氏淋巴瘤（NHL)、小淋巴細胞（SL) NHL、中級/濾 泡性NHL、中級擴散性NHL、慢性淋巴球白血病（CLL)、高 級免疫胚性NHL、高級淋巴母細胞性NHL、高級小的非卵裂 細胞性NHL、容積性疾病NHL、包膜細胞淋巴瘤、與A IDS有 關之淋巴瘤，以及瓦耳登斯壯氏（W a 1 d e n s t r 〇 m ’ s )巨球蛋 白血症0 1 1 .根據申請專利範圍第1 0項之醫藥組合物，其中該B -細胞淋巴瘤為慢性淋巴球白血病（CLL )。 1 2.根據申請專利範圍第1至7項中任一項之醫藥組合 物，其中該B -細胞淋巴瘤為不活動性淋巴瘤。 1 3.根據申請專利範圍第1至7項中任一項之醫藥組合 物，其中該B -細胞淋巴瘤為侵略性淋巴瘤。
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ϋ明說明 發明範圍 本發明係關於在處理Β-細胞淋巴瘤中使用抗-CD20抗體 -或其片段，特別是在混合療法中使用這類的抗體和片段。 發明背景 先前已經報告了對抗C D 2 0抗原之抗體在做為Β _細胞淋巴 · 瘤之診斷及/或治療劑上的用途。C D 2 0是Β -細胞淋巴瘤的 有用標記或標靶，因為該抗原在惡性Β -細胞的表面上以極 、 高之密度表現，也就是在其中可不減退地增殖而導致Β -細 胞淋巴瘤的Β -細胞。 C D 2 0或Β ρ 3 5為Β -淋巴球-限制分化抗原，其在早期前-Β -細胞發展的期間内表現，並維持直到聚細胞分化為止。有 些人相信C D 2 0分子可調節在細胞循環抑制和分化作用必需 之B -細胞活化過程中的步驟。然而，如同所注意到的， C D 2 0通常在贅生（π腫瘤"）的B -細胞上，以極高的程度表現 。C D 2 0抗原引起標靶治療的興趣，因為它不會脫落、調節 或内"ί匕。 先前報告的治療涉及抗-CD20抗體，其已經涉及單獨投 予治療性抗-CD20抗體，或連同第二個以放射性標示之抗-C D 2 0抗體，或化學治療劑一起投予。 事實上，食品及藥物管理局核准一種這類抗-CD20抗體 R i t u X a η ®的治療性用途，用於復發和先前處理的低-級非-霍奇金氏淋巴瘤（NHL)。再者，已經暗示Rituxan®與放射 性標示之抗-C D 2 0抗體在處理B -細胞淋巴瘤上的用途。
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L· 五、發明說明（2) 然而，已經報告了抗-C D 2 0抗體，特別是R 1 t u X a η ® (在美 國、英國為MabThera® ;普通為Rituximab®)可有效地處理 B -細胞淋巴瘤，像是非-霍奇金氏淋巴瘤，但經過處理的 患者通常蒙受到疾病的復發。因此，如果可以發展出更有 效的療法，將會是有益的。 更特定而言，如果抗-CD20抗體在與其他的淋巴瘤處理 混合時具有有利的效力，且如果發展出新穎的混合療法， 可降低復發的可能性和頻率，將是有利的。再者，如果改 善目前處理B -細胞淋巴瘤的草案，能夠利用嵌合型或放射 性標示之抗-CD20抗體來處理罹患對其他處理方法而言為 難以醫治之淋巴瘤的患者，將會是有幫助的。如果使用抗 -C D 2 0抗體，特別是與其他處理混合使用的處理方法，可 用來做為低級、濾泡性非-霍奇金氏淋巴瘤以外的其他類 型之淋巴瘤的治療，亦將是有幫助的。 發明概述 本發明揭示B -細胞淋巴瘤之混合治療性處理，並報告利 用嵌合型或放射性標示之抗-CD20抗體來處理復發或難以 醫治之B -細胞淋巴瘤的益處。特定而言，已經發現利用抗 -C D 2 0抗體之處理，當與細胞分裂素、放射性治療、骨髓 分離（m y e 1 〇 a b 1 a t i v e )或化學治療混合投予時，提供了有 利的協同作用。令人驚訝的是，先前有進行骨髓或幹細胞 移植的患者，當與先前未接受此種治療的患者相比較時， 具有意外增加的全部反應率。 發明說明
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五二#屢制—⑻ 本發明包括處理B -細胞淋巴瘤之混合療法。一般而言， 這類方法包括處理復發之B -細胞淋巴瘤的方法，其中該患 者先前已經處理過淋巴瘤，但是又復發，而對其投予有療 效之含量的篏合型抗-C D 2 0抗體。這類先前處理可包括例 如，先前以抗-C D 2 0抗體處理，包括骨髓或幹細胞移植、 放射性治療和化學治療的處理。先前的化學治療可能是選 自各式各樣的化學治療劑及混合療法，包括CHOP、I CE、 米托沙酉同（Mitozantrone)、阿才唐胞苔（Cytarabine)、 DVP、ATRA、伊達比星（Idarubicin) 'Hoelzer 化學療法、 La La化學療法、ABVD 、CE0P 、2-CdA 、FLAG & IDA(有或 無後續的G-CSF 處理）、VAD、M&P、C-Weekly、ABCM、M0PP 和DHAP 〇 在本發明方法中亦包括處理患有B—細胞淋巴瘤之個體的 方法，其中該個體對其他治療性處理而言為難醫治的’包 括所有上文列舉的那些，也就是説’以欲合型抗-CD20抗 體處理，包括骨體或幹細胞移植、放射性治療和化學治療 的處理。特定而言，包括處理在投予欲合型抗""CD20抗體 之後，並未顯示出可感知的腫瘤減少或退化之患者的方法 ，包括對該患者投予放射性標示之抗_CD20抗體。 特定而言，進行在嵌合型抗體之後，利用放射性標示之 抗體來處理患者的方法，藉此在該嵌合型抗—CD2〇抗體_的, 投藥之後，從大約一週到大約兩年内’投予放射性標示之 抗-CD20抗體。更特定而言，在該嵌合型抗-CD20抗體的投 藥之後，從大約一週到大約九個月内’投予放射性標示之
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第i階段-涉及單一的淋巴結區域或局部涉及單一的淋巴 外之器官或部位。 弟Π 4又-涉及在相同隔膜部位的兩個或以上的淋巴結區域 ，或局部涉及單一有關連之淋巴外的器官或部位，及其區 域性淋巴拮，有或無涉及在隔膜的相同部位上的其他淋巴 結區域。 謂瓜階段-涉及隔膜兩侧的淋巴結區域，可能伴隨有局部 涉及淋巴外的器官或部位，涉及脾臟或兩者均有。 第IV階段-散播性（多重病兆），涉及一或多個淋巴外的部# 位’與涉入之淋巴結有關或無關連，或涉及分開的淋巴外 之器官，並涉及遠離的（非區域性）之淋巴結。 關於更進一步的細目，參見丁116111七6]：11&1：1〇11&1]^〇11-Hodgkin’s Lymphoma Prognostic Factors Project: A predictive model for aggressive non-Hodgkin's Lymphoma, New England J. Med. 329(14): 987-994 ( 1 9 9 3 )。 較佳的抗體、劑量療法，和治療的特別組合，現在將藉 著下列舉例說明的資料來解釋之。 R i tux i mab®和 Y 2 B 8 非-霍奇金氏淋巴瘤（NHL)在美國侵襲大約25〇,〇〇〇人。j 大部份罹患N H L的患者不能藉著化學治療、放射性治療或 利用自體骨驗（A Β Μ Τ )或周圍血液幹細胞（p B s c )支持的高劑
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依據抗體想要的用途，也就是做為診斷或治療劑，在此 項技藝中已知其他的放射性標記，並可為了類似的目的使 用之。例如，已經在臨床診斷中使用的放射性核素，包括 131I 、125I 、123I 、99Tc、67Ga和ιηΙη。為了有效使用在瞄準免 疫治療中，亦已經利用各種放射性核素來標示抗體 (Peirersz 等人（1987) The use of monoclonal antibody conjugates for the diagnosis and treatment 〇f cancer· Immunol . Cell Biol. 65 :111 - 125)。這些放射 性核素包括188Re和186Re，以及9GY，和少部份的199Au和57〇11。 為了治療目的亦使用I — U 3 i )。美國專利第5，4 6 〇，7 8 5號提
供了這類放射性同位素的列表，並將其合併於此以作為參 考0 庙如同在美國專利第5，7 3 6，1 3 7號中的報告，投予放射性 ^不之ΥΒ8共輪物，以及未標示之嵌合型抗—CD20抗體， 、、口果在藏匿有B細胞淋巴母細胞性腫瘤的老鼠中有明顯的 腫1減少。>再者，在其中報告人類臨床試驗中，在以嵌合 型㈡D20,抗體乂的淋-巴瘤患者中顯示出明顯的b一細胞耗盡 黛一 二纟已經發布後合型2B8 ’以Rituxan®之名， ;有一個嵌合型^>核=的抗_癌症單株抗體。因此，顯示至 理中證實其有治^效力20抗體，已經糾'細胞淋巴瘤的處 或紀-標示或兩者的老一&種5气型抗—Ti0 \與帶有銦-標示 、老乳單株抗體的連繽投藥。雖然在這
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五、發明說明（13) 些混合治療中所使用之放射性標示的抗體為老鼠抗體，一 開始以嵌合型抗-C D 2 0處理，充份地耗盡B -細胞族群，使 得H A Μ A反應降低，藉此促進了混合治療和診斷法。 因此，在混合免疫治療的前後文中，可發現老鼠的抗體 特別適合用來做為診斷試劑。再者，在美國專利第5，7 3 6， 1 3 了號中顯示，在投予R i t u X a η ®之後，具有療效之劑量的 釔-標示之抗-CD20抗體，足以（a)清除未被抗-CD20抗體清 除之剩下的周圍血液B -細胞；（b )再度從淋巴結中耗盡B -細胞；或（c )再度從其他組織中耗盡B -細胞。 因此，放射性標記與癌症治療抗體的結合，提供了有價 值的臨床工具，可用來評估這類抗體可能的治療效力，產 生監視處理過程的診斷試劑，並設計可用來促進嵌合型抗 體一開始殺死腫瘤之可能性的額外治療劑。在非-霍奇金 氏淋巴瘤的處理中，提供已經證實之抗-CD20抗體的效力 ，以及淋巴細胞對放射性的已知以敏感牲，對於可用來降 低難以醫治之非-霍奇金氏淋巴瘤的復發頻率的混合療法 中，使用這類嵌合型和放射性標示之治療性抗體，是極為 有利的。此外，如果在其他B -細胞淋巴瘤的處理中，使用 這類混合療法亦將是有利的。 低一級或滤泡性N H L 對於復發或難以醫治之NHL的單一製劑研究 FDA以主要在罹患低-級或濾泡性NHL之患者中的五個單 一製劑的研究為基礎，核准Rituximab®。以從10-500毫克 /平方公尺的範圍，單一Ri tux imab®輸液的早期第I階段
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五、杳日涵丽T2o) σ 中間值為2· 5(範圍：卜9)。對該處理而言，60%的患者是 難以醫治的兩個患者在第一個劑量（3 7 5毫克/立方公尺）了 發展出嚴重的高血壓；其他的接受進一步的治療··在後ΐ 提高之劑量下的毒性是溫和的，雖然並未徹底评估15 〇 0^也 克/立方公尺之劑量含量的患者。八個患者得到兀王的/σ 療（4個以500毫克/立方公尺，3個以650毫克/立方公尺，1 個以825毫克/立方公尺），一個以560毫克/立方公尺處理 的患者達到完全的緩和。一個患者在處理時有進行性的淋 巴球增多症，而所有其他的患者，在周圍血液之淋巴球增 多症方面有減少，但對淋巴結的影響較少。劑量增高的研 究正在進行中。 其他在CLL患者中改善反應的途徑，是使用細胞分裂素 向上調節CD20抗體。在活體外的研究中，將得自CLL患者 的單核細胞與各種細胞分裂素一起培養2 4小時。流動細胞 計數的結果，顯示受到I L - 4、G Μ - C S F和T N F - α明顯的向上 調節（1 7 )。事實上，目前的資料暗示在C L L細胞上觀察到 的CD20向上調節，可能僅限於腫瘤細胞（Venogopal等人 Poster—PanPacific Lymphoma meeting, 1999 年β 月，在 慢性淋巴球白血病（C L L )細胞中，細胞分裂素—誘發向上調 節C D 2 0抗體的表現，可能僅限於腫瘤細胞）。初步的資料 亦暗示干擾素α ，以5 0 0至1 0 0 0單位/毫升之濃度應用時， 僅在2 4小時之後便對C L L細胞向上調節c D 2 0。 因此，藉著在投予Rituximab®之前，或與其同時，對 CLL患者投予某些細胞分裂素，可向上調節CD2〇在惡性B —
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五、發明說明（25)(2 4 )，增加抗體瞄準進入腫瘤内（2 5，2 6 ) 素的細胞毒性（2 7 )。 並促進免疫毒 在組合的試驗中，對罹患復發之低—級或濾泡性_[的患 者’給予干擾素-a(Roferon-A)，一種在NHL中具有單一 製劑臨床活性的細胞分裂素（28)，和Ri tuximab®。皮下投· 予干擾素-α(2·5或5 MIU)，每週三次，持續12週。藉著 母週IV輸液投予毫克/平方公尺）四次，從-處理的第五週開始。〇1^為45%(17/38的患者）；11%有〇1?而 3 4%有PR。在反應者中，DR *ττρ中間值的KapUn_Meier估 計值^別為22.3+和25. 2 +個月（29)。先前的干擾素-α和 含有氨备環黴素之化學療法的組合研究，產生延長的進行 時間:但不符合增加的反應或存活率（3 〇 _ 3 2 )。早期的結 果暗不Rituximab®與干擾素-〇；的組合，可延長僅與 Rl tuxlmab®有關之進行的時間。 Rituximah® ^uG^c^SF 在個別的研究中’在復發之低-級NHL中評估Ri tuximab® ^， 已、、二在/舌體外和活體内證實，在健康的志願者 ^ , 經由其對髓樣前驅細胞的影響，誘發F c R I -陽性 曰白血球’其在ADCC中具有像效應物細胞一樣的能 ^^ j 弟1 / π階段的研究，評估混合處理的毒 性和效力。 在第I和第jj卩皆 丛冰丄虫土 u 白#又中’在投予Rituximab®之前2天’開’ τ咖爪—』 早劑夏的G-CSF(5微克/公斤/天）三天。第 I階段包括增加齋丨旦^ ^ ^ 里的Rituxiinab®(每週125、250 或375 毫
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| TW094114004A TWI322014B (en) | 1998-08-11 | 2000-01-29 | Combination therapies for b-cell lymphomas comprising administration of anti-cd20 antibody |
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| TW094114004A TWI322014B (en) | 1998-08-11 | 2000-01-29 | Combination therapies for b-cell lymphomas comprising administration of anti-cd20 antibody |
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