TWI554281B - 二價疫苗組成物及彼於腫瘤治療上之用途 - Google Patents
二價疫苗組成物及彼於腫瘤治療上之用途 Download PDFInfo
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Description
本發明關於應用在人體健康之生物技術和免疫學。尤其是，本發明關於用於治療惡性腫瘤之疫苗配製劑。
Her1和Her2受體為具有酪胺酸激酶活性之跨膜糖蛋白，其屬於稱為ErbB族之受體一族(Normanno N，等人(2005)。The ErbB receptors and their ligands in cancer：an overview.Curr Drug Targets 6,(3)：243-257)。Her 1在肺癌、乳癌、頭頸癌、結腸直腸癌、胰臟癌、膀胱癌、卵巢腫瘤、膠質母細胞瘤(TM Brand，等人(2011)Molecular Mechanisms of resistance to the EGFR monoclonal antibody cetuximab.Cancer Biol Ther 11(9)：777-792)和前列腺癌(Zhau HY，等人(1996)Androgen-repressed phenotype in human prostate cancer.Proc Natl Acad Sci U S A 93(26)：15152-15157；Liu XH，等人(1993)Androgens regulate the proliferation of human prostate cancer cells in culture by increasing transforming
growth factor-alpha(TGF-alpha)and epidermal growth factor(EGF)/TGF-alpha receptor.J Clin Endocrinol Metab 77(6)：1472-1478；Neal DE，等人(1985)Epidermal-growth-factor receptors in human bladder cancer：comparison of invasive and superficial tumours.Lancet 1(8425)：366-368；Gullick WJ，等人，Expression of epidermal growth factor receptors on human cervical,ovarian,and vulval carcinomas.Cancer Res 46(1)：285-292；Salomon DS，等人(1995)Epidermal growth factor-related peptides and their receptors in human malignancies.Crit Rev Oncol Hematol 19(3)：183-232)中過度表現。Her 1過度表現與頭頸部腫瘤和肺癌之預後差、疾病復發之風險高(Turkeri LN，等人(1998)，Impact of the expression of epidermal growth factor,transforming growth factor alpha,and epidermal growth factor receptor on the prognosis of superficial bladder cancer.Urology 51(4)：645-649；Chow NH，等人(1997)Significance of urinary epidermal growth factor and its receptor expression in human bladder cancer.Anticancer Res 17(2B)：1293-1296)及患有卵巢、結腸癌，膀胱癌，甲狀腺癌及頭頸癌之患者的存活率降低(Grandis，等人(1998)Downmodulation of TGF-alpha protein expression with antisense oligonucleotides inhibits proliferation of head and neck squamous carcinoma but not normal mucosal epithelial
cells.J Cell Biochemr 69(1)：55-62)有關。
再者，Her1之表現量與對常規療法之抗性有關(Holbro T，等人(2003)The ErbB receptors and their role in cancer progression.Exp Cell Res 284(1)：99-110)。還有，在乳房、胃、卵巢及前列腺腫瘤中已發現與正常組織中之Her2的表現相比較下異常的Her2受體表現(Tai W，等人(2010)The role of HER2 in cancer therapy and targeted drug delivery.J Control Release 146(3)：264-275)。此外，在呼吸道之惡性轉化中已觀察到此受體的表現下調(Andrade Filho，等人，2010)且為腫瘤對於抗Her1療法之抗性機制(Brand，等人(2011)Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab.Cancer Biol Ther 11(9)：777-792)。乳房腫瘤中之Her2的過度表現與較低之總體存活率及無復發存活有關。
許多上述腫瘤中具有高水準之共同表現的Her1和Her2，且該兩種受體之過度表現與患者之存活率降低有關(Wiseman SM,，等人(2005)Coexpression of the type 1 growth factor receptor family members HER-1,HER-2,and HER-3 has a synergistic negative prognostic effect on breast carcinoma survival.Cancer.May 1；103(9)：1770-7)。患有Her2陽性之乳房腫瘤的患者具有與該疾病相關之高致死率風險，此外，Her1和Her2在這些腫瘤中共同表現會明顯增加此風險，這表明在這些癌症中之Her1的
表現對Her2之表現具有協同效果(Suo Z，等人(2002)EGFR family expression in breast carcinomas.c-erbB-2 and c-erbB-4 receptors have different effects on survival.J Pathol 196(1)：17-25)。經由實驗已證明在細胞惡性轉化中這些受體之間具有協同性交互作用(Kokai Y，等人(1989)Synergistic interaction of p185c-neu and the EGF receptor leads to transformation of rodent fibroblasts.Cell 58(2)：287-292)。其中共同表現Her1和Her2的腫瘤之其他實例已發現有腦癌、卵巢癌、頭頸癌、肺癌、食道癌和結腸癌(Emanuel SL，等人(2008)Cellular and in vivo activity of JNJ-28871063,a nonquinazoline pan-ErbB kinase inhibitor that crosses the blood-brain barrier and displays efficacy against intracranial tumors.Mol Pharmacol 73(2)：338-348；Ako E，等人(2007)The pan-erbB tyrosine kinase inhibitor CI-1033 inhibits human esophageal cancer cells in vitro and in vivo.Oncol Rep 17(4)：887-893；Venkateswarlu S，等人(2002)Autocrine heregulin generates growth factor independence and blocks apoptosis in colon cancer cells.Oncogene 21(1)：78-86)。
文獻中完善記載Her1和Her2受體在腫瘤中之異常表現和共同表現的生理作用。這些受體透過形成二聚體和異二聚體(Pinkas-Kramarski R，等人(1996)Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions.EMBO J
15(10)：2452-2467)調節腫瘤生物學中之重要過程，諸如持續增殖、血管生成、抑制細胞凋亡、代謝重編程及侵入和轉移能力(Hanahan D，等人(2011)：Hallmarks of cancer：the next generation.Cell 144(5)：646-674)。
Her1和Her2兩種受體具有由細胞外結構域(ECD)、單一跨膜結構域及具有酪胺酸激酶活性之胞內結構域所組成的類似結構。Her1 ECD(ECD-Her1)和Her2 ECD(ECD-Her2)之分子量分別為105及110kDa且可能具有與該分子之其餘部分不同的空間構型。ECD包含四個稱為I、Ⅱ、Ⅲ及Ⅳ之子結構域。子結構域I和Ⅲ為形成配體結合位點之區域並含有潛在之糖基化位點。子結構域Ⅱ為受體之間二聚體化之關鍵區，其稱為“二聚體化臂”(Garrett TP，等人(2002)Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor alpha.Cell 110(6)：763-773；Ferguson KM，等人(2003)EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization.Mol Cell 11(2)：507-517)。
已說明之Her1配體有7種，其中與腫瘤生成最有關的為促進表現該受體之表皮細胞增殖的表皮生長因子(EGF)、轉化生長因子(TGF)及雙調蛋白(Amphiregulin)(Normanno，等人(2005)The ErbB receptors and their ligands in cancer：an overview.Curr Drug Targets 6(3)：243-257)。該ECD-Her1係處於動態平衡並具有多種
構型，包括“封閉”構型及其中子結構域Ⅱ處於更靈活狀態的構型。結合配體使平衡朝向“延展的”或活性構型(能二聚體化之構型狀態)移動(Ferguson KM(2008)Structure-based view of epidermal growth factor receptor regulation.Annu Rev Biophys 37353-373)。
然而，尚未發現特異於Her2之配體。透過此受體傳信不需要生長因子，因為該受體具有組成性形式之活性或“延展的”構型，此種構型使其二聚體化之子結構域暴露出(Cho HS，等人(2003)Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab.Nature 421(6924)：756-760)。因此，Her2受體為ErbB族之所有其他成員，包括Her1的較佳二聚體化伴侶(Franklin MC，等人(2004)Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex.Cancer Cell 5(4)：317-328)。與Her2異二聚體化促成Her1之內吞程度降低並增加回收至形成該異二聚體之受體的膜(Lenferink AE，等人(1998)Differential endocytic routing of homo- and hetero-dimeric ErbB tyrosine kinases confers signaling superiority to receptor heterodimers.EMBO J 17(12)：3385-3397)。
如Baselga J，等人(2009)Novel anticancer targets：revisiting ERBB2 and discovering ERBB3.Nat Rev Cancer 9(7)：463-475中所描述者，由配體誘導之二聚體化允許受體之胞質區的酪胺酸殘基自磷酸化及磷酸轉移。所產生之
磷酸殘基起始多種細胞內傳信途徑。起始的傳信途徑之一為絲裂原活化之蛋白激酶(MAPK)的傳信途徑，細胞外調節激酶Erk1和Erk2參與其活化級聯反應。Erk1和Erk2誘導能增加與細胞增殖有關之基因轉錄作用的轉錄因子表現，諸如細胞週期蛋白D1，其促進細胞週期進展至G1/S期。該異二聚體型組合物為最有效之傳信複合物且直接控制細胞週期(Pinkas-Kramarski R，等人(1996)Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions.EMBO J 15(10)：2452-2467)。
這些腫瘤標的已在臨床研究中被廣泛證實。以這些受體之酪胺酸激酶抑制劑(TKI)，諸如吉非替尼(gefitinib)(Ciardiello F，等人(2000)Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839(Iressa),an epidermal growth factor receptor-selective tyrosine kinase inhibitor.Clin Cancer Res 6(5)：2053-2063)及拉帕替尼(lapatinib)(Kondo N，等人(2010)Antitumor effects of lapatinib(GW572016),a dual inhibitor of EGFR and HER-2,in combination with cisplatin or paclitaxel on head and neck squamous cell carcinoma.Oncol Rep 23(4)：957-963))進行之治療的臨床效果已在評估。亦有使用對抗上述標的之單株抗體(MAb)進行臨床試驗所取得之報告，諸如使用特異於Her1之ECD的西妥昔單抗(cetuximab)(Jean GW，等人(2008)
Epidermal growth factor receptor monoclonal antibodies for the treatment of metastatic colorectal cancer.Pharmacotherapy 8(6)：742-54)和尼妥珠單抗(nimotuzumab)(Ramos TC，等人(2006)Treatment of high-grade glioma patients with the humanized anti-epidermal growth factor receptor(EGFR)antibody h-R3：report from a phase I/II trial.Cancer Biol Ther 5(4)：375-379)，及識別Her2 ECD的曲妥珠單抗(trastuzumab)(Clifford A(2007)Trastuzumab-Mechanism of Action and Use in Clinical Practice N Engl J Med；357：39-51)進行之臨床試驗。雖然這些療法中有些療法(諸如西妥昔單抗)具有強抗腫瘤效果，已說明之抗性的分子機制中該族群之另一受體，例如Her2的表現量增加(Brand TM，等人(2011)Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab.Cancer Biol Ther 11(9)：777-792)。另一方面，ErbB族之其他成員已被發現在表現Her2異二聚體之乳癌和肺癌中對帕妥珠單抗(pertuzumab)抗Her1小鼠單抗具有較好之反應(Agus DB，等人(2005)Phase I clinical study of pertuzumab,a novel HER dimerization inhibitor,in patients with advanced cancer.J Clin Oncol 23(11)：2534-2543)。這支持下列觀點：抑制異二聚體化為有吸引力之癌症療法的策略。
再者，以癌症疫苗進行之主動療法已成為新的治療選擇，其旨在活化具有表現Her1和Her2之腫瘤的患者之免
疫系統反應。然而，此類型之療法具有挑戰性，因其涉及刺激被腫瘤之抑制效果所壓抑之免疫系統，這使得疫苗配製劑有必要使用佐劑，藉以協助產生有效的反應。源自腦膜炎奈瑟氏球菌之外膜蛋白質的非常小尺寸之蛋白脂質體(VSSP)為這類佐劑，其能夠活化樹突狀細胞(DC)並極化朝向第1型輔助T細胞(Th1)反應模式的免疫反應(如2001年12月6日提出之WO 02/45746中所描述者)。Her1和Her2受體為臨床前和臨床研究中評估之不同疫苗候選物的標的。在設計以Her2為基礎之疫苗，DC疫苗時(Czerniecki BJ，等人(2007)Targeting Her2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion.Cancer Res 67(4)：1842-1852)，已使用Her2肽及ECD-Her2。(Ladjemi MZ，等人(2010)Anti-HER2 vaccines：new prospects for breast cancer therapy.Cancer Immunol Immunother 59(9)：1295-1312)。在乳癌患者之第Ⅱ期臨床研究中使用株落刺激因子粒細胞-巨噬細胞(GM-CSF)作為佐劑來評估以源自Her2ECD且由MHC-I呈現之肽p369-377(肽E75)進行之主動免疫。此疫苗能夠在體內產生對抗過度表現Her2之細胞的特定細胞毒性T淋巴細胞(CTL)且目前處在第Ⅱ期臨床研究中(Knutson KL，等人(2002)Immunization of cancer patients with a Her-2/neu,HLA-A2 peptide,p369-377,results in short-lived peptide-specific immunity.Clin Cancer Res 8(5)：1014-1018；Patil R，等人(2010)
Clinical and immunologic responses of HLA-A3+ breast cancer patients vaccinated with the HER2/neu-derived peptide vaccine,E75,in a phase I/Ⅱ clinical trial.J Am Coll Surg 210(2)：140-147)。此外，已設計以Her2之ECD為基礎並以GM-CSF作為佐劑之治療性疫苗，該疫苗能夠延緩表現Her2之癌的生長並延長經免疫化之動物的存活(Helguera，等人(2006)Vaccination with novel combinations of anti-HER2/neu cytokines fusion proteins and soluble protein antigen elicits a protective immune response against HER2/neu expressing tumors.Vaccine 16；24(3)：304-16)。
專利申請案EP-A-661061及US-A-6149921專利中描述刺激或增加對抗神經節苷脂之抗體反應且包含免疫原和免疫佐劑之疫苗組成物。所描述之免疫原為由N-乙醯化之GM3神經節苷脂(N-AcGM3)和N-GlicolilGM3(N-GcGM3)與腦膜炎奈瑟氏球菌之外膜蛋白複合物(OMPC)結合所形成之VSSP。免疫原N-AcGM3/VSSP和N-GcGM3/VSSP的尺寸非常小，在電子顯微鏡幾乎無法看見，能溶於水且具有高浮力。專利WO-A-02145746描述含有下列者之疫苗組成物：(A)一或多種弱免疫原性抗原；(B)具有被納入之神經節苷脂之VSSP，主要為N-AcGM3/VSSP和N-GcGM3/VSSP；及(C)可選擇地，一或多種佐劑。尤其是，其中描述其活性成分為ECD-Her1且使用VSSP和Montanide ISA51 VG作為佐劑之疫苗。
以此疫苗進行之臨床前研究證明其在體外和體內具有抗腫瘤效果(Ramirez BS，等人(2006)Active anti-metastatic immunotherapy in Lewis lung carcinoma with self EGFR extracellular domain protein in VSSP adjuvant.Int J Cancer 119(9)：2190-2199；Ramirez BS，等人(2008)Anti-EGFR activation,anti-proliferative and pro-apoptotic effects of polyclonal antibodies induced by EGFR-based cancer vaccine.Vaccine 26(38)：4918-4926)。
雖然以單價療法已取得結果，但他們尚不夠有效，因為該療法無法完全移除腫瘤團塊，甚至當腫瘤之大小最後確實減小，其在抗性變異體出現後消退。這表明，特定擾動無法廢除複雜之生物系統，諸如腫瘤。關於此點之解釋可為：經由單一療法所產生之瞄準ErbB族成員的抗性變異體會增加該族之其他成員的表現水準(Brand TM，等人(2011)Molecular mechanisms of resistance to the EGFR monoclonal antibody Cetuximab.Cancer Biol Ther 11(9)：777-792)，這使腫瘤能夠逃避免疫系統的攻擊。由於此點，透過將一種以上之ErbB受體去活化所造成之腫瘤生物學的多重擾動可能造成效力增加。
專利申請案WO-A-02145746亦主張包含生長因子受體Her-1、Her-2及PDGF-R或其包含具有或不具有跨膜區之細胞外結構域的任何變異體之組成物的專利。然而，無論是本申請案或本技藝之任何其他文獻中均未教示如何將該兩種受體(尤其是Her1和Her2受體之ECD)組合，藉以
製造能有效誘導經接種疫苗之個體產生抗體的二價疫苗。
本發明之作者已發現當將Her1和Her2之ECD與VSSP-GM3以相同比例混合時可取得能夠誘導產生可抑制Her1和Her2磷酸化之抗體力價的疫苗組成物且這些抗體對腫瘤細胞具有抗增殖作用。本發明者亦發現Her1和Her2之ECD的組合比例對取得所需之免疫反應至關重要，亦即，並非Her1和Her2受體之ECD的任何組合均能觸發此免疫反應。
本發明之目的為用於皮下投予之新疫苗組成物，其具有相同比例之Her1和Her2受體及VSSPs-GM3。本發明之進一步的目的為用於治療罹患由表現生長因子Her1和Her2受體之腫瘤所引起的疾病之患者的方法，其包含皮下投予含有Her1和Her2受體之ECD和VSSP-GM3之疫苗組成物，其中所發現之Her1和Her2受體的ECD之比例相同。
本發明之進一步的目的為具有相同比例之Her1和Her2受體的ECD和VSSP-GM3，以及可為油性或非油性之額外佐劑的疫苗組成物。
本發明之進一步的目的為誘導用於治療表現Her1和Her2受體之惡性腫瘤的免疫反應之方法。
本發明關於用於誘導對抗表現Her1和Her2受體之惡性腫瘤的免疫反應之疫苗組成物，其包含Her1和Her2受
體之ECD或彼等之片段。此疫苗組成物進一步包含從腦膜炎奈瑟氏球菌之外膜蛋白和GM3(VSSP-GM3)純化的非常小尺寸之蛋白脂質體。於一特定之實施態樣中，本發明之組成物進一步包含醫藥上合適之佐劑。這些醫藥上合適之佐劑包括，但不限於油性佐劑，諸如高度純化之礦物油和表面活性劑，及非油性佐劑，諸如氧化鋁(Alumina)。
令人驚訝地，本發明之發明者發現受體之ECD的組合比例與誘導對抗表現Her1和Her2受體之惡性腫瘤的免疫反應有關。本文所描述之二價疫苗組成物包含相同比例之Her1和Her2受體的ECD。為其他比例之兩種活性物質(亦即Her1和Her2受體之ECD)的混合物不具有所需之對免疫系統的效果。於一實施態樣中，本發明之組成物包含濃度在約100至約800微克/劑量之範圍內的Her1和Her2受體之ECD。更特別地，在水溶液中之經由皮下投予的本發明組成物包含800微克/劑量之Her1和Her2受體的ECD或彼等之片段且額外包含1.2毫克/劑量之VSSP-GM3。
於另一實施態樣中，本發明包含這些劑量各為800微克/劑量之Her1和Her2受體的ECD或彼等之片段及1.2毫克/劑量之VSSP-GM3，其可與佐劑(可為Montanide ISA51或氧化鋁)混合。於另一實施態樣中，本發明關於欲用於誘導免疫反應來作為治療表現Her1和Her2受體之惡性腫瘤之方法的疫苗組成物，其包含Her1和Her2受體之ECD或彼等之片段。本發明之治療方法包含經由皮下
投予至少一個劑量之Her1和Her2受體的ECD或彼等之片段(其劑量範圍係在約100至約800微克/劑量之範圍內)及額外之200微克/劑量之VSSP(約1.2毫克/劑量之VSSP-GM)。投藥可每兩個星期經由皮下注射來投予，全部共5劑，然後再投予1年維持劑量。於一特定之實施態樣中，本發明包含經由肌肉內途徑投予之具有佐劑Montanide ISA51的疫苗組成物。
本發明包含藉由蛋白質合成或遺傳工程技術取得之Her1和Her2受體的ECD或彼等之片段之用途。在本發明中，術語二價疫苗配製劑或二價疫苗組成物可以互換使用，且在所有情況下其係指包含Her1和Her2受體之細胞外結構域(ECD)或彼等之片段，以用來產生對抗表現Her1和Her2受體之惡性腫瘤的免疫反應的疫苗組成物，且其可額外包含VSSP-GM3。
可以此疫苗組成物治療之惡性腫瘤包括表現至少一種Her族之受體，尤其是Her1和/或Her2之腫瘤。較佳者為表現該兩種受體之腫瘤，更佳者為過度表現該兩種受體之腫瘤。於一較佳之實施態樣中，本發明包含上皮來源之腫瘤，更特別地，頭頸癌、乳癌、肺癌、結腸癌、胰臟癌、前列腺癌、膀胱癌和卵巢腫瘤及神經膠質瘤。縮寫MAb及PAb分別指單株和多株抗體。
第1圖顯示每14天經由皮下途徑以在200微克之
VSSP中的100微克ECD-Her1和100微克ECD-Her2將BALB/c小鼠(n=5)免疫化，共進行4次，在最後一次免疫化後30天的IgG抗體之動力學。在第7、21、35、56、87和102天抽血，使用ELISA分析測量免疫血清中之IgG抗體力價。當以ECD-Her1(a)和ECD-Her2(b)塗層時，以對數(1/力價+1)表示每一萃取日之IgG抗體的動力學。圖中顯示個別小鼠(n=5)之抗體反應，該反應特異於ECD-Her1(c)和ECD-Her2(d)且在免疫計劃之第87天藉由繪製抗體力價倒數加1之對數來測量反應。不同字母表示使用Bonferroni校正試驗，藉由雙向ANOVA(治療組因子)測試之顯著性差異(p<0.05)。
第2圖顯示採用流式細胞術，由Her1+Her2二價疫苗及單價疫苗Her1和Her2誘導之免疫血清對MDAMB468和MCF7/HER2腫瘤細胞株之識別率。在免疫計劃之第35天，將上述之人類腫瘤細胞株與免疫血清(n=5)或與稀釋200倍之免疫前血清之混合物，以及受體表現之對照組一起培育：濃度為10微克/毫升之尼妥珠單抗和曲妥珠單抗。接著，以山羊PAbs抗小鼠IgG標記細胞，並與異硫氰酸螢光素共軛結合。藉由流式細胞術將經標記之細胞可視化。使用Flow Jo軟體版本5.7.2測定血清和單株抗體所識別之細胞百分比。不同的字母表示使用Bonferroni校正試驗，藉由雙向ANOVA(治療組因子)測試之統計顯著性(p<0.05)。
第3圖顯示採用流式細胞術，由Her1+Her2二價疫苗
及單價疫苗Her1和Her2誘導之免疫血清對H292腫瘤細胞株之識別率。在免疫計劃之第35天，將人類腫瘤細胞與免疫血清(n=5)或與稀釋300倍之免疫前血清之混合物，以及受體表現之對照組一起培育：濃度為10微克/毫升之尼妥珠單抗和曲妥珠單抗。接著，以山羊PAbS抗小鼠IgG標記細胞，並與異硫氰酸螢光素共軛結合。藉由流式細胞術將經標記之細胞可視化。使用Flow Jo軟體版本5.7.2測定由血清和單株抗體識別之細胞百分比。不同的字母表示使用Bonferroni校正試驗，藉由雙向ANOVA(治療組因子)測試之統計顯著性(p<0.05)。
第4圖顯示出投予Her1+Her2二價疫苗誘導之免疫血清所引起的Her1+Her2磷酸化抑制作用。將H292細胞與五種由Her1+Her2二價疫苗及單價疫苗Her1和Her2所誘導之免疫血清的混合物一起培育。藉由西方點墨法測定以EGF和以不同治療劑刺激後Her1+Her2磷酸化的程度。使用未經治療之細胞作為陰性對照組，且以免疫前血清(PI)之混合物所治療者作為特異性陰性對照組。使用TKI AG1478作為抑制作用之陽性對照組。該圖片顯示出以不同治療劑取得之P-Her1(a)和P-Her2(b)的水準。條形圖顯示出選自執行的兩個實驗中之一個代表性實驗的圖片之密度分析。
第5圖顯示由Her1+Her2二價疫苗誘導之抗體對H292腫瘤細胞株的抗增殖作用。在免疫計劃之第87天，將H292細胞在5種以1：20稀釋之免疫血清的混合物中培
育48小時。使用PI血清之混合物作為實驗中之陰性對照組。藉由MTT比色法測定540nm處之OD值減去620nm處之OD值的光密度(OD值)差異以決定細胞存活力。當減去與PI血清一起培育的吸光度差值時可找出最大的存活力百分比。棒條代表各治療劑之一式三份的三次實驗之平均值。不同的字母表示根據Dunnett T3試驗之統計學意義，在a對b方面，p<0.01，在a對c方面，p<0.01。
第6圖顯示以含有等量或不等量之各受體的Her1+Her2二價疫苗配製劑誘導之識別ECD-Her1和ECD-Her2的抗體力價。每14天經由皮下途徑以下列各組合將BALB/c小鼠(n=5)免疫化，共進行4次：第1組，100微克之ECD-Her1和100微克之ECD-Her2；第2組，100微克之ECD-Her1和200微克之ECD-Her2；第3組，100微克之ECD-Her1和300微克之ECD-Her2；第4組，200微克之ECD-Her1和100微克之ECD-Her2；第5組，300微克之ECD-Her1和100微克之ECD-Her2。所有配製劑包含200微克之VSSP。採用ELISA分析，在第56天抽血所取得之血清上進行ECD-Her1和ECD-Her2特異性抗體力價的測定。當以ECD-Her1(a)和ECD-Her2(b)塗層時，各萃取日之IgG抗體動力學係以倒數加1的對數表示。藉由繪製抗體力價之倒數來測定個別小鼠(n=5)之IgG抗體反應。
藉由雙向ANOVA(治療組因子)，使用Bonferroni校正試驗測試時未觀察到顯著差異(p<0.05)。下列實施例僅
用於說明，而非用於限制本發明之申請專利範圍。
以含有100微克之ECD-Her1和100微克之ECD-Her2的二價疫苗配製劑經由皮下途徑將BALb/c小鼠細胞株免疫化。以含有100微克之ECD-Her1的單價疫苗配製劑將第二組相同之小鼠細胞株免疫化，並以含有100微克之ECD-Her2的單價疫苗配製劑將第三組免疫化。上述三種疫苗配製劑含有200微克之VSSP佐劑。在第0、14、28、42和72天進行免疫接種並在第-2、21、56、87和102天抽血以用於處理血清。使用ELISA方法測定血清中對抗Her1和Her2之ECD的特異性抗體力價。
以Her1+Her2二價疫苗免疫化之小鼠產生對抗ECD-Her1和ECD-Her2之特異性IgG同型抗體。所誘導出之對抗各受體的抗體力價與那些由對應之單價疫苗所誘導者並無不同。在對抗ECD-Her1之抗體反應的情況中，由Her1+Her2二價疫苗及單價疫苗誘導之力價均達到抗體力價數值之1/10.000。由二價及單價疫苗兩者所誘導之對抗ECD-Her2的反應達到抗體力價數值之1/200.000(第1圖)。
此結果顯示出在單一疫苗配製劑中混合兩種受體並不影響他們個別之免疫原性，這證實此疫苗配製劑之可能用
途。
將來自以Her1+Her2二價疫苗及單價疫苗Her1和Her2免疫化之小鼠的血清稀釋成1/200，並與105個下列腫瘤細胞株之細胞一起培育：源自乳腺癌之MDA-MB468(ATCC，HTB-132)、從以全長Her2轉染MCF7(ATCC HTB-22)產生的MCF7/Her2。使用PI血清作為陰性特異性對照組。使用識別Her1之hR3單株抗體及識別Her2之賀癌平(Herceptin)單株抗體作為陽性對照组。
由二價疫苗所產生之血清識別MDA-MB468細胞的百分比與由單價疫苗Her1所產生之血清的識別百分比相同。再者，根據Dunnett T3試驗，由二價疫苗所產生之血清識別MCF7/Her2細胞的百分比與由單價疫苗Her2所產生之血清的識別百分比相同(p>0.05)(第2圖)。這些受體之識別強度亦非常類似(表1)。
這證明含有截短之Her1和Her2受體的二價配製劑所誘導的抗體不會影響對腫瘤細胞膜中之全尺寸Her1和Her2受體的識別。其亦顯示出當該對抗Her1和Her2之抗體係從以此兩種受體為基底之配製劑產生時，此識別品質不受影響，因為該識別作用(包括識別之細胞數目及識別強度兩者)與從單價疫苗產生之血清所取得者相同。
將來自以Her1+Her2二價疫苗和Her1和Her2單價疫苗免疫化之小鼠的血清稀釋成1/300，再與源自肺部鱗狀細胞癌的腫瘤細胞株H292(ATCC CRL-1848)一起培育。使用免疫前血清作為陰性特異性對照組。使用可識別Her1之hR3單株抗體及可識別Her2之賀癌平單株抗體作為陽性對照组。
根據Dunnett T3試驗，與由Her1和Her2單價苗疫所產生之血清的識別百分比相比較，由該二價疫苗所產生之血清對H292細胞的識別百分比為統計學上較高(p>0.05)(第3圖)。
這證明由二價配製劑誘導之多株抗體具有較高之腫瘤細胞識別閾值，因為其能夠同時識別細胞膜上之兩種受體，Her1和Her2。這表明相對於該單價疫苗，二價疫苗在對H292腫瘤細胞之生物效應方面具有較高的潛力(此係藉由經識別之受體的數目測定)。此為來自涉及腫瘤增殖
之Her族之受體的活化作用被抑制的情況。
將來自以Her1+Her2二價疫苗及單價疫苗Her1和Her2免疫化之小鼠的血清稀釋成1/100，並與來自H292腫瘤細胞株之細胞一起培育。以100奈克/毫升之EGF刺激細胞10分鐘，然後裂解之。使用偵測磷酸化EGFR及總EGFR的特異性抗體，藉由西方點墨分析測定免疫血清對EGFR磷酸化之抑制效果。在此分析中，使用10μM之AG1478酪胺酸激酶抑制劑作為抑制磷酸化之陽性對照組，並使用PI血清作為陰性特異性對照組。
就磷酸化方面進行測量，由二價疫苗所產生之血清抑制Her1和Her2受體活化的程度較由單價疫苗Her1和Her2所產生之血清更大。將來自西方點墨分析之膜進行光密度分析。來自光密度分析之數據得出：相關於PI血清，由Her1+Her2二價疫苗所誘導之免疫血清所造成之Her1磷酸化減少11.2倍。當以單價疫苗Her1所誘導之血清進行同樣的分析時，Her1磷酸化減少1.7倍。在來自單價疫苗Her2組之血清的情況中，磷酸化減少2.2倍。在Her2的情況中，相關於PI血清，來自以Her1+Her2二價疫苗免疫化之小鼠的血清所誘導之Her2磷酸化減少8.7倍。當以由單價疫苗Her1所誘導之血清進行相同的分析時，Her2磷酸化減少1.7倍，而來自Her2單價疫苗組之
血清使磷酸化減少3.5倍(第4圖)。
這證明二價疫苗相對於單價疫苗之優勢。二價疫苗可能不僅能夠透過阻斷配體結合及對抗二聚體化臂之抗體直接抑制形成同二聚體(Her1/Her1和Her2/Her2)之Her1或Her2受體磷酸化，其在降低為Her1/Her2異二聚體之一部分的受體之活化方面亦可能較單價疫苗更有效。
將來自以Her1+Her2二價疫苗及單價疫苗Her1和Her2免疫化之小鼠的血清稀釋成1/20，並與H292細胞一起培育48小時。在此時間後，除去培養上清液並加入濃度為1毫克/毫升之MTT試劑。培育4小時後，除去上清液並加入100微升之二甲亞碸，以溶解甲臢(formazan)晶體；以ELISA讀計測定540nm處之OD值減去620nm處之OD值的OD差值，以測量吸光度。經由測定540nm處和620nm處之間的吸光度差值來評估存活細胞。以在PI血清中所得到之吸光度差值作為最大存活力百分比。
根據Dunnett T3試驗，以由Her1+Her2二價疫苗誘導之血清治療的腫瘤細胞之存活力較那些與由單價疫苗所誘導之血清一起培育之腫瘤細胞的存活力差(p>0.05)(第5圖)。這證明就抗增殖效果而言，投予二價疫苗所誘導之對細胞的抗腫瘤效果較由表現Her1和Her2受體之單價疫苗所誘導者強。這表明二價疫苗可能為對抗表現Her1和
Her2二種受體之上皮腫瘤的有效治療劑。
以含有不相等之ECD-Her1和ECD-Her2組合的二價疫苗配製劑經由皮下途徑將Balb/c小鼠免疫化。以100微克之ECD-Her1和100微克之ECD-Her2將第1組免疫化；以100微克之ECD-Her1和200微克之ECD-Her2將第2組免疫化；以100微克之ECD-Her1和300微克之ECD-Her2將第3組免疫化；以200微克之ECD-Her1和100微克之ECD-Her2將第4組免疫化；以300微克之ECD-Her1和100微克之ECD-Her2將第5組免疫化。所有提及之佐劑疫苗配製劑包含200微克之VSSP。在第0、14和28天經由皮下注射進行免疫接種並在第42天抽血以處理血清。採用ELISA法測定對抗Her1和Her2之ECD的特異性抗體力價，並藉由FACS評估上述血清識別表現Her1和Her2之H125腫瘤細胞株的能力(第6圖)。
所有評估之組別中，免疫血清所識別之腫瘤細胞的百分比為100%，此可由評估之配製劑變體所誘導之對抗Her1和Her2的抗體力價之能力說明。然而，其中組合同等劑量之兩種受體的第1組(表2)所測得之識別品質較佳(以平均螢光強度(MFI)測量)。
Claims (5)
- 一種疫苗組成物，其包含呈相同比例且濃度介於100至800μg/劑量之Her1和Her2受體的不含跨膜域之胞外結構域(ECD)及源自腦膜炎奈瑟氏球菌(Neisseria meningitidis)之外膜蛋白和神經節苷脂GM3的非常小尺寸之蛋白脂質體(VSSP-GM3)，藉以誘導對抗表現Her1和Her2受體之惡性腫瘤的免疫反應。
- 如申請專利範圍第1項之疫苗組成物，其中該疫苗組成物進一步包含醫藥上合適之佐劑。
- 如申請專利範圍第2項之疫苗組成物，其中該醫藥上合適之佐劑選自Montanide ISA 51或氧化鋁(Alumina)。
- 如申請專利範圍第1項之疫苗組成物，其中該疫苗組成物係經由皮下投予。
- 如申請專利範圍第1項之疫苗組成物，其係用於在每兩週經由皮下投予800μg/劑量之Her1和Her2受體之胞外結構域(ECD)和1.2mg/劑量之VSSP-GM3達至少5個劑量，且接著每個月以維持劑量投予持續至少一年，藉以誘導對抗表現Her1和Her2受體之惡性腫瘤的免疫反應。
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