TW201348264A - Composition - Google Patents

Abstract

The present invention relates to a composition comprising at least one mimotope of an epitope of alpha-synuclein for use in a method for preventing and/or treating synucleinopathies, wherein said at least one mimotope is coupled or fused to a pharmaceutically acceptable carrier protein selected from the group consisting of a non-toxic diphtheria toxin mutant, keyhole limpet hemocyanin (KLH), diphtheria toxin (DT), tetanus toxid (TT) and Haemophilus influenzae protein D (protein D).

Description

組成物 Composition

本發明關於一藥物，係使用於預防及/或治療共核蛋白病(synucleinopathies)。 The present invention relates to a medicament for the prevention and/or treatment of synucleinopathies.

共核蛋白病(Synucleinopathies)為一群多種神經退化性病症，其共用一病理特徵：在神經病理學實驗特徵損傷處，在特定族群之神經元及神經膠質細胞中，可偵測到甲型共核(alpha-syn，a-syn)蛋白異常聚集物。 Synucleinopathies are a group of neurodegenerative disorders that share a pathological feature: in a neuropathological experimental lesion, a type A co-nucleus can be detected in neurons and glial cells of a particular group ( Alpha-syn, a-syn) abnormal aggregates of proteins.

甲型共核蛋白(a-syn，一開始被認為PARK1及PARK4)是一140個胺基酸蛋白質，廣泛表現於人類神經系統中，包含腦部，如腦皮質新成部(neocortex)、海馬體(hippocampus)、齒狀回(dentate gyrus)、嗅球(olfactory bulb)、紋狀體(striatum)、視丘(thalamus)及小腦(cerebellum)。甲型共核蛋白(alpha-syn)亦高度表現於造血系統家族成員中，包含B細胞，T細胞及自然殺手細胞及單核細胞及血小板。至今，其在這些細胞中真正的角色尚未清楚，但已被證實參與在巨核細胞(血小板的前驅物)中的分化。 A-type synuclein (a-syn, initially considered to be PARK1 and PARK4) is a 140 amino acid protein widely expressed in the human nervous system, including the brain, such as neocortex (neocortex), hippocampus Hippocampus, dentate gyrus, olfactory bulb, striatum, thalamus, and cerebellum. Alpha-synuclear (alpha-syn) is also highly expressed in members of the hematopoietic system, including B cells, T cells and natural killer cells as well as monocytes and platelets. To date, its true role in these cells has not been known, but it has been shown to be involved in differentiation in megakaryocytes (precursors of platelets).

大部分共同的共核蛋白病(Synucleinopathies)包括但不限於路易氏體症(Lewy body disorders，簡稱LBDs)，如帕金森氏病(Parkinson’s disease，簡稱PD)、帕金森氏失智症(Parkinson’s disease with dementia，簡稱PDD)及路易氏體失智症(dementia with Lewy bodies，簡稱DLB)，及多發性系統退化症(multiple system atrophy，簡稱MSA)或第一型腦內鐵沉積性神經退化症(Neurodegeneration with Brain Iron Acculation type I，簡稱 NBIA Type I)。另外，進一步神經退化疾病基於典型的、含有甲型共核蛋白(alpha-syn)之損傷，被分類為共核蛋白病(Synucleinopathies)，如漸進性核上眼神經痲痺症(progressive supranuclear palsy，簡稱PSP)、額葉聶型失智(frontotemporal dementia，簡稱FTD)、畢克氏症(Pick’s disease，簡稱PiD)及皮質基底核退化症(cortico-basal degeneration，簡稱CBD)。目前治療這些疾病之選項包括系統性藥物，如L-多巴(L-dopa)、抗膽鹼藥物及單胺氧化酶(monoamine oxidase)抑制劑。然而，目前所有的治療選項僅讓症狀緩和，卻無誘發病人長期、疾病減輕之效益。 Most common synucleinopathies include, but are not limited to, Lewy body disorders (LBDs), such as Parkinson's disease (PD), Parkinson's disease (Parkinson's disease). With dementia (PDD) and dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) or type 1 intracerebral iron depositional neurodegeneration ( Neurodegeneration with Brain Iron Acculation type I, referred to as NBIA Type I). In addition, further neurodegenerative diseases are classified as synucleinopathies, such as progressive supranuclear palsy, based on typical alpha-syn-containing lesions. PSP), frontotemporal dementia (FTD), Pick's disease (PiD) and cortico-basal degeneration (CBD). Current options for treating these diseases include systemic drugs such as L-dopa, anticholinergics, and monoamine oxidase inhibitors. However, all current treatment options only ease the symptoms, but do not induce long-term, disease-reducing benefits.

路易氏體病症(Lewy body disorders，簡稱LBD)係漸進式神經退化性病症，其特徵為顫抖(tremor)、運動遲緩(bradykinesia)、僵硬(rigidity)及腦部減少多巴性神經元(dopaminergic neurons)。在路易氏體失智症(dementia with Lewy bodies，簡稱DLB)及帕金森氏失智症(Parkinson’s disease with dementia，簡稱PDD)病例中，其症狀包括認知損傷。在西方國家，超過60歲之族群有至多2%發展出典型之帕金森氏病(Parkinson’s disease，簡稱PD)/路易氏體病症(Lewy body disorders，簡稱LBD)之症狀。目前僅可進行症狀性治療。不幸的是，這些治療僅提供在較早期之暫時性緩解，並未停止病程。帕金森氏病(Parkinson’s disease，簡稱PD)/路易氏體病症(Lewy body disorders，簡稱LBD)之致病機轉尚未完全清楚，但顯示出基因易感性(genetic susceptibility)及環境因子參與於該疾病中。儘管所有的基因的顯著進展(genetic advances)帕金森氏病(Parkinson’s disease，簡稱PD)/路易氏體病症(Lewy body disorders，簡稱LBD)係主要為未知起因之偶發性病症。 Lewy body disorders (LBD) are progressive neurodegenerative disorders characterized by tremor, bradykinesia, rigidity, and dopaminergic neurons in the brain. ). In cases of dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD), the symptoms include cognitive impairment. In Western countries, up to 2% of people over the age of 60 develop symptoms of Parkinson's disease (PD)/Lewy body disorders (LBD). Currently only symptomatic treatment is available. Unfortunately, these treatments only provide temporary relief at an earlier stage and do not stop the course. The pathogenesis of Parkinson's disease (PD)/Lewy body disorders (LBD) is not fully understood, but shows that genetic susceptibility and environmental factors are involved in the disease. in. Although all genes have significant advances, Parkinson's disease (PD)/Lewy body disorders (LBD) are mainly sporadic disorders of unknown origin.

病人遭受此疾病，其發展成特徵為腦部皮質層及皮質下之細胞內普遍存在包涵體(inclution)，稱之為路易氏體(Lewy bodies，簡稱LBs)。特別高含量之多巴性神經元或投射神經元顯示此典型之致病特徵。 最近，許多研究顯示，突觸蛋白甲型共核蛋白(alpha-syn)在路易氏體病症(Lewy body disorders，簡稱LBD)致病機轉中，扮演重要角色。在路易氏體病症(Lewy body disorders，簡稱LBD)中，甲型共核蛋白(alpha-syn)蓄積於路易氏體(Lewy bodies，簡稱LBs)，遍佈影響腦部區域。另外，甲型共核蛋白(alpha-syn)基因之單點突變及二重覆(duplication)或多重複(multiplication)於少數家族性帕金森氏症(Parkinsonism)中可被證明。重要的是，基於在轉殖基因(tg)小鼠及黑腹果蠅(Drosophila melanogaster)中，過度表現性試驗結果顯示，當動物模型模擬帕金森氏病(Parkinson’s disease，簡稱PD)許多特徵時，在帕金森氏病(Parkinson’s disease，簡稱PD)/路易氏體病症(Lewy body disorders，簡稱LBD)之致病機轉是被強調的。 The patient suffers from this disease, which is characterized by the widespread presence of inclusions in the cortical and subcortical cells of the brain, known as Lewy bodies (LBs). Particularly high levels of dop-like neurons or projection neurons show this typical pathogenic feature. Recently, many studies have shown that synaptic protein alpha-syngene (alpha-syn) plays an important role in the pathogenesis of Lewy body disorders (LBD). In Lewy body disorders (LBD), alpha-syn accumulates in Lewy bodies (LBs), which affect the brain. In addition, single point mutations of the alpha-syn gene and duplication or multiplication can be demonstrated in a few familial Parkinsonism. Importantly, based on transgenic (tg) mice and Drosophila melanogaster, overexpression tests showed that when animal models mimic many features of Parkinson's disease (PD) The pathogenesis of Parkinson's disease (PD)/Lewy body disorders (LBD) is emphasized.

另一非常重要之共核蛋白病為多發性系統退化症(Multiple System Atrophy，簡稱MSA)。多發性系統退化症(Multiple System Atrophy，簡稱MSA)係為不規則之神經退化性病症，其可用症狀分類為抗L-多巴帕金森氏症(L-DOPA-resistant Parkinsonism)，小腦運動失調(cerebellar ataxia)及自主神經失調(dysautonomia)。病人遭受多重系統神經性損失(multi-system neuronal loss)，其影響不同腦部位，包括紋狀體(striatum)、黑質(substantia nigra)、小腦(cerebellum)、橋腦(pons)及下橄欖體(inferior olives)及脊髓(spinal cord)。多發性系統退化症(Multiple System Atrophy，簡稱MSA)利用甲型共核蛋白陽性神經膠狀細胞細胞質之包涵體(alpha-syn-positive glial cytoplasmic inclusions，簡稱GCI)及少數神經元包涵體遍佈中樞神經系統來辨別的。這些包涵體(inclusions)與紋狀黑質性退化(striatonigral degeneration)、橄欖體橋腦小腦萎縮(olivopontocerebellar atrophy，簡稱OPCA)及參與延腦及脊髓之自主神經核相關。利用分析轉殖基因小鼠模型，分析寡樹突神經膠細胞(oligodendroglia)中過度表現甲型共核蛋白，了解甲型共核蛋白陽性神經膠狀細胞細胞質之包涵體 (alpha-syn-positive glial cytoplasmic inclusions，簡稱GCI)在多發性系統退化症(Multiple System Atrophy，簡稱MSA)致病機轉之重要性。在tg小鼠中，過度表現人類甲型共核蛋白可觀察到，類神經膠狀細胞細胞質之包涵體凝結塊(GCI-like aggregates)及多發性系統退化症(Multiple System Atrophy，簡稱MSA)生物化學標示物。 Another very important synuclear disease is Multiple System Atrophy (MSA). Multiple System Atrophy (MSA) is an irregular neurodegenerative disorder, and its available symptoms are classified as L-DOPA-resistant Parkinsonism, cerebellar dysmotility ( Cerebellar ataxia) and autonomic dysonia (dysautonomia). The patient suffers from multi-system neuronal loss, which affects different brain parts, including striatum, substantia nigra, cerebellum, pons, and lower olives. Inferior olives and spinal cord. Multiple System Atrophy (MSA) uses alpha-syn-positive glial cytoplasmic inclusions (GCI) and a small number of neuronal inclusions throughout the central nervous system. The system to distinguish. These inclusions are associated with striatonigral degeneration, olivopontocerebellar atrophy (OPCA), and autonomic nucleus involved in the brain and spinal cord. Using a mouse model of transgenic genes to analyze the overexpression of alpha-nuclear protein in oligodendroglia, and to understand the inclusion bodies of cytoplasm of type A synuclein-positive glial cells. (alpha-syn-positive glial cytoplasmic inclusions, referred to as GCI) is important in the pathogenesis of multiple system Atrophy (MSA). In tg mice, overexpression of human alpha-type nuclear proteins can be observed in GCI-like aggregates (GCI-like aggregates) and multiple systemic atrophy (MSA) organisms. Chemical marker.

雖然甲型共核蛋白蓄積導致共核蛋白病中(synucleopathies)神經退化之典型特徵之精確機轉尚未清楚被了解，最近研究指出甲型共核蛋白異常形成及蓄積，參與在共核蛋白病之退化性過程。最近，不同形式之甲型共核蛋白在路易氏體(Lewy bodies，LBs)中已被辨認。除了該蛋白全長型式，不同形式之修飾甲型共核蛋白已被辨認，包括磷酸化(phosphorylated)、硝酸化(nitrated)及單(mono-)、雙(di-)或三(tri-)泛素化甲型共核蛋白(ubiquitinated alpha-syn)。另外，在轉殖基因小鼠及PD病人中之腦部組織中皆可發現C端截切形式蛋白，如甲型共核蛋白1-119(alpha-syn 1-119)、甲型共核蛋白1-122(alpha-syn 1-122)及甲型共核蛋白1-123(alpha-syn 1-123)。目前相信，在路易氏體(Lewy bodies，簡稱LBs)及路易氏軸突(lewy neurites)中之甲型共核蛋白有至多15%被截切。之前試管中試驗，利用截切形式之甲型共核蛋白可證明缺乏C端20-30個胺基酸之甲型共核蛋白証明可增加蓄積之傾向及在路易氏體(Lewy bodies，簡稱LBs)及路易氏軸突(lewy neurites)中發現絲狀體(filaments)之形成。這些截切版本扮演類似阿茲海默症(Alzheimer’s disease，AD)之截切及修飾之類澱粉樣蛋白β(amyloid beta，簡稱Aβ)。這些截切及修飾之類澱粉樣蛋白β(amyloid beta，簡稱Aβ)被認扮演為斑塊沉積之晶種物質，並在試管內及活體內顯示較高之凝集傾向及高度神經毒性(neurotoxicity)及突觸毒性(synaptotoxicity)。 Although the precise mechanism of the typical feature of neuronal degeneration in synuclear disease has not been clearly understood, recent studies have indicated abnormal formation and accumulation of alpha-nuclear proteins, which are involved in synuclear disease. Degenerative process. Recently, different forms of alpha-nuclear proteins have been identified in Lewy bodies (LBs). In addition to the full-length version of the protein, different forms of modified alpha-nuclear proteins have been identified, including phosphorylated, nitrated, and mono-, di- or tri-tri Ubiquitinated alpha-syn. In addition, C-terminal truncated forms of proteins such as alpha-syn 1-119 and alpha-nuclear proteins can be found in brain tissues of transgenic mice and PD patients. 1-122 (alpha-syn 1-122) and alpha-nuclear protein 1-123 (alpha-syn 1-123). It is currently believed that up to 15% of the alpha-nuclear proteins in Lewy bodies (LBs) and lewy neurites are truncated. Previous tests in vitro, using a truncated form of alpha-nuclear protein, demonstrated that the lack of C-terminal 20-30 amino acids of the alpha-nuclear protein proved to increase the tendency to accumulate and in Lewy bodies (LBs) And the formation of filaments in lewy neurites. These cut-off versions play an amyloid beta (abbreviated as Aβ) similar to the cut and modification of Alzheimer's disease (AD). These cut and modified amyloid beta (Aβ) are recognized as seed materials for plaque deposition and show high agglutination tendency and high neurotoxicity in vitro and in vivo. And synaptotoxicity.

因此，全長之甲型共核蛋白及截切及/或修飾形式之甲型共 核蛋白，顯示具有晶種效果之潛力，且被相信蓄積導致形成寡體(oligomer)。基於最近研究顯示，例如在PD/LBD疾病發展中，突觸端及神經軸突形成寡體(oligomer)扮演重要角色，且可增加存在截切形式之甲型共核蛋白。因此，減少甲型共核蛋白沉積及寡聚作用(oligomerisation)可被用於治療甲型共核蛋白病(synucleopathies)，特別是自發性LBD/PD及MSA，且可成為第一治療這些神退化性疾病之策略，除目前治療僅緩解症狀策略之外，如L-DOPA使用。 Therefore, full-length alpha-nuclear proteins and truncated and/or modified forms of alpha Nucleoproteins, showing potential for seeding effects, are believed to accumulate resulting in the formation of oligomers. Based on recent studies, for example, in the development of PD/LBD disease, synaptic terminals and axonal oligomers play an important role, and can increase the presence of a truncated form of a type A nuclear protein. Therefore, reduction of alpha-nuclear protein deposition and oligomerization (oligomerisation) can be used to treat synucleopathies, especially spontaneous LBD/PD and MSA, and can be the first treatment for these degenerative Strategies for sexually transmitted diseases, except for current treatments that only relieve symptomatic strategies, such as L-DOPA.

Iwatsubo T.(Neuropathology 27(5)(2007))證實甲型共核蛋白(a-syn)沉澱物及其磷酸化與甲型共核蛋白病(alpha-synucleinopathies)致病機轉相互關聯。該作者發現甲型共核蛋白(a-syn)其第129號的絲胺酸廣泛性的磷酸化，進而沉澱於共核蛋白病(synuclopathy)損傷處。美國專利公開號2007/213253指出突變的人類甲型共核蛋白(alpha-synuclein)與其胜肽衍生物也許可用來抑制野生型人類甲型共核蛋白蓄積。WO專利公開號2004/041067揭露一種預防或治療與甲型共核蛋白蓄積相關疾病物與方法，其包含甲型共核蛋白片段之用途。美國專利公開號2003/166558揭露胜肽可使用於誘發蛋白質沉澱物之免疫反應。美國專利公開號2005/198694指出，甲型共核蛋白片段包含至少100個胺基酸，且其C端刪除第1至23號胺基酸。 Iwatsubo T. (Neuropathology 27(5) (2007)) confirmed that the alpha-synuclein (a-syn) precipitate and its phosphorylation are associated with pathogenesis of alpha-synucleinopathies. The authors found that a-type synuclein (a-syn) has extensive phosphorylation of serine 129, which is precipitated in the synuclopathy lesion. U.S. Patent Publication No. 2007/213253 teaches that mutant human alpha-synuclein and its peptide derivatives may be useful for inhibiting the accumulation of wild-type human alpha-type nuclear proteins. WO Patent Publication No. 2004/041067 discloses the use of a type A synuclein fragment for preventing or treating diseases and methods associated with accumulation of alpha-nuclear protein. U.S. Patent Publication No. 2003/166558 discloses that a peptide can be used to induce an immune response to a protein precipitate. U.S. Patent Publication No. 2005/198694 teaches that a type A synuclein fragment comprises at least 100 amino acids and its C-terminus deletes amino acids Nos. 1 to 23.

Liang等人(J.Neurochem.99(2006)：470-482)研究甲型共核蛋白(alpha-synuclein)在大鼠中之調控。他們觀察到喜好酒精之大鼠，其表現甲型共核蛋白(alpha-synuclein)之比率與非喜好酒精之大鼠較為增加。 Liang et al. (J. Neurochem. 99 (2006): 470-482) investigated the regulation of alpha-synuclein in rats. They observed alcohol-loving rats, which showed an increase in the ratio of alpha-synuclein to non-alcoholic rats.

Hamilton BA(Genomics 83(2004)：739-742)證實甲型共核蛋白(alpha-synuclein)，其第53號胺基酸為蘇安酸及丙胺酸(53Thr and 53Ala)之分佈。 Hamilton BA (Genomics 83 (2004): 739-742) confirmed alpha-synuclein, the amino acid 53 of which is the distribution of sulphonic acid and alanine (53Thr and 53Ala).

US 2005/0037013揭露致免疫性甲型共核蛋白 (alpha-synuclein)片段，其70-140號殘基可誘發對抗專一性之抗原決定位(epitope)之免疫反應。 US 2005/0037013 discloses immunogenic alpha-nuclear protein The (alpha-synuclein) fragment, whose residues 70-140, induces an immune response against the specific epitope.

WO 2006/045037關於C端被截切之甲型共核蛋白(alpha-synuclein)分子可被使用於篩選供治療路易氏體病(Lewy body disease)有效之藥理活性。 WO 2006/045037 for C-terminally cleaved alpha-synuclein molecules can be used to screen for pharmacological activity effective for the treatment of Lewy body disease.

雖然利用親神經性分子及植入可分泌多巴細胞之實驗性治療已得到有指望之結果，設計一替代性途徑，其可減少甲型共核蛋白(alpha-synuclein)蓄積於神經元是為需要的。甲型共核蛋白(alpha-synuclein)聚集物可能為免疫治療之目標，其令人注目之證據逐漸累積中。當然，最近顯示出具有潛在性可治療共核蛋白病(synucleopathies)。高度表現人類甲型共核蛋白(alpha-syn)之Tg小鼠接種人類甲型共核蛋白(alpha-syn)之疫苗。小鼠接種疫苗後，製造出大量相關親合性之抗體，其可減低甲型共核蛋白(alpha-syn)在神經元細胞本體及突觸蓄積，此舉與降低神經退化相關。再者，被接種疫苗之動物產生之抗體亦可偵測到神經細胞膜上不正常之聚集型甲型共核蛋白(alpha-syn)，並促使這些聚集物裂解，可能經由溶酶體(lysosomal)之途徑。利用施予外生性甲型共核蛋白(alpha-syn)專一性抗體之主動式免疫治療法，亦被觀察到相類似之影響。這些結果建議接種疫苗為減少神經元蓄積甲型共核蛋白(alpha-syn)聚集物，及進一步發展此途徑，可能於治療路易氏體症(Lewy body disorder，簡稱LBD)及共核蛋白病(synucleopathies)得到益處。 Although experimental treatments using neurotropic molecules and implantation of secretable dopa cells have yielded promising results, designing an alternative approach that reduces the accumulation of alpha-synuclein in neurons is needs. Alpha-synuclein aggregates may be the target of immunotherapy, and its compelling evidence is gradually accumulating. Of course, there have recently been shown to have potentially treatable synucleopathies. Tg mice that highly express human alpha-synuclear (alpha-syn) are vaccinated with human alpha-syn vaccine. After vaccination in mice, a large number of related affinity antibodies are produced, which can reduce the accumulation of alpha-syn in neuronal cell bodies and synapses, which is associated with reduced neurodegeneration. Furthermore, antibodies produced by vaccinated animals can also detect abnormal aggregated alpha-syn on the neuronal membrane and promote the cleavage of these aggregates, possibly via lysosomal. The way. Similar effects were observed with active immunotherapy with exogenous alpha-syn specific antibodies. These results suggest that vaccination to reduce neuronal accumulation of alpha-syn aggregates, and further development of this pathway, may be in the treatment of Lewy body disorder (LBD) and synuclearopathy ( Synucleopathies) benefit.

本發明之目的係提供一藥物，係以疫苗為基礎，來預防及治療共核蛋白病。 The object of the present invention is to provide a medicament based on a vaccine for the prevention and treatment of synuclearopathy.

本發明係關於一組成物，包括類甲型共核蛋白(alpha-synuclein)一抗原決定位(epitope)之至少一擬抗原決定位 (mimotope)，用於預防及/或治療共核蛋白病(synucleinopathies)，其中上述之至少一擬抗原決定位(mimotope)為結合或融合，較佳為結合，於一藥學上可接受之攜帶蛋白，該攜帶蛋白選自由無毒白喉毒素(non-toxic diphtheria toxin mutant)、血氰蛋白(keyhole limpet hemocyanin，簡稱KLH)、白喉毒素(diphtheria toxin，簡稱DT)、破傷風類毒素(tetanus toxid，簡稱TT)及流感嗜血桿菌共同蛋白D(Haemophilus influenzae protein D，簡稱protein D)所組成之群組。 The present invention relates to a composition comprising at least one quasi-antigenic epitope of an alpha-synuclein-epitope (mimotope) for preventing and/or treating synucleinopathies, wherein at least one of the above mitopes is a binding or fusion, preferably a binding, in a pharmaceutically acceptable carrier protein. The carrier protein is selected from the group consisting of non-toxic diphtheria toxin mutant, keyhole limpet hemocyanin (KLH), diphtheria toxin (DT), and tetanus toxid (TT). And a group consisting of Haemophilus influenzae protein D (abbreviated as protein D).

該擬抗原決定位(mimotope)之致免疫性可驚人地增加，若擬抗原決定位(mimotope)被融合或結合於一攜帶蛋白，該攜帶蛋白選自由無毒白喉毒素(non-toxic diphtheria toxin mutant)、血氰蛋白(keyhole limpet hemocyanin，簡稱KLH)、白喉毒素(diphtheria toxin，DT)、破傷風類毒素(tetanus toxid，簡稱TT)及流感嗜血桿菌共同蛋白D(Haemophilus influenzae protein D，簡稱protein D)所組成之群組，其中特別較佳地為無毒白喉毒素(non-toxic diphtheria toxin mutant)，如CRM197。 The immunogenicity of the mimotope can be dramatically increased. If the mimotope is fused or bound to a carrier protein, the carrier protein is selected from non-toxic diphtheria toxin mutant. , keyhole limpet hemocyanin (KLH), diphtheria toxin (DT), tetanus toxid (TT) and Haemophilus influenzae protein D (protein D) The group formed is particularly preferably a non-toxic diphtheria toxin mutant such as CRM197.

第1A圖 利用DQPVLPD-CRM197之組合治療動物，其中間值注入式胜肽效價，並且與控制組比較。 Panel 1A Animals were treated with a combination of DQPVLPD-CRM197 with a median value of the peptide titer and compared to the control group.

第1B圖 利用YDRPVQPDR-CRM197之組合治療動物，其中間值注入式胜肽效價，並且與控制組比較。 Panel 1B Animals were treated with a combination of YDRPVQPDR-CRM197 with a median value of the peptide titer and compared to the control group.

第1C圖 利用KNDEGAP-CRM197之組合治療動物，其中間值注入式胜肽效價，並且與控制組比較。 1C Figure Animals were treated with a combination of KNDEGAP-CRM197 with a median value of the peptide titer and compared to the control group.

第2A圖 利用DQPVLPD-KLH之組合治療動物，其中間值注入式胜肽效價，並且與控制組比較。 Figure 2A The animals were treated with a combination of DQPVLPD-KLH with a median value of the peptide titer and compared to the control group.

第2B圖 利用YDRPVQPDR-KLH之組合治療動物，其中間值注入式 胜肽效價，並且與控制組比較。 Figure 2B Treatment of animals with a combination of YDRPVQPDR-KLH, with interim value injection The peptide titer was compared to the control group.

第2C圖 利用KNDEGAP-KLH之組合治療動物，其中間值注入式胜肽效價，並且與控制組比較。 2C Figure Animals were treated with a combination of KNDEGAP-KLH with a median value of the peptide titer and compared to the control group.

第2D圖 利用DHPVHPDS-KLH之組合治療動物，其中間值注入式胜肽效價，並且與控制組比較。 2D Figure Animals were treated with a combination of DHPVHPDS-KLH with a median value of the peptide titer and compared to the control group.

第3A圖 利用DQPVLPD-CRM197之組合治療動物，其中間值MCP-1濃度，並且與控制組比較。 Figure 3A Animals were treated with a combination of DQPVLPD-CRM197 with a median value of MCP-1 and compared to the control group.

第3B圖 利用YDRPVQPDR-CRM197之組合治療動物，其中間值MCP-1濃度，並且與控制組比較。 Figure 3B Animals were treated with a combination of YDRPVQPDR-CRM197 with a median value of MCP-1 concentration and compared to the control group.

第3C圖 利用KNDEGAP-CRM197之組合治療動物，其中間值MCP-1濃度，並且與控制組比較。 Figure 3C Animals were treated with a combination of KNDEGAP-CRM197 with a median value of MCP-1 and compared to the control group.

第3D圖 利用DHPVHPDS-CRM197之組合治療動物，其中間值MCP-1濃度，並且與控制組比較。 Figure 3D Animals were treated with a combination of DHPVHPDS-CRM197 with a median value of MCP-1 and compared to the control group.

第4A圖 利用DQPVLPD-KLH之組合治療動物，其中間值MCP-1濃度，並且與控制組比較。 Figure 4A Animals were treated with a combination of DQPVLPD-KLH with a median value of MCP-1 and compared to the control group.

第4B圖 利用YDRPVQPDR-KLH之組合治療動物，其中間值MCP-1濃度，並且與控制組比較。 Figure 4B Animals were treated with a combination of YDRPVQPDR-KLH with a median value of MCP-1 and compared to the control group.

第4C圖 利用KNDEGAP-KLH之組合治療動物，其中間值MCP-1濃度，並且與控制組比較。 Figure 4C Animals were treated with a combination of KNDEGAP-KLH with a median value of MCP-1 and compared to the control group.

第4D圖 利用DHPVHPDS-KLH之組合治療動物，其中間值MCP-1濃度，並且與控制組比較。 Figure 4D Figure Animals were treated with a combination of DHPVHPDS-KLH with median MCP-1 concentration and compared to control group.

第5A圖 利用CRM197之組合治療動物，其周邊血液之單核細胞百分比，並且與控制組比較。 Figure 5A The percentage of monocytes in the peripheral blood of animals treated with a combination of CRM197 and compared to the control group.

第5B圖 利用KLH之組合治療動物，其周邊血液之單核細胞百分比，並且與控制組比較。 Figure 5B shows the percentage of monocytes in the peripheral blood of animals treated with a combination of KLH and compared to the control group.

第6A圖 利用KNDEGAP-CRM197之組合治療動物，其中間值 lin-CD11b+甲型共核蛋白-Fluor488+單核細胞百分比。 Figure 6A Figure of the treatment of animals with a combination of KNDEGAP-CRM197, the median value lin-CD11b + alpha-type synuclein - Fluor 488 + monocyte percentage.

第6B圖 利用DHPVHPDS-CRM197之組合治療動物，其中間值 lin-CD11b+甲型共核蛋白-Fluor488+單核細胞百分比。 Figure 6B Figure of the treatment of animals with a combination of DHPVHPDS-CRM197, the median value lin-CD11b + alpha-type synuclein - Fluor 488 + monocyte percentage.

第6C圖 利用KNDEGAP-KLH之組合治療動物，其中間值lin-CD11b+ 甲型共核蛋白-Fluor488+單核細胞百分比。 Figure 6C The animals were treated with a combination of KNDEGAP-KLH with a median value of lin-CD11b+ Percentage of alpha-type nuclear protein-Fluor488+ monocytes.

第6D圖 利用DHPVHPDS-KLH之組合治療動物，其中間值lin-CD11b+ 甲型共核蛋白-Fluor488+單核細胞百分比。 Figure 6D Figure Animals were treated with a combination of DHPVHPDS-KLH with a median value of lin-CD11b+ Percentage of alpha-type nuclear protein-Fluor488+ monocytes.

在此使用「抗原決定位(epitope)」一詞，係指抗原之致免疫性(immunogenicity)區域，該區域為抗體所辨識之處。一個抗原可能具有一個或多個抗原決定位(epitope)，每一個抗原決定位(epitope)皆可與特定的抗體結合。 The term "epitope" is used herein to refer to the immunogenicity region of an antigen that is recognized by the antibody. An antigen may have one or more epitopes, and each epitope may bind to a particular antibody.

關於本發明「擬抗原決定位(minotope)」一詞，係指一物質，其拓撲結構(topology)與抗原決定位(epitope)極為相似。該擬抗原決定位(minotope)與抗體的抗原結合區域相同，該抗體與特定的抗原具有免疫專一性。該擬抗原決定位(minotope)在宿主會引起免疫反應，該反應與抗原所引起的反應是相似的。擬抗原決定位(minotope)在試管內抑制分析試驗(例如ELISA抑制分析試驗)中，可作為抗原決定位(epitope)的競爭者，該抑制作用是參與在抗原決定位(epitope)與一抗體結合於上述之抗原決定位(epitope)。然而，本發明之擬抗原決定位(minotope)在試管內抑制分析試驗中，並無預防或與抗原決定位(epitope)結合部位相互競爭，雖然其在哺乳動物中具有誘發特定免疫反應之能力。本發明之化合物包含上述之擬抗原決定位(minotopes，以上所列皆是)，其有預防自發性T細胞的反應，縱使 化合物中之胜肽，其胺基酸序列與自然生成的甲型共核蛋白(alpha synuclein)不同。 The term "minotope" as used in the present invention refers to a substance whose topology is very similar to an epitope. The minotope is identical to the antigen binding region of the antibody, and the antibody is immunospecific with a particular antigen. The minotope causes an immune response in the host, which is similar to the response caused by the antigen. The minotope can be used as an epitope competitor in an in vitro inhibition assay (eg, an ELISA inhibition assay) that participates in binding to an antibody at the epitope (epitope). In the above epitope (epitope). However, the minotope of the present invention does not prevent or compete with the epitope binding site in an in vitro inhibition assay, although it has the ability to induce a specific immune response in a mammal. The compounds of the present invention comprise the aforementioned epitopes (minotopes, listed above) which prevent spontaneous T cell responses, even The peptide in the compound has an amino acid sequence different from the naturally occurring alpha synuclein.

本發明之擬抗原決定位(minotopes)習知的生產方式為化學合成方法來加以生產，亦可為一被分離的胜肽或是其他胜肽或多胜肽中的一部份。另外，擬抗原決定位胜肽片段(peptide minotope)亦可利用微生物來製造，若有需要可再進行分離、純化。擬抗原決定位胜肽片段(peptide minotope)亦可利用微生物來製造，該微生物可為細菌、酵母菌、真菌、真核細胞(例如哺乳或是昆蟲細胞)或是重組病毒載體，例如腺病毒(adenovirus)、痘病毒(poxvirus)、皰疹病毒(herpesvirus)、賽姆利基森林病毒(Simliki forest virus)、桿狀病毒(baculovirus)、噬菌體(bacteriophage)、辛德比病毒(sindbis virus)或是仙台病毒(sendai virus)。適合生產擬抗原決定位胜肽片段(peptide minotope)的細菌包括大腸桿菌(E.coli)、枯草桿菌(B.subtilis)或是任何其他可表現胜肽之細菌。適合表現擬抗原決定位胜肽片段(peptide minotope)的酵母菌包括啤酒酵母菌(Saccharomyces cerevisiae)、裂殖酵母菌(Schizosaccharomyces pombe)、念珠菌屬(Candida)、嗜甲醇酵母菌(Pichia pastoris)或是其他適合表現擬抗原決定位胜肽片段(peptide minotope)的酵母菌。相對應之方法皆為習知。另外，習知的分離及純化方法為凝膠過濾法(gel filtration)、親和性層析法(affinity chromatography)、離子交換層析法(ion exchange chromatography)等。 The conventional production mode of the minotopes of the present invention is produced by a chemical synthesis method, and may be an isolated peptide or a part of other peptides or peptides. In addition, the peptide minotope can also be produced by using microorganisms, and can be separated and purified if necessary. A peptide minotope can also be produced using a microorganism, which can be a bacterium, a yeast, a fungus, a eukaryotic cell (such as a mammal or an insect cell), or a recombinant viral vector, such as an adenovirus ( Adenovirus), poxvirus, herpesvirus, Simmliki forest virus, baculovirus, bacteriophage, sindbis virus or Sendai Virus (sendai virus). Bacteria suitable for the production of the peptide minotope include E. coli, B. subtilis or any other bacterium capable of expressing a peptide. Yeast suitable for expressing the peptide minotope include Saccharomyces cerevisiae, Schizosaccharomyces pombe, Candida, Pichia pastoris or It is another yeast suitable for expressing the peptide minotope. The corresponding methods are all known. Further, conventional separation and purification methods are gel filtration, affinity chromatography, ion exchange chromatography, and the like.

為了達到擬抗原決定位胜肽片段分離的目的，需製造一融合多胜肽，該融合多胜肽為轉譯性融合(共價鍵鍵結)形成異種多胜肽(heterologous polypeptide)，可為親和性層析法所分離。傳統上異種多胜肽為His-標幟(His-tag，例如His6；6個組胺酸殘基，6 histidine residues)，GST-標幟(GST-Tag，Glutathione-S-transferase)等等。該融合多胜肽不僅幫助擬抗原決定位純化，亦可預防擬抗原決定位胜肽片段在純化時被分解。 若在純化後欲去除異種多胜肽，該融合蛋白在擬抗原決定位胜肽片段及異種多胜肽之融合處需包含一切點。該切點需包含一胺基酸序列，該胺基酸序列可被一酵素之專一性切開(例如蛋白酶)。 In order to achieve the purpose of separating the antigenic epitope peptide fragments, it is necessary to produce a fusion polypeptide which is a translational fusion (covalent bond) to form a heterologous polypeptide, which can be affinity Separation by sex chromatography. Traditionally, the heterologous peptides are His-tags (e.g., His6; 6 histidine residues), GST-Tag (Glutathione-S-transferase), and the like. The fusion polypeptide not only assists in the purification of the pseudo epitope, but also prevents the pseudo epitope from being decomposed during purification. If the heterologous multi-peptide is to be removed after purification, the fusion protein needs to contain all points in the fusion of the pseudo-determinant peptide fragment and the heterologous multi-peptide. The cleavage site is required to comprise an amino acid sequence which can be specifically cleaved by an enzyme (e.g., a protease).

本發明之擬抗原決定位在N端及/或C端或其附近可被修飾，因此，一半胱胺酸殘基(Cystein residue)可結合於上述之處。 The pseudo epitope of the present invention may be modified at or near the N-terminus and/or the C-terminus, and thus, a Cystein residue may be bonded to the above.

本發明之擬抗原決定位較佳為抗原性多胜肽，該抗原多胜肽胺基酸序列與甲型共核蛋白胺基酸序列不同。因此，本發明之擬抗原決定位不僅包含一個或多個天然的胺基酸殘基，亦包含一個或多個非天然胺基酸(例如非20個「典型」之胺基酸)或也許完全由非天然胺基酸所組成。可誘發抗體之合適抗原亦可從商業上之胜肽資料庫獲得。較佳的是，這些胜肽係至少7個胺基酸，更佳的是最多到16個胺基酸，較佳的是最多到14或20個胺基酸(例如5至16個胺基酸殘基)。惟，關於本發明使用較長之胜肽作為誘發抗體之抗原亦可。再者，本發明之擬抗原決定位亦可為多胜肽之一部分，故包含在N端及/或C端近一步包含至少一個胺基酸殘基。 Preferably, the pseudo epitope of the present invention is an antigenic polypeptide which differs from the alpha-nuclear amino acid sequence. Thus, the antigenic epitope of the present invention comprises not only one or more natural amino acid residues, but also one or more unnatural amino acids (eg, not 20 "typical" amino acids) or perhaps completely It consists of an unnatural amino acid. Suitable antigens that can elicit antibodies can also be obtained from commercial peptide libraries. Preferably, these peptides are at least 7 amino acids, more preferably up to 16 amino acids, preferably up to 14 or 20 amino acids (e.g. 5 to 16 amino acids) Residues). However, it is also possible to use a longer peptide as an antigen for inducing an antibody in the present invention. Furthermore, the pseudo epitope of the present invention may also be part of a polypeptide, and thus comprises at least one amino acid residue in the N-terminus and/or C-terminus.

為了預備本發明之擬抗原決定位(例如在此揭示之誘發抗體之抗原)，噬菌體資料庫、胜肽資料庫亦合適用於製造組合化學或由高量篩選技術，以取得大部份各式之結構(引用：A Laboratory Manual by Carlos F.Barbas(Editor),et al；Willats WG Phage display：practicalities and prospects.Plant Mol.Biol.2002 Dec.；50(6)：837-54)。 In order to prepare the antigenic epitope of the present invention (for example, the antigen-inducing antigen disclosed herein), the phage database and the peptide database are also suitable for manufacturing combinatorial chemistry or high-volume screening techniques to obtain most of the various types. Structure (reference: A Laboratory Manual by Carlos F. Barbas (Editor), et al; Willats WG Phage display: practicalities and prospects. Plant Mol. Biol. 2002 Dec.; 50(6): 837-54).

關於本發明在此使用「抗原決定位(epitope)」一詞，係指抗原中可產生免疫性的區域，特別是抗體可專一性結合之處。一抗原也許具有一個或多個抗原決定位，每一個皆可與抗體結合，該抗體可辨視特定之抗原決定位。 As used herein, the term "epitope" as used herein refers to a region of the antigen that produces immunity, particularly where the antibody can specifically bind. An antigen may have one or more epitopes, each of which may bind to an antibody that recognizes a particular epitope.

本發明之組成物，包含至少一、至少二、至少三、至少四、至少五或至少十個擬抗原決定位，在此敘明。 Compositions of the invention comprising at least one, at least two, at least three, at least four, at least five or at least ten miter epitopes, as set forth herein.

關於本發明之較佳實施例，無毒白喉毒素(non-toxic diphtheria toxin mutant)選自CRM 197，CRM 176，CRM 228，CRM 45，CRM 9，CRM 102，CRM 103及CRM 107所組成之群組，其中CRM 197特別是較佳的。 In a preferred embodiment of the invention, the non-toxic diphtheria toxin mutant is selected from the group consisting of CRM 197, CRM 176, CRM 228, CRM 45, CRM 9, CRM 102, CRM 103 and CRM 107. Where CRM 197 is particularly preferred.

本發明擬抗原決定位(mimotope)特別較佳者為與無毒白喉毒素(non-toxic diphtheria toxin mutant)融合或共軛結合，如CRM 197(無毒但與白喉毒素抗原性相同之變異體)、CRM 176、CRM 228、CRM 45(Uchida et al J.Biol.Chem.218；3838-3844，1973)、CRM 9、CRM 45、CRM 102、CRM 103、CRM 107及其他突變種由Nicholls and Youle in genetically Engineered Toxins,Ed：Frankel,Marcel Dekker Inc,1992中所敘述。融合蛋白之方法，如擬抗原決定位與其他胜肽、多胜肽或蛋白質為本領域所習知。 The mimotope of the present invention is particularly preferably fused or conjugated to a non-toxic diphtheria toxin mutant, such as CRM 197 (a non-toxic variant having the same antigenicity as diphtheria toxin), CRM 176, CRM 228, CRM 45 (Uchida et al J. Biol. Chem. 218; 3838-3844, 1973), CRM 9, CRM 45, CRM 102, CRM 103, CRM 107 and other mutants by Nicholls and Youle in genetically Engineered Toxins, Ed: Frankel, Marcel Dekker Inc, 1992. Methods of fusing proteins, such as pseudo epitopes and other peptides, polypeptides or proteins, are well known in the art.

本發明另一相關之組成物，包括一甲型共核蛋白(alpha-synuclein)抗原決定位之至少一擬抗原決定位作為預防及/或治療共核蛋白病(synucleinopathies)之方法。 Another related composition of the present invention comprises at least one quasi-antigenic epitope of an alpha-synuclein epitope as a method of preventing and/or treating synucleinopathies.

在這組成物中，至少一擬抗原決定位可與藥學可接受之攜帶蛋白融合或共軛結合，較佳為血氰蛋白(Keyhole Limpet Hemocyanin，簡稱KLH)、破傷風類毒素(tetanus toxid，簡稱TT)、白蛋白結合蛋白(albumin-binding protein)、牛血清蛋白(bovine serum albumin)、一樹枝狀聚合物(dendrimer)(MAP；Biol.Chem.358：581)，胜肽鏈結器(peptide linker)(或是側區，flanking regions)及敘述於Singh et al.,Nat.Biotech.17(1999),1075-7081(特別是在此文件之表1)及O’Hagan et al.,Nature Reviews,Drug Discovery 2(9)(2003),727-735中之物質(特別是該文中內生性免疫增強作用化合物及其運輸系統之處)或是上述物質混合。本文中之共軛結合化學(conjugation chemistry，如經由異雙功能(hetero-bifunctional)化合物，如GMBS或是其他在”Bioconjugate Techniques”,Greg T.Hermanson中所敘述) 選自在本領域中具有通常知識者所習知之化學反應。當然，至少一擬抗原決定位可與藥學可接受之攜帶蛋白融合或共軛結合，該攜帶蛋白選自血氰蛋白(keyhole limpet hemocyanin，簡稱KLH)、白喉毒素(diphtheria toxin，簡稱DT)、破傷風類毒素(tetanus toxid，簡稱TT)及流感嗜血桿菌共同蛋白D(Haemophilus influenzae protein D，簡稱protein D)所組成之群組。 In this composition, at least one antigenic epitope can be fused or conjugated to a pharmaceutically acceptable carrier protein, preferably a keyhole Limpet Hemocyanin (KLH) or a tetanus toxid (TT). ), albumin-binding protein, bovine serum albumin, dendrimer (MAP; Biol. Chem. 358: 581), peptide linker ) (or flanking regions) and described in Singh et al., Nat. Biotech. 17 (1999), 1075-7081 (especially in Table 1 of this document) and O'Hagan et al., Nature Reviews , Drug Discovery 2 (9) (2003), substances in 727-735 (especially where the endogenous immunopotentiating compound and its transport system are herein) or a mixture of the above. Conjugation chemistry (such as described by Greg T. Hermanson, via hetero-bifunctional compounds such as GMBS or others in "Bioconjugate Techniques") It is selected from chemical reactions well known to those of ordinary skill in the art. Of course, at least one antigenic epitope can be fused or conjugated to a pharmaceutically acceptable carrier protein selected from the group consisting of: keyhole limpet hemocyanin (KLH), diphtheria toxin (DT), tetanus. A group consisting of toxin (ttanus toxid, TT for short) and Haemophilus influenzae protein D (abbreviated as protein D).

本發明之組成物可經由任何適合之方式投予藥物，例如：皮內注射(i.d.)、靜脈注射(i.v.)、腹腔注射(i.p.)、肌肉注射(i.m.)、鼻腔內(intranasally)、口服(orally)、皮下(subcutaneously)、穿皮(transdermally)、皮內(intradermally)等及其他任何適合之遞送裝置(O’Hagan et al.,Nature Reviews,Drug Discovery 2(9),(2003),727-735)。因此，本發明之至少一擬抗原決定位較佳為配製成靜脈(intravenous)、皮下(subcutaneous)、皮內(intradermal)或肌肉(intramuscular)投予藥物(參閱如”Handbook of Pharmaceutical Manufacturing Formulations”,Sarfaraz Niazi,CRC Press Inc,2004)。 The composition of the present invention can be administered by any suitable means, for example, intradermal injection (id), intravenous (iv), intraperitoneal (ip), intramuscular (im), intranasal (intranasally), orally ( Orally), subcutaneously, transdermally, intradermally, etc., and any other suitable delivery device (O'Hagan et al., Nature Reviews, Drug Discovery 2(9), (2003), 727 -735). Therefore, at least one of the antigenic epitopes of the present invention is preferably formulated into an intravenous, subcutaneous, intradermal or intramuscular drug (see, for example, "Handbook of Pharmaceutical Manufacturing Formulations"" , Sarfaraz Niazi, CRC Press Inc, 2004).

本發明之組成物，包含擬抗原決定位(mimotope)之劑量為0.1 ng至10 mg，較佳為10 ng至1 mg，特別是100 ng至100 μg或可替換為100 fmol至10 μmol，較佳為10 pmol至1 μmol，特別是100 pmol至10 nmol。通常，該疫苗亦包含輔助性物質，例如緩衝液，穩定劑等。 The composition of the present invention, comprising a mimotope dose, is from 0.1 ng to 10 mg, preferably from 10 ng to 1 mg, especially from 100 ng to 100 μg or alternatively from 100 fmol to 10 μmol. It is preferably from 10 pmol to 1 μmol, especially from 100 pmol to 10 nmol. Typically, the vaccine also contains ancillary substances such as buffers, stabilizers and the like.

通常，本發明之組成物亦包含輔助性物質，例如緩衝液，穩定劑等。較佳的是，這樣的輔助性物質，如藥學上可接受之賦型劑，例如水、緩衝液及/或穩定劑，其總量為0.1至99%(重量百分比)，較佳為5至80%(重量百分比)，特別是10至70%(重量百分比)。合適的投予藥物療程包含在投予起始性疫苗(initial vaccine)(在1或2個月)時，每週地、雙週地、四週地(每月地)或是雙月地治療達1至12個月；亦可2至5個月，特別是3至4個月，此後6至12個月或甚至幾年後再施予追加疫苗(booster vaccine) 較佳-除非已有其他疫苗之建議。 In general, the compositions of the present invention also contain auxiliary substances such as buffers, stabilizers and the like. Preferably, such auxiliary substances, such as pharmaceutically acceptable excipients, such as water, buffers and/or stabilizers, are present in a total amount of from 0.1 to 99% by weight, preferably from 5 to 80% by weight, especially 10 to 70% by weight. A suitable medication regimen consists of weekly, biweekly, peripheral (monthly) or bimonthly treatment when an initial vaccine is administered (at 1 or 2 months) 1 to 12 months; may also be 2 to 5 months, especially 3 to 4 months, and then 6 to 12 months or even years after the application of additional vaccine (booster vaccine) Better - unless there are other vaccine recommendations.

關於本發明較佳實施例，在個體施予至少一擬抗原決定位(mimotope)每一劑量為0.1 ng至10 mg，較佳為0.5至500 μg，更佳為1至100 μg。一較佳實施例中，這些劑量皆係本發明之組成物所揭示之全部的擬抗原決定位(mimotope)。在另一較佳實施例中，這些劑量係本發明所揭示之組成物中，單一之擬抗原決定位(mimotope)。亦可能提供一疫苗，包含各式的擬抗原決定位(mimotope)相同或不同之劑量。然而，本發明所揭示之擬抗原決定位(mimotope)亦可選擇性地施予個體每一劑量為0.1 ng至10 mg，較佳為10 ng至1 mg，特別是100 ng至300μg/kg體重。 With respect to a preferred embodiment of the invention, at least one mitope is administered to the individual at a dose of from 0.1 ng to 10 mg, preferably from 0.5 to 500 μg, more preferably from 1 to 100 μg. In a preferred embodiment, these dosages are all mimotopes disclosed by the compositions of the present invention. In another preferred embodiment, these dosages are a single mimotope in the compositions disclosed herein. It is also possible to provide a vaccine comprising various doses of the same or different mitopes. However, the mimotope disclosed in the present invention can also be selectively administered to an individual at a dose of 0.1 ng to 10 mg, preferably 10 ng to 1 mg, particularly 100 ng to 300 μg/kg body weight per dose. .

擬抗原決定位(mimotope)與所攜帶性物質結合，所製備之單一給藥量，其劑量亦有所不同，依宿主治療或特別的給藥模式而定。本發明組成物之劑量，是根據一些因子，包括疾病的情況、年齡、性別、個體的體重及個體誘發特定反應之抗體，而有所不同。劑量療程之調整為提供最適宜之治療反應。例如，其一天的劑量可分次施予，或因治療情況危急而出現之適應症，劑量可予以適當的減低。疫苗之劑量亦可因提供適當之預防性劑量反應，依血液循環狀況，而有所不同。舉例而言，該擬抗原決定位及本發明之組成物，可視本發明所提供之給藥誘發抗體程度，間隔幾日、一或二週或甚至幾個月或幾年投予個體藥物。 The mitope is combined with the substance to be carried, and the single dose to be administered is also different in dosage depending on the host treatment or the particular mode of administration. The dosage of the composition of the present invention will vary depending on factors such as the condition of the disease, age, sex, weight of the individual, and the individual's antibody that elicits a particular response. The dosage regimen is adjusted to provide the most appropriate therapeutic response. For example, a one-day dose may be administered in divided doses, or an indication arising from a critical condition of treatment, and the dose may be appropriately reduced. The dose of the vaccine may also vary depending on the blood circulation status provided by the provision of a suitable prophylactic dose response. For example, the pseudo-antigenic epitope and the composition of the present invention can be administered to an individual drug at intervals of a few days, one or two weeks, or even months or years, depending on the degree of administration of the antibody provided by the present invention.

本發明之該組成物之一較佳實施例為2至10之間，較佳為2至7之間，甚至更佳為至多5，最佳為至多4次投予。這些接種疫苗之次數根據基礎之免疫反應。一特別較佳實施例，連續性的施予疫苗之時間間隔為2週至5年之間，較佳為1個月至至多3年之間，更佳為2個月至1.5年之間。一示範性疫苗接種計畫為3至4個起始性疫苗接種(initial vaccination)在6至8週且至多6個月期間。之後，疫苗接種可以每2至10年重複接種。重複投予本發明之擬抗原決定位可最大化治療性疫苗接種之 最終效益。 A preferred embodiment of the composition of the present invention is between 2 and 10, preferably between 2 and 7, even more preferably at most 5, most preferably at most 4 doses. The number of these vaccinations is based on the underlying immune response. In a particularly preferred embodiment, the continuous administration of the vaccine is between 2 weeks and 5 years, preferably between 1 month and up to 3 years, more preferably between 2 months and 1.5 years. An exemplary vaccination program is 3 to 4 initial vaccinations over a period of 6 to 8 weeks and up to 6 months. Thereafter, vaccination can be repeated every 2 to 10 years. Repeated administration of the antigenic epitope of the present invention maximizes therapeutic vaccination The final benefit.

關於本發明最佳實施例，至少一擬抗原決定位製劑含至少一佐劑(aduvant)。 In a preferred embodiment of the invention, at least one of the epitope-determining formulations comprises at least one adjuvant (aduvant).

佐劑(aduvant)為多種化合物或其混合物，其可增加對抗原(例如擬抗原決定位)之免疫反應。佐劑所扮演的主要角色可為遞送系統，主要可為免疫調節者(immune modulator)或是兩者強大的特徵。合適之佐劑包含適合用於哺乳類，包含人類。 Adjuvants are a variety of compounds or mixtures thereof that increase the immune response to an antigen (eg, a pseudo-antigenic epitope). The primary role played by the adjuvant may be the delivery system, which may be primarily an immunomodulator or a powerful feature of both. Suitable adjuvants include those suitable for use in mammals, including humans.

關於本發明特別的較佳實施例，在組成物中至少使用一佐劑於該組成物中，可刺激先天性之免疫系統，在此敘明。 With regard to a particularly preferred embodiment of the invention, at least one adjuvant is used in the composition to stimulate the innate immune system, as described herein.

先天性免疫反應在細胞表面由Toll-like接受器(TLR’s)及細胞內由Nod-LRR蛋白(NLR)所調節且分別由D1及D0區域所調節。先天性免疫反應包含TLR活化後細胞介素(cytokine)之反應生成且主要的NLRs(包含Ipaf)活化後，半光天冬酶-1(Caspase-1)及介白素-1β(IL-1β)分泌作用。該反應是由特定之抗原獨立所引起的，但亦可由一佐劑作為特定抗原所引發之合適免疫反應。該抗原可被外部之疫苗或感染所替代，或可為內生性，例如腫瘤相關抗原。 The innate immune response is regulated on the cell surface by Toll-like receptors (TLR's) and intracellularly by Nod-LRR protein (NLR) and is regulated by the D1 and D0 regions, respectively. Innate immune response involves the formation of cytokine after TLR activation and activation of major NLRs (including Ipaf), caspase-1 and interleukin-1β (IL-1β) ) Secretion. The reaction is caused by the specific antigen alone, but may also be an appropriate immune response elicited by an adjuvant as a specific antigen. The antigen may be replaced by an external vaccine or infection, or may be endogenous, such as a tumor associated antigen.

數種不同之TLR亦被辨識。這些TLRs被不同之配位體(ligands)結合並且活化，並且逐漸發生於不同之器官或是結構上。因此在本領域中，亦關注於發展特定之TLRs，具誘發反應能力之免疫增強劑。舉例而言，US 4,666,886揭露特定之脂蛋白分子為TLR2作用體。WO 2009/118296，WO 2008/005555，WO 2009/111337及WO 2009/067081揭露每一TLR7小分子分類的作用體。WO 2007/040840及WO 2010/014913揭露可治療疾病之TLR7及TLR8之作用體。這些各式之化合物包含小分子免疫增強劑(small immunopotentiators，簡稱SMIPs)。 Several different TLRs have also been identified. These TLRs are bound and activated by different ligands and gradually occur in different organs or structures. Therefore, in the art, attention is also directed to the development of specific TLRs, immunopotentiators having responsiveness. For example, US 4,666,886 discloses that a particular lipoprotein molecule is a TLR2 actor. The role of each TLR7 small molecule classification is disclosed in WO 2009/118296, WO 2008/005555, WO 2009/111337 and WO 2009/067081. WO 2007/040840 and WO 2010/014913 disclose the roles of TLR7 and TLR8 which can treat diseases. These various compounds contain small immunopotentiators (SMIPs).

該至少一佐劑可刺激先天性之免疫系統，較佳包含或由下列 所組成一Toll-like接受體(Toll-like receptor)作用劑(agonist)，較佳為TLR1，TLR2，TLR3，TLR4，TLR5，TLR7，TLR8或TLR9作用劑，特別較佳為TLR4作用劑。 The at least one adjuvant may stimulate the innate immune system, preferably comprising or consisting of A Toll-like receptor agonist is preferably formed, preferably a TLR1, TLR2, TLR3, TLR4, TLR5, TLR7, TLR8 or TLR9 agent, particularly preferably a TLR4 agent.

Toll-like接受體(Toll-like receptor)作用劑為本領域所習知。舉例而言，TLR2作用劑為Pam3CysSerLys4、肽聚醣(peptidoglycan,Ppg)、PamCys，一TLR3作用劑為IPH 31XX，一TLR4作用劑為胺基葡萄糖胺磷酸根(Aminoalkyl glucosaminide phosphate)、E6020、CRX-527、CRX-601、CRX-675,5D24.D4、RC-527，一TLR7作用劑為Imiquimod、3M-003、Aldara、852A、R850、R848、CL097，一TLR8作用劑為3M-002，一TLR9作用劑為鞭毛蛋白(Flagellin)、Vaxlmmune、CpG ODN(AVE0675，HYB2093)、CYT005-15 AllQbG10、dSLIM。 Toll-like receptor agents are well known in the art. For example, the TLR2 agent is Pam3CysSerLys4, peptidoglycan (Ppg), PamCys, a TLR3 agent is IPH 31XX, and a TLR4 agent is Aminoalkyl glucosaminide phosphate, E6020, CRX- 527, CRX-601, CRX-675, 5D24.D4, RC-527, a TLR7 agent is Imiquimod, 3M-003, Aldara, 852A, R850, R848, CL097, a TLR8 agent is 3M-002, a TLR9 The agents are Flagellin, Vaxlmmune, CpG ODN (AVE0675, HYB2093), CYT005-15 AllQbG10, dSLIM.

關於本發明之TLR作用劑較佳實施例選自單磷酸脂質A(monophosphoryl lipid A，簡稱MPL)，3-去-O-醯化單磷酸脂質A(3-de-O-acylated monophosphoryl lipid A，簡稱3D-MPL)、poly I：C、GLA、鞭毛蛋白(flagellin)、R848、imiquimod及CpG所組成之群組。 A preferred embodiment of the TLR agent of the present invention is selected from the group consisting of monophosphoryl lipid A (MPL), 3-de-O-acylated monophosphoryl lipid A (3-de-O-acylated monophosphoryl lipid A, Abbreviated as 3D-MPL), a group consisting of poly I:C, GLA, flagellin, R848, imiquimod and CpG.

本發明之組成物可能包含單磷酸脂質A(monophosphoryl lipid A，簡稱MPL)。MPL可為合成生產之MPL或取自天然資源。在本發明中當然可能添加一化學修飾之MPL於組成物中。以上所舉例之MPL為該領域中所習知。 The composition of the present invention may comprise monophosphoryl lipid A (MPL). MPL can be synthetically produced MPL or taken from natural resources. It is of course possible in the present invention to add a chemically modified MPL to the composition. The MPL exemplified above is well known in the art.

關於本發明進一步較佳實施例中，至少一佐劑包含或由下列所組成：一皂素(saponin)，較佳為QS21，一油包水乳化劑(water in oil emulsion)及一微脂體(liposome)。 In a further preferred embodiment of the invention, at least one adjuvant comprises or consists of: saponin, preferably QS21, a water in oil emulsion and a liposome (liposome).

該至少一佐劑較佳係選自MF59、AS01、AS02、AS03、AS04、氫氧化鋁及磷酸鋁所組成之群組。 Preferably, the at least one adjuvant is selected from the group consisting of MF59, AS01, AS02, AS03, AS04, aluminum hydroxide, and aluminum phosphate.

舉例一習知使用於人類之佐劑，適合於遞送系統包括但不限 於明礬(alum)(例如：磷酸鋁、硫酸鋁或氫氧化鋁)、磷酸鈣、微脂體、水包油乳化劑，如MF59(4.3% w/v鯊烯squalene，0.5% w/v聚山梨醇酯80 polysorbate 80(Tween 80)，0.5% w/v山梨醇酐三油脂sorbitan trioleate(Span 85))、油包水乳化劑如Montanide及聚(DL-乳酸交酯-co-乙交酯)(poly(D,L-lactide-co-glycolide，PLG)微米分子或奈米分子。 For example, a conventional adjuvant for human use, suitable for delivery systems including but not limited to Alum (for example: aluminum phosphate, aluminum sulfate or aluminum hydroxide), calcium phosphate, liposome, oil-in-water emulsifier, such as MF59 (4.3% w/v squalene, 0.5% w/v Sorbitol 80 polysorbate 80 (Tween 80), 0.5% w/v sorbitan sorbitan trioleate (Span 85), water-in-oil emulsifier such as Montanide and poly (DL-lactide-co-glycolide) (poly(D, L-lactide-co-glycolide, PLG) micron molecule or nano molecule.

舉例一習知合適之免疫調節型佐劑可使用於人類，包括但不限於從Aquilla樹皮萃取出之皂素(QS21、Quil A)，TLR4作用劑，如MPL(單磷酸脂質A，monophosphoryl lipid A)、3DMPL(3-O-去醯化單磷酸脂質A，3-O-deacylated monophosphoryl lipid A)或GLA-AQ、LT/CT變異物、細胞介素，如各種之介白素(interleukins)(如介白素-2、介白素-12)或顆粒單核球群落刺激生長因子(GM-CSF)或相類似之物。 For example, a suitable immunomodulatory adjuvant can be used in humans, including but not limited to saponin extracted from Aquilla bark (QS21, Quil A), TLR4 agent such as MPL (monophosphoryl lipid A) ), 3DMPL (3-O-deacylated monophosphoryl lipid A) or GLA-AQ, LT/CT variants, interleukins, such as various interleukins ( Such as interleukin-2, interleukin-12) or particulate mononuclear community stimulation of growth factors (GM-CSF) or similar.

舉例一習知合適之免疫調節型佐劑及遞送與免疫調節物質，使用於人類，包括但不限於ISCOMS(參閱如Sjölander et al.(1998)J.Leukocyte BIol.64：713；WO90/03184，WO96/11711，WO 00/48630，WO98/36772，WO00/41720 WO06/134423及WO07/026,190)或GLA-EM，其為結合Toll-like接受體作用劑(如TLR4作用劑)及水包油乳化劑。 For example, a suitable immunomodulatory adjuvant and delivery and immunomodulatory substance are used in humans, including but not limited to ISCOMS (see, for example, Sjölander et al. (1998) J. Leukocyte BIol. 64: 713; WO 90/03184, WO 96/11711, WO 00/48630, WO 98/36772, WO 00/41720 WO 06/134423 and WO 07/026, 190) or GLA-EM, which combines a Toll-like acceptor agent (such as a TLR4 agent) and an oil-in-water emulsion Agent.

更進一步示範可增加本發明擬抗原決定位組成物效率之佐劑，包括但不限於：(1)水包油乳化劑製劑(包含或不包含其他特定之免疫刺激劑，如胞壁醯肽(muramyl peptides)(參閱如下)或細菌細胞壁成分)，如(a)SAF，包含10%鯊烷(Squalane)，0.4% Tween 80，5% pluronic-blocked聚分子L121及thr-MDP從微流體化(microfluidized)至超微型(submicron)乳化劑或震盪至形成一較大分子之乳化劑，及(b)RIBI^TM佐劑系統(RIBI^TM adjuvant system，RAS)，(Ribi Immunochem,Hamilton,Mont.)包含2%鯊烯(Squalene)，0.2% Tween 80，及一個或多個細菌細胞壁成分，如單磷酸脂質A(monophosphoryl lipid A，MPL)，繭蜜糖二黴菌酸酯(trehalose dimycolate，TDM)，細胞壁骨架(cell wall skeleton,CWS)，較佳為MPL+CWS(DETOX^TM)；(2)可使用皂素佐劑，如QS21，STIMULON^TM(Camabridge Bioscience,Worcester,Mass.)，Abisco®(Isconova，瑞典)，或Iscomatrix®(Commonwealth Serum Laboratories，澳洲)，或由皂素佐劑所產生之顆粒，如ISCOMs(immunostimulating complexes，免疫刺激複合物)，該免疫刺激複合物可缺乏額外之清潔劑，如WO00/07621；(3)完整之佛朗氏佐劑(Complete Freund’s Adjuvant,CFA)及非完整之佛朗氏佐劑(Imcomplete Freund’s Adjuvant，IFA)；(4)細胞介素(cytokines)，如介白素(interleukins)(如介白素-1，介白素-2，介白素-4，介白素-5，介白素-6，介白素-7，介白素-12(WO99/44636)等)，干擾素(interferons)(如珈瑪干擾素)、巨噬細胞群落刺激因子(macrophage colony stimulating factor，M-CSF)、腫瘤壞死因子(tumor necrosis factor,TNF)等；(5)單磷酸脂質A(monophosphoryl lipid A，MPL)或3-O-去醯化單磷酸脂質A(3-O-deacylated monophosphoryl lipid A，3D-MPL)(參閱GB-2220221，EP-A-0689454)、當使用肺炎球菌醣時隨意地缺乏明礬(參閱WO00/56358)；(6)組合3dMPL與，如QS21及/或水包油乳化劑(參閱EP-A-0835318,EP-A-0735898,EP-A-0761231)；(7)一聚氧乙烯醚(polyoxyethylene ether)或一聚氧乙烯酯(polyoxyethylene ester)(參閱WO99/52549)；(8)一聚氧乙烯山梨糖醇酯界面活化劑(polyoxyethylene sorbitan ester surfactant)結合一辛苯昔醇(octoxynol)(WO01/21207)或一聚氧乙烯烷基醚或酯(polyoxyethylene alkyl ether or ester)界面活化劑結合至少一額外之非離子界面活性劑，如辛苯昔醇(octoxynol)(WO01/21152)；(9)一皂素及一免疫刺激寡核酸(如CpG寡核酸)(WO00/62800)；(10)一免疫刺激劑及一金屬鹽粒子(參閱WO00/23105)；(11)一皂素及一水包油乳化劑，如WO99/11241；(12)一皂素(如QS21)+3dMPL+IM2(隨意加一固醇)，如WO98/57659；(13)其他物質，其作用如免疫刺激劑，以增強該組成物之效 果。胞壁醯肽包括N-乙醯基-胞壁醯-L-蘇胺醯基-D-異麬醯胺酸(N-acetyl-muramyl-L-threonyl-D-isoglutamine，簡稱thr-MDP)，N-25乙醯基-胞壁醯-L-丙胺醯基-D-異麬醯胺酸(N-25 acetyl-normuramyl-L-alanyl-D-isoglutamine，nor-MDP)，N-乙醯基-胞壁醯-L-丙胺醯基-D-異麬醯胺-L-丙胺酸-2-(1’-2’-雙軟脂醯-sn-甘油-3-氫氧基磷酸氧)-乙胺(N-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1'-2'-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamine，MTP-PE)等。 Further demonstrating adjuvants that increase the efficiency of the antigenic epitope composition of the invention, including but not limited to: (1) oil-in-water emulsifier formulations (with or without other specific immunostimulating agents, such as cell wall purine peptides) Muramyl peptides (see below) or bacterial cell wall components), such as (a) SAF, containing 10% squalane, 0.4% Tween 80, 5% pluronic-blocked poly-L121 and thr-MDP from microfluidization ( microfluidized) to pico (Submicron) emulsifying or shock to form a larger molecule of emulsifier, and (b) RIBI ^TM adjuvant system ^{(RIBI TM adjuvant system, RAS)} , (Ribi Immunochem, Hamilton, Mont.) containing 2% Squalene, 0.2% Tween 80, and one or more bacterial cell wall components, such as monophosphoryl lipid A (MPL), trehalose dimycolate (TDM), cell wall skeleton (cell wall skeleton, CWS), preferably ^{MPL + CWS (DETOX TM);} (2) using saponin adjuvants, such as ^{QS21, STIMULON TM (Camabridge Bioscience,} Worcester, Mass.), Abisco® (Isconova, Sweden), or Iscomatrix® (Commonwealth Serum Laboratories, Australia) Or particles produced by saponin adjuvants, such as ISCOMs (immunostimulating complexes), which may lack additional detergents, such as WO00/07621; (3) complete Fraunhofer adjuvant (Complete Freund's Adjuvant, CFA) and Imcomplete Freund's Adjuvant (IFA); (4) cytokines, such as interleukins (eg interleukin-1) Acetin-2, interleukin-4, interleukin-5, interleukin-6, interleukin-7, interleukin-12 (WO99/44636), etc., interferons (such as 珈(ma interferon), macrophage colony stimulating factor (M-CSF), tumor necrosis factor (TNF), etc.; (5) monophosphoryl lipid A (MPL) or 3 -O-deacylated monophosphoryl lipid A (3D-MPL) (see GB-2220221, EP-A-0689454), arbitrarily lacking alum when using pneumococcal sugar (see WO00) /56358); (6) combining 3dMPL with, for example, QS21 and/or oil-in-water emulsifier (see EP-A-0835318, EP-A-0735898, EP-A-0761231); (7) polyoxygen Polyoxyethylene ether or polyoxyethylene ester (see WO99/52549); (8) polyoxyethylene sorbitan ester surfactant combined with octoxynol ( Octoxynol) (WO 01/21207) or a polyoxyethylene alkyl ether or ester interface activator in combination with at least one additional nonionic surfactant such as octoxynol (WO 01/21152) (9) monosaponin and an immunostimulatory oligonucleic acid (such as CpG oligonucleic acid) (WO 00/62800); (10) an immunostimulating agent and a metal salt particle (see WO 00/23105); (11) a soap And an oil-in-water emulsifier, such as WO99/11241; (12) a saponin (such as QS21) + 3dMPL + IM2 (optional plus sterol), such as WO98/57659; (13) other substances, such as An immunostimulant to enhance the effect of the composition. Cell wall purine peptides include N-acetyl-muramyl-L-threonyl-D-isoglutamine (thr-MDP), N-25 acetyl-normuramyl-L-alanyl-D-isoglutamine, nor-MDP, N-ethyl fluorenyl - cell wall 醯-L-alaninyl-D-isodecylamine-L-alanine-2-(1'-2'-bis-lipid oxime-sn-glycerol-3-hydroxyoxyphosphate)- Ethylamine (N-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1 ' -2 ' -dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamine, MTP-PE).

本發明特別較佳組成物包含佐劑為一水包油乳化劑及或無Toll-like接受體作用劑，及微脂體及/或含皂素之佐劑、及或無Toll-like接受體作用劑。本發明之該組成物可亦包含氫氧化鋁及或無Toll-like接受體作用劑作為佐劑。 Particularly preferred compositions of the present invention comprise an adjuvant comprising an oil-in-water emulsifier and or no Toll-like receptor agent, and a liposome and/or saponin-containing adjuvant, and or no Toll-like receptor Agent. The composition of the present invention may also comprise aluminum hydroxide and or no Toll-like acceptor agent as an adjuvant.

關於本發明抗原決定位(epitope)較佳實施例包含或由下列所組成胺基酸序列KNEEGAP或DMPVDPDN。 Preferred embodiments of the epitope of the present invention comprise or consist of the amino acid sequence KNEEGAP or DMPVDPDN.

上述之抗原決定位(epitope)之擬抗原決定位(mimotope)為本領域之技藝人士所習知(參閱如WO 2009/103105，WO 2011/020133)。 The above-mentioned antigenic epitopes of epitopes are known to those skilled in the art (see, e.g., WO 2009/103105, WO 2011/020133).

本發明之組成物較佳為包含至少一擬抗原決定位包含或由下列所組成該胺基酸序列(X₁)_nX₂X₃X₄X₅GX₆P(X₇)_m (式I)，其中X₁為任何胺基酸殘基，X₂ 為一胺基酸殘基選自離胺酸(lysine，K)，精胺酸(arginine，R)，丙胺酸 (alanine，A)及組胺酸(histidine，H)所組成之群組，X₃ 為一胺基酸殘基選自天冬醯胺酸(asparagine，N)，麩醯胺酸(glutamine，Q)，絲胺酸(serine，S)，甘胺酸(glycine，G)及丙胺酸(alanine，A)，較佳為天冬醯胺酸(asparagine，N)，絲胺酸(serine，S)，甘胺酸(glycine，G)及丙胺酸(alanine，A)所組成之群組，X₄為一胺基酸殘基選自麩胺酸(glutamic acid，E)，天冬安酸(aspartic acid，D)及丙胺酸(alanine，A)所組成之群組，X₅為一胺基酸殘基選自麩胺酸(glutamic acid，E)及天冬安酸(aspartic acid，D)所組成之群組，X₆為一胺基酸殘基選自丙胺酸(alanine，A)及酪胺酸(tyrosine，Y)所組成之群組，X₇為任何胺基酸殘基，n及m分別為0或大於0之整數，其中，關於式I之胺基酸序列並不完全相同於，或不包含甲型共核蛋白之7-基體(7-mer)多胜肽片段KNEEGAP，且其中至少一擬抗原決定位(mimotope)包含式I之胺基酸序列具有與抗體結合之能力，該抗體係對甲型共核蛋白抗原決定位具專一性，包含該胺基酸序列KNEEGAP。 Preferably, the composition of the present invention comprises at least one pseudo-antigenic epitope comprising or consisting of the amino acid sequence (X ₁ ) _n X ₂ X ₃ X ₄ X ₅ GX ₆ P(X ₇ ) _m (Formula I Wherein X ₁ is any amino acid residue and X ₂ is an amino acid residue selected from the group consisting of lysine (K), arginine (R), alanine (A) and A group consisting of histidine (H), the amino acid residue of X ₃ is selected from the group consisting of asparagine (N), glutamine (Q), and serine ( Serine, S), glycine (G) and alanine (A), preferably asparagine (N), serine (S), glycine (glycine) , G) and alanine (A) group, X ₄ is an amino acid residue selected from the group consisting of glutamic acid (E), aspartic acid (D) and propylamine a group consisting of alanine (A), wherein X ₅ is an amino acid residue selected from the group consisting of glutamic acid (E) and aspartic acid (D), X ₆ is an amino acid residue selected from alanine (alanine, a) and tyrosine (tyrosine, Y) composed of the group, X ₇ Any amino acid residue, n and m are each an integer of 0 or greater than 0, wherein the amino acid sequence of formula I is not identical or does not comprise a 7-matrix of the alpha-nuclear protein (7- Mer) a peptide fragment KNEEGAP, and wherein at least one mimotope comprises an amino acid sequence of formula I having the ability to bind to an antibody, the anti-system having specificity for the alpha-nuclear protein epitope The amino acid sequence KNEEGAP is included.

該詞「胺基酸具有與抗體結合之能力，該抗體係對甲型共核蛋白抗原決定位具專一性」意為上述胜肽可與甲型共核蛋白專一性抗體結合，該抗體由甲型共核蛋白或其片段投藥予哺乳動物後所產生。上述胜肽具有上述結合能力可誘發哺乳動物中甲型共核蛋白專一性抗體之生成。稍後抗體依序結合於本發明之化合物，亦結合至甲型共核蛋白。 The phrase "amino acid has the ability to bind to an antibody, and the anti-system has specificity for the alpha-nuclear protein epitope" means that the above peptide can bind to a specific antibody of a type A synuclein, which is composed of a A type of synuclein or a fragment thereof is produced after administration to a mammal. The aforementioned peptide has the above-described binding ability to induce the production of a specific antibody against a type A synuclein in a mammal. The antibody is then sequentially bound to the compound of the invention and also to the alpha-nuclear protein.

關於本發明特別較佳實施例X₂為一胺基酸殘基選自離胺酸(lysine，K)及精安酸(arginine，R)及/或X₆為丙胺酸(alanine，A)所組成之群組。 With respect to a particularly preferred embodiment of the invention X ₂ is an amino acid residue selected from the group consisting of lysine (K) and arginine (R) and/or X ₆ is alanine (A). The group that makes up.

關於本發明擬抗原決定位(mimotope)特別較佳實施例包含或由下列所組成胺基酸序列，其選自由(X₁)_nKNDEGAP(X₇)_m、(X₁)_nANEEGAP(X₇)_m、(X₁)_nKAEEGAP(X₇)_m、(X₁)_nKNAEGAP(X₇)_m、(X₁)_nRNEEGAP(X₇)_m、(X₁)_nHNEEGAP(X₇)_m、(X₁)_nKNEDGAP(X₇)_m、(X₁)_nKQEEGAP(X₇)_m、(X₁)_nKSEEGAP(X₇)_m、(X₁)_nKNDDGAP(X₇)_m、(X₁)_nRNDEGAP(X₇)_m、(X₁)_nRNEDGAP(X₇)_m、(X₁)_nRQEEGAP(X₇)_m、(X₁)_nRSEEGAP(X₇)_m、(X₁)_nANDEGAP(X₇)_m、(X₁)_nANEDGAP(X₇)_m、(X₁)_nHSEEGAP(X₇)_m、(X₁)_nASEEGAP(X₇)_m、(X₁)_nHNEDGAP(X₇)_m、(X₁)_nHNDEGAP(X₇)_m、(X₁)_nRNAEGAP(X₇)_m、(X₁)_nHNAEGAP(X₇)_m、(X₁)_nKSAEGAP(X₇)_m、(X₁)_nKSDEGAP(X₇)_m、(X₁)_nKSEDGAP(X₇)_m、(X₁)_nRQDEGAP(X₇)_m、(X₁)_nRQEDGAP(X₇)_m、(X₁)_nHSAEGAP(X₇)_m、(X₁)_nRSAEGAP(X₇)_m、(X₁)_nRSDEGAP(X₇)_m、(X₁)_nRSEDGAP(X₇)_m、(X₁)_nHSDEGAP(X₇)_m、(X₁)_nHSEDGAP(X₇)_m、(X₁)_nRQDDGAP(X₇)_m所組成之群組，較佳為(X₁)_nKNDEGAP(X₂)_m、(X₁)_nRNEEGAP(X₂)_m、(X₁)_nRNDEGAP(X₂)_m、(X₁)_nKNAEGAP(X₂)_m、(X₁)_nKSDEGAP(X₂)_m、(X₁)_nRNAEGAP(X₂)_m或(X₁)_nRSEEGAP(X₂)_m。 A particularly preferred embodiment of the mimotope of the present invention comprises or consists of an amino acid sequence selected from the group consisting of (X ₁ ) _n KNDEGAP(X ₇ ) _m , (X ₁ ) _n ANEEGAP (X _{7 m} , (X ₁ ) _n KAEEGAP(X ₇ ) _m , (X ₁ ) _n KNAEGAP(X ₇ ) _m , (X ₁ ) _n RNEEGAP(X ₇ ) _m , (X ₁ ) _n HNEEGAP(X ₇ ) _m , (X ₁ ) _n KNEDGAP(X ₇ ) _m , (X ₁ ) _n KQEEGAP(X ₇ ) _m , (X ₁ ) _n KSEEGAP(X ₇ ) _m , (X ₁ ) _n KNDDGAP(X ₇ ) _m , ( X ₁ ) _n RNDEGAP(X ₇ ) _m , (X ₁ ) _n RNEDGAP(X ₇ ) _m , (X ₁ ) _n RQEEGAP(X ₇ ) _m , (X ₁ ) _n RSEEGAP(X ₇ ) _m , (X _{1 n} ANDEGAP(X ₇ ) _m , (X ₁ ) _n ANEDGAP(X ₇ ) _m , (X ₁ ) _n HSEEGAP(X ₇ ) _m , (X ₁ ) _n ASEEGAP(X ₇ ) _m , (X ₁ ) _n HNEDGAP(X ₇ ) _m , (X ₁ ) _n HNDEGAP(X ₇ ) _m , (X ₁ ) _n RNAEGAP(X ₇ ) _m , (X ₁ ) _n HNAEGAP(X ₇ ) _m , (X ₁ ) _n KSAEGAP( X ₇ ) _m , (X ₁ ) _n KSDEGAP(X ₇ ) _m , (X ₁ ) _n KSEDGAP(X ₇ ) _m , (X ₁ ) _n RQDEGAP(X ₇ ) _m , (X ₁ ) _n RQEDGAP (X _{7 m} , (X ₁ ) _n HSAEGAP(X ₇ ) _m , (X ₁ ) _n RSAEGAP(X ₇ ) _m , (X ₁ ) _n RSDEGAP(X ₇ ) _m , (X ₁ ) _n RSEDGAP(X ₇ ) _m , (X ₁ ) _n HS a group consisting of DEGAP(X ₇ ) _m , (X ₁ ) _n HSEDGAP(X ₇ ) _m , (X ₁ ) _n RQDDGAP(X ₇ ) _m , preferably (X ₁ ) _n KNDEGAP(X ₂ ) _m , (X ₁ ) _n RNEEGAP(X ₂ ) _m , (X ₁ ) _n RNDEGAP(X ₂ ) _m , (X ₁ ) _n KNAEGAP(X ₂ ) _m , (X ₁ ) _n KSDEGAP(X ₂ ) _m , ( X ₁ ) _n RNAEGAP(X ₂ ) _m or (X ₁ ) _n RSEEGAP(X ₂ ) _m .

關於本發明之該組成物包含較佳為至少一擬抗原決定位(mimotope)包含或由下列所組成一胺基酸序列，選自由(X₁)_nQASFAME(X₇)_m、(X₁)_nTASWKGE(X₇)_m、(X₁)_nQASSKLD(X₇)_m、(X₁)_nTPAWKGE(X₇)_m、(X₁)_nTPSWAGE(X₇)_m、(X₁)_nTPSWKGE(X₇)_m，其中X₁為任何胺基酸殘基，X₇為任何胺基酸殘基，n及m分別為0或大於0之整數，上述之至少一擬抗原決定位(minotope)具有與一抗體結合之能力，該抗體係 對甲型共核蛋白抗原決定位具專一性，包含該胺基酸序列KNEEGAP。 The composition of the present invention comprises preferably at least one mitope comprising or consisting of an amino acid sequence selected from (X ₁ ) _n QASFAME (X ₇ ) _m , (X ₁ ) _n TASWKGE(X ₇ ) _m , (X ₁ ) _n QASSKLD(X ₇ ) _m , (X ₁ ) _n TPAWKGE(X ₇ ) _m , (X ₁ ) _n TPSWAGE(X ₇ ) _m , (X ₁ ) _n TPSWKGE (X ₇ ) _m , wherein X ₁ is any amino acid residue, X ₇ is any amino acid residue, n and m are each 0 or an integer greater than 0, and at least one of the above mentioned epitopes (minotope) Having the ability to bind to an antibody that is specific for the alpha-nuclear protein epitope, comprising the amino acid sequence KNEEGAP.

使用於預防及/或治療共核蛋白病(synucleinopathies)。 Used for the prevention and / or treatment of synucleinopathies.

關於本發明較佳實施例至少一擬抗原決定位(mimotope)包含該胺基酸序列(X_1’)_n’X_2’X_3’PVX_4’X_5’X_6’(X_7’)_m’ (式II)，其中X_1’ 為任何胺基酸殘基，X_2’ 為一胺基酸殘基選自由天冬胺酸(aspartic acid，D)及麩胺酸(glutamic acid，E)所組成之群組，X_3’ 為任何胺基酸殘基，X_4’ 為任何胺基酸殘基，X_5’ 為一胺基酸殘基選自由脯胺酸(proline，P)及丙胺酸(alanine，A)所組成之群組，X_6’ 為一胺基酸殘基選自由天冬胺酸(aspartic acid，D)及麩胺酸(glutamic acid，E)所組成之群組，X_7’ 為任何胺基酸殘基，n及m分別為0或大於0之整數，其中，關於式II之胺基酸序列並不完全相同於，或不包含甲型共核蛋白之8-基體(8-mer)多胜肽片段，其具有該胺基酸序列DMPVDPDN，且其中至少一擬抗原決定位(mimotope)包含式II之胺基酸序列具有與抗體結合之能力，該抗體係對甲型共核蛋白抗原決定位具專一性，包含該胺基酸序列DMPVDPDN。 With respect to a preferred embodiment of the invention at least one mimotope comprises the amino acid sequence (X _{1 '} ) _n' X _2' X _3' PVX _4' X _5' X _6' (X _7' ) _{m '} (Formula II), wherein X _{1 '} is any amino acid residue, and X _{2 '} is an amino acid residue selected from aspartic acid (D) and glutamic acid (E) In the group formed, X _{3 '} is any amino acid residue, X _{4 '} is any amino acid residue, and X _{5 '} is an amino acid residue selected from proline (P) and propylamine. a group consisting of alanine (A), X _{6 '} is an amino acid residue selected from the group consisting of aspartic acid (D) and glutamic acid (E). X _{7 '} is any amino acid residue, n and m are each an integer of 0 or greater than 0, wherein the amino acid sequence of formula II is not identical or does not comprise a type A-nuclear protein 8- a matrix (8-mer) polypeptide fragment having the amino acid sequence DMPVDPDN, and wherein at least one mitope comprises an amino acid sequence of formula II having the ability to bind to an antibody, the anti-systemic pair A-type nuclear protein epitope is specific, including Acid sequence DMPVDPDN.

關於本發明較佳實施例之X_3’為一胺基酸殘基，選自由麩醯胺酸(glutamine，Q)、絲胺酸(serine，S)、蘇胺酸(threonine，T)、精安酸(arginine，R)、天冬醯胺酸(asparagine，N)、纈胺酸(valine，V)、組胺酸(histidine，H)、甲硫胺酸(methionine，M)、酪胺酸(tyrosine，Y)、丙胺酸(alanine，A)及白胺酸(leucin，L)所組成之群組。 The preferred embodiment of the invention X _{3 '} is an amino acid residue selected from the group consisting of glutamine (Q), serine (S), threonine (T), refined Arginine (R), aspartic acid (asparagine, N), valine (V), histidine (H), methionine (M), tyrosine (tyrosine, Y), alanine (A) and leucine (leucin, L) group.

關於本發明較佳實施例之X_4’為一胺基酸殘基，選自由麩醯胺酸(glutamine，Q)、色胺酸(tryptophane，W)、蘇胺酸(threonine，T)、精安酸(arginine，R)、天冬醯胺酸(aspartic acid，D)、異白胺酸(isoleucin，I)、纈胺酸(valine，V)、組胺酸(histidine，H)、脯胺酸(proline，P)、酪胺酸(tyrosine，Y)、丙胺酸(alanine，A)、絲胺酸(serine，S)及白胺酸(leucin，L)所組成之群組。 The preferred embodiment of the invention X _{4 '} is an amino acid residue selected from the group consisting of glutamine (Q), tryptophane (W), threonine (T), and refined Arginine (R), aspartic acid (D), isoleic acid (isoleucin, I), valine (V), histidine (H), guanamine A group consisting of proline (P), tyrosine (Y), alanine (A), serine (S), and leucine (L).

本發明之擬抗原決定位係為本發明組成物之部份，其較佳胺基酸序列選自由(C)DQPVLPD、(C)DMPVLPD、(C)DSPVLPD、(C)DSPVWAE、(C)DTPVLAE、(C)DQPVLPDN、(C)DMPVLPDN、(C)DSPVLPDN、(C)DQPVTAEN、(C)DSPVWAEN、(C)DTPVLAEN、(C)HDRPVTPD、(C)DRPVTPD、(C)DVPVLPD、(C)DTPVYPD、(C)DTPVIPD、(C)HDRPVTPDN、(C)DRPVTPDN、(C)DNPVHPEN、(C)DVPVLPDN、(C)DTPVYPDN、(C)DTPVIPDN、(C)DQPVLPDG、(C)DMPVLPDG、(C)DSPVLPDG、(C)DSPVWAEG、(C)DRPVAPEG、(C)DHPVHPDS、(C)DMPVSPDR、(C)DSPVPPDD、(C)DQPVYPDI、(C)DRPVYPDI、(C)DHPVTPDR、(C)EYPVYPES、(C)DTPVLPDS、(C)DMPVTPDT、(C)DAPVTPDT、(C)DSPVVPDN、(C)DLPVTPDR、(C)DSPVHPDT、(C)DAPVRPDS、(C)DMPVWPDG、(C)DAPVYPDG、(C)DRPVQPDR、(C)YDRPVQPDR、(C)DMPVDPEN、(C)DMPVDADN、DQPVLPD(C)、DMPVLPD(C)、(C)EMPVDPDN及(C)DNPVHPE所組成之群組。 The pseudo epitope of the present invention is a part of the composition of the present invention, and the preferred amino acid sequence is selected from the group consisting of (C) DQPVLPD, (C) DMVPLPD, (C) DSPVLPD, (C) DSPVWAE, (C) DTPVLAE. , (C) DQPVLPDN, (C) DMPVLPDN, (C) DSPVLPDN, (C) DQPVTAEN, (C) DSPVWAEN, (C) DTPVLAEN, (C) HDRPVTPD, (C) DRPVTPD, (C) DVPVLPD, (C) DTPVYPD , (C) DTPVIPD, (C) HDRPVTPDN, (C) DRPVTPDN, (C) DNPVHPEN, (C) DVPVLPDN, (C) DTPVYPDN, (C) DTPVIPDN, (C) DQPVLPDG, (C) DMPVLPDG, (C) DSPVLPDG , (C) DSPVWAEG, (C) DRPVAPEG, (C) DHPVHPDS, (C) DMPVSPDR, (C) DSPVPPDD, (C) DQPVYPDI, (C) DRPVYPDI, (C) DHPVTPDR, (C) EYPVYPES, (C) DTPVLPDS , (C) DMPVTPDT, (C) DAPVTPDT, (C) DSPVVPDN, (C) DLPVTPDR, (C) DSPVHPDT, (C) DAPVRPDS, (C) DMPVWPDG, (C) DAPVYPDG, (C) DRPVQPDR, (C) YDRPVQPDR , (C) DMPVDPEN, (C) DMPVDADN, DQPVLPD (C), DMVPLPD (C), (C) EMPVDPDN and (C) DNPVHPE group.

關於本發明特別地較佳實施例n’及/或m’為1及X_1’及/或X_7’為半 胱胺酸(cysteine，C)。 Particularly preferred embodiments of the invention n' and/or m' are 1 and X _{1 '} and/or X _{7 '} is cysteine (C).

關於本發明擬抗原決定位特別地較佳實施例包含7至30，較佳為7至20，更佳為7至16，最佳為8或9胺基酸殘基。 Particularly preferred embodiments with respect to the pseudoepitope of the present invention comprise from 7 to 30, preferably from 7 to 20, more preferably from 7 to 16, most preferably from 8 or 9 amino acid residues.

關於本發明擬抗原決定位特別地較佳實施例包含或由下列胺基酸序列所組成，係選自由DQPVLPD、DSPVLPD、DVPVLPD、DSPVLPDG、YDRPVQPDR、DHPVHPDS、DAPVRPDS、KNDEGAP、KQEEGAP及KSEEGAP所組成之群組，特別是DQPVLPD及YDRPVQPDR。當然，為了利用成對之擬抗原決定位與一攜帶蛋白，該擬抗原決定位於N端及/或C端，可包含一半胱胺酸殘基，在此敘明。 Particularly preferred embodiments relating to the pseudoepitope of the present invention comprise or consist of the following amino acid sequences selected from the group consisting of DQPVLPD, DSPVLPD, DVPVLPD, DSPVLPDG, YDRPVQPDR, DHPVHPDS, DAPVRPDS, KNDEGAP, KQEEGAP and KSEEGAP Group, especially DQPVLPD and YDRPVQPDR. Of course, in order to utilize a pair of pseudo-antigenic epitopes and a carrier protein, the pseudo-antigen is located at the N-terminus and/or C-terminus and may comprise a cysteine residue, as described herein.

關於本發明之組成物特別地較佳實施例包含下列擬抗原決定位及攜帶蛋白及/或佐劑之組合(參閱表A)。 Particularly preferred embodiments of the compositions of the present invention comprise the following pseudo epitopes and combinations of carrier proteins and/or adjuvants (see Table A).

表ATable A

擬抗原決定位(SEQ)：A=DQPVLPD、B=DSPVLPD、C=DVPVLPD、D=DSPVLPDG、E=YDRPVQPDR、F=DHPVHPDS、G=DAPVRPDS、H=KNDEGAP、I=KQEEGAP、J=KSEEGAP(該擬抗原決定位在C端或N端包含一半胱胺酸殘基，其可與攜帶蛋白結合) Antigenic epitope (SEQ): A=DQPVLPD, B=DSPVLPD, C=DVPVLPD, D=DSPVLPDG, E=YDRPVQPDR, F=DHPVHPDS, G=DAPVRPDS, H=KNDEGAP, I=KQEEGAP, J=KSEEGAP The epitope contains a cysteine residue at the C-terminus or the N-terminus, which binds to the carrier protein)

攜帶蛋白(CAR)：C1=CRM197,C2=KLH Carrying protein (CAR): C1=CRM197, C2=KLH

佐劑(ADJ)：A1=明礬(Alum)、A2=以皂基為基礎之製劑、A3=QS21(純的)、A4=以鯊烯為基礎之製劑、A5=Addavax(山梨醇酐三油脂(0.5% w/v)溶於鯊烯油(5% v/v)-Tween 80(0.5% w/v)溶於檸檬酸鈉緩衝液(10 mM、pH 6.5))、A6=MF59(0.5%聚山梨醇酯80、0.5%山梨醇酐三油脂、4.3%鯊烯、水為注射用、10 mM檸檬酸鈉緩衝液)、、A7=AS03、A8=AF03、A9=單磷酸脂質A(MPL)、A10=MPLA(脂質A衍生物，為沙門氏桿菌之脂多醣體)、A11=合成之MPL、A11=合成之MPL、A12=A1+A3、A13=A1+A5、A14= A1+A9、A15=A3+A9、A16=A3+A4、A17=A4+A9、A18=A3+A4+A9、A19=A1+A3+A4、A20=A1+A4+A9、A21=A1+A3+A9、A22=Ribi佐劑系統、A23=QS21(包裹性，encapsulated)、A24=CpG、A25=A1+A23、A26=A1+A24、A27=A1+A2、A28=A1+A9+A24、A29=A1+A3+A24、A30=A1+A23+A24、A31=A4+A3、A32=A4+A9、A33=A4+A23、A34=A4+A24、A35=A4+A9+A24、A36=A4+A3+A24、A37=A4+A23+A24、A38=A4+A3+A9、A39=A4+A23+A9、A40=A4+A3+A9+A24、A41=A4+A23+A9+A24、A42=A9+A23、A43=A1+A3+A9+A24、A44=A1+A9+A23+A24 Adjuvant (ADJ): A1 = Alum, A2 = soap-based formulation, A3 = QS21 (pure), A4 = squalene-based formulation, A5 = Addavax (sorbitol tri-fat) (0.5% w/v) soluble in squalene oil (5% v/v)-Tween 80 (0.5% w/v) dissolved in sodium citrate buffer (10 mM, pH 6.5), A6=MF59 (0.5 % polysorbate 80, 0.5% sorbitan tri fat, 4.3% squalene, water for injection, 10 mM sodium citrate buffer), A7=AS03, A8=AF03, A9=monophosphate lipid A ( MPL), A10=MPLA (lipid A derivative, lipopolysaccharide of Salmonella), A11=synthetic MPL, A11=synthetic MPL, A12=A1+A3, A13=A1+A5, A14= A1+A9, A15=A3+A9, A16=A3+A4, A17=A4+A9, A18=A3+A4+A9, A19=A1+A3+A4, A20=A1+A4+A9, A21=A1+ A3+A9, A22=Ribi adjuvant system, A23=QS21 (encapsulated, encapsulated), A24=CpG, A25=A1+A23, A26=A1+A24, A27=A1+A2, A28=A1+A9+A24 , A29=A1+A3+A24, A30=A1+A23+A24, A31=A4+A3, A32=A4+A9, A33=A4+A23, A34=A4+A24, A35=A4+A9+A24, A36 =A4+A3+A24, A37=A4+A23+A24, A38=A4+A3+A9, A39=A4+A23+A9, A40=A4+A3+A9+A24, A41=A4+A23+A9+A24 , A42=A9+A23, A43=A1+A3+A9+A24, A44=A1+A9+A23+A24

特別地較佳佐劑組成物包含A1、A4、A12=A1+A3、A14=A1+A9、A18=A3+A4+A9、A21=A1+A3+A9、A26=A1+A24、A28=A1+A9+A24、A29=A1+A3+A24、A34=A4+A24、A38=A4+A3+A9及A42=A9+A23。這些較佳之佐劑組成物可與本發明之擬抗原決定位結合，以獲得本發明之組成物。 Particularly preferred adjuvant compositions comprise A1, A4, A12=A1+A3, A14=A1+A9, A18=A3+A4+A9, A21=A1+A3+A9, A26=A1+A24, A28=A1 +A9+A24, A29=A1+A3+A24, A34=A4+A24, A38=A4+A3+A9 and A42=A9+A23. These preferred adjuvant compositions can be combined with the pseudo epitopes of the present invention to obtain the compositions of the present invention.

在表A所提及之佐劑為本領域所習知(參閱如Reed SG,Trend Immunol 30(2008)：23-32)。 The adjuvants mentioned in Table A are well known in the art (see, e.g., Reed SG, Trend Immunol 30 (2008): 23-32).

關於本發明之組成物特別地較佳實施例包含或由下列所組成之組合：擬抗原決定位、攜帶蛋白及佐劑，選自由A-C1-A1、A-C1-A3、A-C1-A4/A5/A6、A-C1-A9、A-C1-A12、A-C1-A14、A-C1-A16、A-C1-A17、A-C1-A18、A-C1-A21、A-C1-A26、E-C1-A1、E-C1-A3、E-C1-A4/A5/A6、E-C1-A9、E-C1-A12、E-C1-A14、E-C1-A16、E-C1-A17、E-C1-A18、E-C1-A21、E-C1-A26、A-C2-A1、A-C2-A3、A-C2-A4/A5/A6、A-C2-A9、A-C2-A12、A-C2-A14、A-C2-A16、A-C2-A17、A-C2-A18、A-C2-A21、A-C2-A26、E-C2-A1、 E-C2-A3、E-C2-A4/A5/A6、E-C2-A9、E-C2-A12、E-C2-A14、E-C2-A16、E-C2-A17、E-C2-A18、E-C2-A21及E-C2-A26所組成之群組，較佳為A-C1-A1、A-C1-A14、A-C1-A18、A-C1-A26、E-C1-A1、E-C1-A14、E-C1-A18、E-C1-A26、A-C2-A1、A-C2-A14、A-C2-A18,A-C2-A26、E-C2-A1、E-C2-A14、E-C2-A18及E-C2-A26，其變化於表A所敘明(參閱前項)。 Particularly preferred embodiments of the compositions of the present invention comprise or consist of a combination of an antigenic epitope, a carrier protein and an adjuvant selected from the group consisting of A-C1-A1, A-C1-A3, A-C1- A4/A5/A6, A-C1-A9, A-C1-A12, A-C1-A14, A-C1-A16, A-C1-A17, A-C1-A18, A-C1-A21, A- C1-A26, E-C1-A1, E-C1-A3, E-C1-A4/A5/A6, E-C1-A9, E-C1-A12, E-C1-A14, E-C1-A16, E-C1-A17, E-C1-A18, E-C1-A21, E-C1-A26, A-C2-A1, A-C2-A3, A-C2-A4/A5/A6, A-C2- A9, A-C2-A12, A-C2-A14, A-C2-A16, A-C2-A17, A-C2-A18, A-C2-A21, A-C2-A26, E-C2-A1 E-C2-A3, E-C2-A4/A5/A6, E-C2-A9, E-C2-A12, E-C2-A14, E-C2-A16, E-C2-A17, E-C2- A group of A18, E-C2-A21 and E-C2-A26, preferably A-C1-A1, A-C1-A14, A-C1-A18, A-C1-A26, E-C1- A1, E-C1-A14, E-C1-A18, E-C1-A26, A-C2-A1, A-C2-A14, A-C2-A18, A-C2-A26, E-C2-A1 E-C2-A14, E-C2-A18 and E-C2-A26, the changes are described in Table A (see the previous paragraph).

關於本發明特別較佳實施例，利用本發明之組成物及/或多種化合物治療及/或預防及/或改善共核蛋白病(synucleinopathy)，係選自由路易氏體症(Lewy body disorders，簡稱LBDs)，較佳為帕金森氏病(Parkinson’s disease，簡稱PD)、帕金森氏失智症(Parkinson’s disease with dementia，簡稱PDD)及路易氏體失智症(dementia with Lewy bodies，簡稱DLB)，及多發性系統退化症(multiple system atrophy，簡稱MSA)或第一型腦內鐵沉積性神經退化症(Neurodegeneration with Brain Iron Acculation type I，簡稱NBIA Type I)、漸進性核上眼神經痲痺症(progressive supranuclear palsy，簡稱PSP)、額葉聶型失智(frontotemporal dementia，簡稱FTD)、畢克氏症(Pick’s disease，簡稱PiD)及皮質基底核退化症(cortico-basal degeneration)所組成之群組。 With respect to a particularly preferred embodiment of the present invention, the use of the compositions and/or compounds of the present invention for the treatment and/or prevention and/or amelioration of synucleinopathy is selected from Lewy body disorders (abbreviated as Lewy body disorders). LBDs), preferably Parkinson's disease (PD), Parkinson's disease with dementia (PDD), and dementia with Lewy bodies (DLB), And multiple system atrophy (MSA) or first type of brain iron deposition syndrome (Neurodegeneration with Brain Iron Acculation type I, NBIA Type I), progressive nucleus of the nerve palsy ( Progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Pick's disease (PiD) and cortico-basal degeneration .

關於本發明較佳實施例，帕金森氏病(Parkinson’s disease，簡稱PD)之運動型症狀(motor symptoms)，係選自由靜止性顫抖(resting tremor)、運動遲緩(bradykinesia)、僵硬(rigidity)、姿勢性不穩(postural instability)及駝背姿(stooped posture)、肌張力障礙(dystonia)、疲倦(fatigue)、精細動作靈巧度(fine motor dexterity)及運動協調度(motor coordination)受損、損害粗大動作協調(gross motor coordination)、運動缺乏(poverty of movement，減少手臂擺動)、靜坐不能(akathisia)、語言困難(speech problems)、喪失臉部表情(loss of facial expression)、寫字過小症(micrographia)、吞嚥困難(difficulty swallowing)、***功能障礙(sexual dysfunction)及流涎(drooling)組成之群組。 In a preferred embodiment of the invention, the motor symptoms of Parkinson's disease (PD) are selected from the group consisting of resting tremor, bradykinesia, rigidity, Postural instability and stooped posture, dystonia, fatigue, fine motor dexterity, and motor coordination are impaired Gross motor coordination, poorness of movement, akathisia, speech problems, loss of facial expression, micrographia ), dysphagia (difficulty swallowing), sexual dysfunction (sexual) Dysfunction) and rodroling group.

本發明另一可能關於治療及/或預防共核蛋白病(synucleinopathies)之方法，經由投予有需要之個體適當劑量之組成物，該組成物於申請專利範圍中所定義，在此敘明。 Another possible method of the invention for treating and/or preventing synucleinopathies is by administering to a subject in need thereof a suitable dosage of the composition as defined in the scope of the patent application, which is herein incorporated.

在此使用之「預防」一詞，不僅涵蓋預防疾病發生率之措施，如降低危險因子，亦包含遏止其進展及降低其一旦發生之後果。 The term "prevention" as used herein does not only cover measures to prevent the incidence of disease, such as reducing risk factors, but also to curb its progress and reduce its consequences once it occurs.

在此使用之「治療」一詞，或其同義，包含促進及/或逆轉疾病之症狀(如神經退化性疾病)。一化合物當其使用於本發明篩選之方法，造成改善於任何疾病相關之參數，皆等同於治療性化合物。該「治療」一詞，代表治療性療法及預防性藥物或預防性措施。舉例而言，這些病人可從本發明之組成物及方法得到益處，包括這些病人已罹患疾病或是生理失調(如退化性疾病、缺乏或失去認知功能)，及預防這些病人之疾病或生理失調(如使用本發明之預防性療法)。 The term "treatment" as used herein, or synonymous, encompasses the promotion and/or reversal of symptoms of a disease (eg, neurodegenerative diseases). A compound which, when used in the methods of screening of the present invention, results in an improvement in any disease related parameter, is equivalent to a therapeutic compound. The term "treatment" refers to therapeutic therapies and preventive or preventive measures. For example, these patients may benefit from the compositions and methods of the present invention, including those patients who have developed a disease or a physiological disorder (such as a degenerative disease, lack or loss of cognitive function), and prevention of diseases or physiological disorders in these patients. (eg, using the prophylactic treatment of the invention).

本發明在此進一步敘明下列實施例： The invention further clarifies the following examples herein:

1.組成物包含一甲型共核蛋白抗原決定位之至少一擬抗原決定位，用於預防及/或治療共核蛋白病(synucleinopathies)之方法，其中，上述至少一擬抗原決定位為結合或融合於藥學上可接受之攜帶蛋白，該攜帶蛋白選自由一無毒白喉毒素(non-toxic diphtheria toxin mutant)、血氰蛋白(keyhole limpet hemocyanin，簡稱KLH)、白喉毒素(diphtheria toxin，簡稱DT)、破傷風類毒素(tetanus toxid，簡稱TT)及流感嗜血桿菌共同蛋白D(Haemophilus influenzae protein D，簡稱protein D)所組成之群組。 A method for preventing and/or treating a synucleinopathies, wherein the composition comprises at least one antigenic epitope of a alpha-nuclear protein epitope, wherein the at least one antigenic epitope is a binding Or fused to a pharmaceutically acceptable carrier protein selected from the group consisting of a non-toxic diphtheria toxin mutant, a keyhole limpet hemocyanin (KLH), and a diphtheria toxin (DT). , a group consisting of tetanus toxin (TT) and Haemophilus influenzae protein D (protein D).

2.關於實施例1之組成物，其中無毒白喉毒素(non-toxic diphtheria toxin mutant)選自由CRM 197，CRM 176 CRM 228，CRM 45，CRM 9，CRM 102，CRM 103及CRM 107所組成之群組，特別是CRM 197。 2. The composition of embodiment 1, wherein the non-toxic diphtheria toxin mutant is selected from the group consisting of CRM 197, CRM 176 CRM 228, CRM 45, CRM 9, CRM 102, CRM 103 and CRM 107 Group, especially CRM 197.

3.關於實施例1或2之組成物，其中該至少一擬抗原決定位 製備成可供皮下、皮內、穿皮、或肌肉給藥。 3. The composition of embodiment 1 or 2, wherein the at least one quasi-antigenic epitope It is prepared for subcutaneous, intradermal, transdermal, or intramuscular administration.

4.關於實施例1至3任一實施例之組成物，其中該至少一擬抗原決定位與至少一佐劑製成製劑。 4. The composition of any of embodiments 1 to 3, wherein the at least one antigenic epitope is formulated with at least one adjuvant.

5.關於實施例4之組成物，其中至少一佐劑可刺激先天性免疫系統。 5. The composition of embodiment 4 wherein at least one adjuvant stimulates the innate immune system.

6.關於實施例5之組成物，其中至少一佐劑可刺激先天性免疫系統，包含或由Toll-like接受體(TLR)作用劑所組成，較佳為一TLR.1，TLR2，TLR3，TLR4，TLR5，TLR7，TLR8或TLR9作用劑，特別較佳為一TLR4作用劑。 6. The composition of embodiment 5, wherein at least one adjuvant stimulates the innate immune system, comprising or consisting of a Toll-like receptor (TLR) agent, preferably a TLR.1, TLR2, TLR3, The TLR4, TLR5, TLR7, TLR8 or TLR9 agent is particularly preferably a TLR4 agent.

7.關於實施例6之組成物，其中TLR作用劑選自由單磷酸脂質A(monophosphoryl lipid A，簡稱MPL)，3-去-O-醯化單磷酸脂質A(3-de-O-acylated monophosphoryl lipid A，簡稱3D-MPL)、poly I：C、GLA、鞭毛蛋白(flagellin)、R848、imiquimod及CpG所組成之群組。 7. The composition of embodiment 6, wherein the TLR agent is selected from the group consisting of monophosphoryl lipid A (MPL), 3-de-O-acylated monophosphoryl. A combination of lipid A (abbreviated as 3D-MPL), poly I:C, GLA, flagellin, R848, imiquimod, and CpG.

8.關於實施例4至7任一實施例之組成物，其中至少一佐劑包含或由一皂素(saponin)，較佳為QS21，一油包水乳化劑(water in oil emulsion)及一微脂體(liposome)所組成。 8. The composition of any of embodiments 4 to 7, wherein at least one adjuvant comprises or consists of a saponin, preferably QS21, a water in oil emulsion and a Made up of liposome.

9.關於實施例4之組成物，其中至少一佐劑，選自由MF59，AS01，AS02，AS03，AS04，氫氧化鋁及磷酸鋁所組成之群組。 9. The composition of embodiment 4, wherein at least one adjuvant is selected from the group consisting of MF59, AS01, AS02, AS03, AS04, aluminum hydroxide and aluminum phosphate.

10.關於實施例1至9任一實施例之組成物，其中該抗原決定位包含KNEEGAP或DMPVDPDN胺基酸序列。 10. The composition of any of embodiments 1 to 9, wherein the epitope comprises a KNEEGAP or DMPVDPDN amino acid sequence.

11.關於實施例1至10任一實施例之組成物，其中至少一擬抗原決定位包含該胺基酸序列(X₁)_nX₂X₃X₄X₅GX₆P(X₇)_m (式I)， 其中X₁為任何胺基酸殘基，X₂ 為一胺基酸殘基選自離胺酸(lysine，K)，精胺酸(arginine，R)，丙胺酸(alanine，A)及組胺酸(histidine，H)所組成之群組，X₃ 為一胺基酸殘基選自天冬醯胺酸(asparagine，N)，麩醯胺酸(glutamine，Q)，絲胺酸(serine，S)，甘胺酸(glycine，G)及丙胺酸(alanine，A)，較佳為天冬醯胺酸(asparagine，N)，絲胺酸(serine，S)，甘胺酸(glycine，G)及丙胺酸(alanine，A)所組成之群組，X₄為一胺基酸殘基選自麩胺酸(glutamic acid，E)，天冬安酸(aspartic acid，D)及丙胺酸(alanine，A)所組成之群組，X₅為一胺基酸殘基選自麩胺酸(glutamic acid，E)及天冬安酸(aspartic acid，D)所組成之群組，X₆為一胺基酸殘基選自丙胺酸(alanine，A)及酪胺酸(tyrosine，Y)所組成之群組，X₇為任何胺基酸殘基，n及m分別為0或大於0之整數，其中，關於式I之胺基酸序列並不完全相同於，或不包含甲型共核蛋白之7-基體(7-mer)多胜肽片段KNEEGAP，且其中至少一擬抗原決定位(mimotope)包含式I之胺基酸序列具有與抗體結合之能力，該抗體係對甲型共核蛋白抗原決定位具專一性，包含該胺基酸序列KNEEGAP。 11. The composition of any of embodiments 1 to 10, wherein at least one pseudo epitope comprises the amino acid sequence (X ₁ ) _n X ₂ X ₃ X ₄ X ₅ GX ₆ P(X ₇ ) _m (Formula I), wherein X ₁ is any amino acid residue, and X ₂ is an amino acid residue selected from the group consisting of lysine (K), arginine (R), and alanine (alanine, A) and a group consisting of histidine (H), X ₃ is an amino acid residue selected from asparagine (N), glutamine (Q), silk Amine (Sine), glycine (G) and alanine (A), preferably asparagine (N), serine (S), glycine a group consisting of acid (glycine, G) and alanine (A), X ₄ is an amino acid residue selected from the group consisting of glutamic acid (E), aspartic acid (D) And a group consisting of alanine (A), X ₅ is a group of amino acid residues selected from the group consisting of glutamic acid (E) and aspartic acid (D) Group, X ₆ is a group of amino acid residues selected from the group consisting of alanine (A) and tyrosine (Y). X ₇ is any amino acid residue, n and m are each an integer of 0 or greater than 0, wherein the amino acid sequence of formula I is not identical or does not comprise a 7-matrix of a type A nuclear protein (7-mer) a multi-peptide fragment KNEEGAP, and wherein at least one mimotope comprises an amino acid sequence of formula I having the ability to bind to an antibody, the anti-system of the alpha-nuclear protein epitope Specificity, including the amino acid sequence KNEEGAP.

12.關於實施例11之組成物，其中X₂為一胺基酸殘基選自由離胺酸(lysine，K)、精安酸(arginine，R)及/或X₆為丙胺酸(alanine，A)所組成之群組。 12. The composition of embodiment 11, wherein X ₂ is an amino acid residue selected from the group consisting of lysine (K), arginine (R), and/or X ₆ is alanine (alanine, A) The group consisting of.

13.關於實施例11或12之組成物，其中該擬抗原決定位包含一胺基酸序列，其選自由(X₁)_nKNDEGAP(X₇)_m、(X₁)_nANEEGAP(X₇)_m、(X₁)_nKAEEGAP(X₇)_m、(X₁)_nKNAEGAP(X₇)_m、(X₁)_nRNEEGAP(X₇)_m、(X₁)_nHNEEGAP(X₇)_m、(X₁)_nKNEDGAP(X₇)_m、(X₁)_nKQEEGAP(X₇)_m、(X₁)_nKSEEGAP(X₇)_m、(X₁)_nKNDDGAP(X₇)_m、(X₁)_nRNDEGAP(X₇)_m、(X₁)_nRNEDGAP(X₇)_m、(X₁)_nRQEEGAP(X₇)_m、(X₁)_nRSEEGAP(X₇)_m、(X₁)_nANDEGAP(X₇)_m、(X₁)_nANEDGAP(X₇)_m、(X₁)_nHSEEGAP(X₇)_m、(X₁)_nASEEGAP(X₇)_m、(X₁)_nHNEDGAP(X₇)_m、(X₁)_nHNDEGAP(X₇)_m、(X₁)_nRNAEGAP(X₇)_m、(X₁)_nHNAEGAP(X₇)_m、(X₁)_nKSAEGAP(X₇)_m、(X₁)_nKSDEGAP(X₇)_m、(X₁)_nKSEDGAP(X₇)_m、(X₁)_nRQDEGAP(X₇)_m、(X₁)_nRQEDGAP(X₇)_m、(X₁)_nHSAEGAP(X₇)_m、(X₁)_nRSAEGAP(X₇)_m、(X₁)_nRSDEGAP(X₇)_m、(X₁)_nRSEDGAP(X₇)_m、(X₁)_nHSDEGAP(X₇)_m、(X₁)_nHSEDGAP(X₇)_m、(X₁)_nRQDDGAP(X₇)_m所組成之群組，較佳為(X₁)_nKNDEGAP(X₂)_m、(X₁)_nRNEEGAP(X₂)_m、(X₁)_nRNDEGAP(X₂)_m、(X₁)_nKNAEGAP(X₂)_m、(X₁)_nKSDEGAP(X₂)_m、(X₁)_nRNAEGAP(X₂)_m或(X₁)_nRSEEGAP(X₂)_m。 13. The composition of embodiment 11 or 12, wherein the pseudo epitope comprises an amino acid sequence selected from the group consisting of (X ₁ ) _n KNDEGAP(X ₇ ) _m , (X ₁ ) _n ANEEGAP (X ₇ ) _m , (X ₁ ) _n KAEEGAP(X ₇ ) _m , (X ₁ ) _n KNAEGAP(X ₇ ) _m , (X ₁ ) _n RNEEGAP(X ₇ ) _m , (X ₁ ) _n HNEEGAP(X ₇ ) _m , (X ₁ ) _n KNEDGAP(X ₇ ) _m , (X ₁ ) _n KQEEGAP(X ₇ ) _m , (X ₁ ) _n KSEEGAP(X ₇ ) _m , (X ₁ ) _n KNDDGAP(X ₇ ) _m , (X ₁ ) _n RNDEGAP(X ₇ ) _m , (X ₁ ) _n RNEDGAP(X ₇ ) _m , (X ₁ ) _n RQEEGAP(X ₇ ) _m , (X ₁ ) _n RSEEGAP(X ₇ ) _m , (X ₁ ) _n ANDEGAP(X ₇ ) _m , (X ₁ ) _n ANEDGAP(X ₇ ) _m , (X ₁ ) _n HSEEGAP(X ₇ ) _m , (X ₁ ) _n ASEEGAP(X ₇ ) _m , (X ₁ ) _n HNEDGAP (X ₇ ) _m , (X ₁ ) _n HNDEGAP(X ₇ ) _m , (X ₁ ) _n RNAEGAP(X ₇ ) _m , (X ₁ ) _n HNAEGAP(X ₇ ) _m , (X ₁ ) _n KSAEGAP(X ₇ ) _m , (X ₁ ) _n KSDEGAP(X ₇ ) _m , (X ₁ ) _n KSEDGAP(X ₇ ) _m , (X ₁ ) _n RQDEGAP(X ₇ ) _m , (X ₁ ) _n RQEDGAP(X ₇ ) _m , (X ₁ ) _n HSAEGAP(X ₇ ) _m , (X ₁ ) _n RSAEGAP(X ₇ ) _m , (X ₁ ) _n RSDEGAP(X ₇ ) _m , (X ₁ ) _n RSEDGAP(X ₇ ) _m , _{(X 1) n HSDEGAP (X} 7) m _{(X 1) n HSEDGAP (X} 7) m, the group consisting of _{(X 1) n RQDDGAP (X} 7) m, preferably _{(X 1) n KNDEGAP (X} 2) m, (X 1) n RNEEGAP (X ₂ ) _m , (X ₁ ) _n RNDEGAP(X ₂ ) _m , (X ₁ ) _n KNAEGAP(X ₂ ) _m , (X ₁ ) _n KSDEGAP(X ₂ ) _m , (X ₁ ) _n RNAEGAP(X ₂ ) _m or (X ₁ ) _n RSEEGAP(X ₂ ) _m .

14.關於實施例1至13任一實施例之組成物，包含至少一擬抗原決定位包括一胺基酸序列，選自由(X₁)_nQASFAME(X₇)_m、(X₁)_nTASWKGE(X₇)_m、(X₁)_nQASSKLD(X₇)_m、(X₁)_nTPAWKGE(X₇)_m、(X₁)_nTPSWAGE(X₇)_m、(X₁)_nTPSWKGE(X₇)_m所組成之群組，其中X₁ 為任何胺基酸殘基，X₇為任何胺基酸殘基，n及m分別為0或大於0之整數，上述之至少一擬抗原決定位(minotope)具有與一抗體結合之能力，該抗體係 對甲型共核蛋白抗原決定位具專一性，包含該胺基酸序列KNEEGAP使用於預防及/或治療共核蛋白病。 14. The composition of any of embodiments 1 to 13, comprising at least one pseudo epitope comprising an amino acid sequence selected from the group consisting of (X ₁ ) _n QASFAME(X ₇ ) _m , (X ₁ ) _n TASWKGE (X ₇ ) _m , (X ₁ ) _n QASSKLD(X ₇ ) _m , (X ₁ ) _n TPAWKGE(X ₇ ) _m , (X ₁ ) _n TPSWAGE(X ₇ ) _m , (X ₁ ) _n TPSWKGE(X ₇ ) a group consisting of _m , wherein X ₁ is any amino acid residue, X ₇ is any amino acid residue, n and m are each 0 or an integer greater than 0, and at least one of the above-mentioned pseudo-antigenic epitopes (minotope) has the ability to bind to an antibody that is specific for the alpha-nuclear protein epitope, and the amino acid sequence KNEEGAP is used for the prevention and/or treatment of synuclearopathy.

15.關於實施例1至14任一實施例之組成物，其中至少一擬抗原決定位包含該胺基酸序列(X_1’)_n’X_2’X_3’PVX_4’X_5’X_6’(X_7’)_m’ (式II)，其中X_1’ 為任何胺基酸殘基，X_2’ 為一胺基酸殘基選自由天冬胺酸(aspartic acid，D)及麩胺酸(glutamic acid，E)所組成之群組，X_3’ 為任何胺基酸殘基，X_4’ 為任何胺基酸殘基，X_5’ 為一胺基酸殘基選自由脯胺酸(proline，P)及丙胺酸(alanine，A)所組成之群組，X_6’ 為一胺基酸殘基選自由天冬胺酸(aspartic acid，D)及麩胺酸(glutamic acid，E)所組成之群組，X_7’ 為任何胺基酸殘基，n’及m’分別為0或大於0之整數，其中，關於式II之胺基酸序列並不完全相同於，或不包含甲型共核蛋白之8-基體(8-mer)多胜肽片段DMPVDPDN，且其中至少一擬抗原決定位(mimotope)包含式II之胺基酸序列具有與抗體結合之能力，該抗體係對甲型共核蛋白抗原決定位具專一性，包含該胺基酸 序列DMPVDPDN。 15. The composition of any of embodiments 1 to 14, wherein at least one of the pseudo-antigenic epitopes comprises the amino acid sequence (X _{1 '} ) _n' X _2' X _3' PVX _4' X _5' X _{6 '} (X _7' ) _m' (Formula II), wherein X _{1 '} is any amino acid residue, X _{2 '} is an amino acid residue selected from aspartic acid (D) and glutamine a group consisting of glutamic acid (E), X _{3 '} is any amino acid residue, X _{4 '} is any amino acid residue, X _{5 '} is an amino acid residue selected from lysine (proline, P) and a group of alanine (A), X _{6 '} is an amino acid residue selected from aspartic acid (D) and glutamic acid (E) a group consisting of X _{7 '} is any amino acid residue, n' and m' are each an integer of 0 or greater than 0, wherein the amino acid sequence of formula II is not identical, or An 8-mer (8-mer) polypeptide fragment DMPVDPDN comprising a type A nuclear protein, and wherein at least one mitope comprises an amino acid sequence of formula II having the ability to bind to an antibody, the anti-system Specificity for the alpha-nuclear protein epitope, including the amino acid Sequence DMPVDPDN.

16.關於實施例15之組成物，其中X_3’為一胺基酸殘基，選自由麩醯胺酸(glutamine，Q)、絲胺酸(serine，S)、蘇胺酸(threonine，T)、精安酸(arginine，R)、天冬醯胺酸(asparagine，N)、纈胺酸(valine，V)、組胺酸(histidine，H)、甲硫胺酸(methionine，M)、酪胺酸(tyrosine，Y)、丙胺酸(alanine，A)及白胺酸(leucin，L)所組成之群組。 16. The composition of embodiment 15, wherein X _{3 '} is an amino acid residue selected from the group consisting of glutamine (Q), serine (S), threonine (Treonine, T ), arginine (R), aspartic acid (asparagine, N), valine (V), histidine (H), methionine (M), A group consisting of tyrosine (Y), alanine (A), and leucine (L).

17.關於實施例15或16之組成物，其中X_4’為一胺基酸殘基，選自由麩醯胺酸(glutamine，Q)、色胺酸(tryptophane，W)、蘇胺酸(threonine，T)、精安酸(arginine，R)、天冬醯胺酸(aspartic acid，D)、異白胺酸(isoleucin，I)、纈胺酸(valine，V)、組胺酸(histidine，H)、脯胺酸(proline，P)、酪胺酸(tyrosine，Y)、丙胺酸(alanine，A)、絲胺酸(serine，S)及白胺酸(leucin，L)所組成之群組。 17. The composition of embodiment 15 or 16, wherein X _{4 '} is an amino acid residue selected from the group consisting of glutamine (Q), tryptophane (W), threonine (threonine) , T), arginine (R), aspartic acid (D), isoleic acid (isoleucin, I), valine (V), histidine (histidine, H), proline (P), tyrosine (Y), alanine (A), serine (S) and leucine (leucin, L) group.

18.關於實施例15至17任一實施例之組成物，其中擬抗原決定位具有一胺基酸序列，選自由(C)DQPVLPD、(C)DMPVLPD、(C)DSPVLPD、(C)DSPVWAE、(C)DTPVLAE、(C)DQPVLPDN、(C)DMPVLPDN、(C)DSPVLPDN、(C)DQPVTAEN、(C)DSPVWAEN、(C)DTPVLAEN、(C)HDRPVTPD、(C)DRPVTPD、(C)DVPVLPD、(C)DTPVYPD、(C)DTPVIPD、(C)HDRRVTPDN、(C)DRPVTPDN、(C)DNPVHPEN、(C)DVPVLPDN、(C)DTPVYPDN、(C)DTPVIPDN、(C)DQPVLPDG、(C)DMPVLPDG、(C)DSPVLPDG、(C)DSPVWAEG、(C)DRPVAPEG、(C)DHPVHPDS、(C)DMPVSPDR、(C)DSPVPPDD、(C)DQPVYPDI、(C)DRPVYPDI、(C)DHPVTPDR、(C)EYPVYPES、(C)DTPVLPDS、(C)DMPVTPDT、(C)DAPVTPDT、(C)DSPVVPDN、(C)DLPVTPDR、(C)DSPVHPDT、(C)DAPVRPDS、(C)DMPVWPDG、(C)DAPVYPDG、(C)DRPVQPDR、(C)YDRPVQPDR、(C)DMPVDPEN、(C)DMPVDADN、DQPVLPD(C)、DMPVLPD(C)、(C)EMPVDPDN及(C)DNPVHPE所組成之群組。 18. The composition of any of embodiments 15 to 17, wherein the pseudo-antigenic epitope has an amino acid sequence selected from the group consisting of (C) DQPVLPD, (C) DMVPLPD, (C) DSPVLPD, (C) DSPVWAE, (C) DTPVLAE, (C) DQPVLPDN, (C) DMPVLPDN, (C) DSPVLPDN, (C) DQPVTAEN, (C) DSPVWAEN, (C) DTPVLAEN, (C) HDRPVTPD, (C) DRPVTPD, (C) DVPVLPD, (C) DTPVYPD, (C) DTPIPIPD, (C) HDRRVTPDN, (C) DRPVTPDN, (C) DNPVHPEN, (C) DVPVLPDN, (C) DTPVYPDN, (C) DTPVIPDN, (C) DQPVLPDG, (C) DMPVLPDG, (C) DSPVLPDG, (C) DSPVWAEG, (C) DRPVAPEG, (C) DHPVHPDS, (C) DMPVSPDR, (C) DSPVPPDD, (C) DQPVYPDI, (C) DRPVYPDI, (C) DHPVTPDR, (C) EYPVYPES, (C) DTPVLPDS, (C) DMPVTPDT, (C) DAPVTPDT, (C) DSPVVPDN, (C) DLPVTPDR, (C) DSPVHPDT, (C) DAPVRPDS, (C) DMPVWPDG, (C) DAPVYPDG, (C) DRPVQPDR, (C) Groups of YDRPVQPDR, (C) DMPVDPEN, (C) DMPVDADN, DQPVLPD (C), DMRPLPD (C), (C) EMPVDPDN, and (C) DNPVHPE.

19.關於實施例11至17任一實施例之組成物，其特徵在於n’及/或m’為1及X_1’及/或X_7’為半胱胺酸(cysteine，C)。 19. The composition of any of embodiments 11 to 17, characterized in that n' and/or m' is 1 and X1 _' and/or X7 _' is cysteine (C).

20.關於實施例11至19任一實施例之組成物，其中擬抗原決定位包含7至30，較佳為7至20，更佳為7至16，最佳為8或9胺基酸殘基。 20. The composition of any of embodiments 11 to 19, wherein the pseudo epitope comprises from 7 to 30, preferably from 7 to 20, more preferably from 7 to 16, most preferably from 8 or 9 amino acid residues. base.

21.關於實施例1至20任一實施例之組成物，其中共核蛋白病(synucleinopathy)係選自由路易氏體症(Lewy body disorders，簡稱LBDs)，較佳為帕金森氏病(Parkinson’s disease,PD)、帕金森氏失智症(Parkinson’s disease with dementia，簡稱PDD)及路易氏體失智症(dementia with Lewy bodies，簡稱DLB)，及多發性系統退化症(multiple system atrophy，簡稱MSA)或第一型腦內鐵沉積性神經退化症(Neurodegeneration with Brain Iron Acculation type I，簡稱NBIA Type I)，漸進性核上眼神經痲痺症(progressive supranuclear palsy，簡稱PSP)、額葉聶型失智(frontotemporal dementia，簡稱FTD)、畢克氏症(Pick’s disease，簡稱PiD)及皮質基底核退化症(cortico-basal degeneration，簡稱CBD)。 21. The composition of any of embodiments 1 to 20, wherein the synucleinopathy is selected from the group consisting of Lewy body disorders (LBDs), preferably Parkinson's disease. , PD), Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) Or the first type of brain iron deposition syndrome (Neurodegeneration with Brain Iron Acculation type I, referred to as NBIA Type I), progressive suprauclear palsy (PSP), frontal nemesis dementia (frontotemporal dementia, referred to as FTD), Pick's disease (PiD) and cortico-basal degeneration (CBD).

22.關於實施例1至21任一實施例之組成物，其中至少一擬抗原決定位選自由DQPVLPD、DSPVLPD、DVPVLPD、DSPVLPDG、YDRPVQPDR、DHPVHPDS、DAPVRPDS、KNDEGAP、KQEEGAP及KSEEGAP，特別是DQPVLPD及YDRPVQPDR所組成之群組。 22. The composition of any of embodiments 1 to 21, wherein at least one of the pseudo epitopes is selected from the group consisting of DQPVLPD, DSPVLPD, DVPVLPD, DSPVLPDG, YDRPVQPDR, DHPVHPDS, DAPVRPDS, KNDEGAP, KQEEGAP, and KSEEGAP, particularly DQPVLPD and YDRPVQPDR The group formed.

23.關於實施例1至22任一實施例之組成物，包含至少一擬抗原決定位、攜帶蛋白及/或佐劑之組合，於表A所敘明，較佳為A-C1-A1、A-C1-A14、A-C1-A18、A-C1-A26、E-C1-A1、E-C1-A14、E-C1-A18、E-C1-A26、A-C2-A1、A-C2-A14、A-C2-A18,A-C2-A26、E-C2-A1、E-C2-A14、E-C2-A18及E-C2-A26。 23. The composition of any of embodiments 1 to 22 comprising at least one analogy epitope, a carrier protein and/or a combination of adjuvants, as described in Table A, preferably A-C1-A1. A-C1-A14, A-C1-A18, A-C1-A26, E-C1-A1, E-C1-A14, E-C1-A18, E-C1-A26, A-C2-A1, A- C2-A14, A-C2-A18, A-C2-A26, E-C2-A1, E-C2-A14, E-C2-A18 and E-C2-A26.

本發明進一步於下列圖表及實例闡明，惟，不限於此。 The invention is further illustrated in the following figures and examples, but is not limited thereto.

第1A圖表示利用可交替之佐劑，包含TLR4、皂素或水包 油乳化劑，可促進較佳注入式胜肽之專一性免疫力，當DQPVLPD-CRM197共軛物與上述佐劑結合，相較於單純佐劑或氫氧化鋁與DQPVLPD-CRM197共軛物結合。 Figure 1A shows the use of alternative adjuvants, including TLR4, saponin or water pack An oil emulsifier that promotes the specific immunity of a preferred injectable peptide. When the DQPVLPD-CRM197 conjugate is combined with the above adjuvant, it binds to the DQPVLPD-CRM197 conjugate as compared to a simple adjuvant or aluminum hydroxide.

第1B圖表示利用可交替之佐劑，包含TLR4及較少之皂素或水包油乳化劑，可促進較佳注入式胜肽之專一性免疫力，當YDRPVQPDR-CRM197共軛物與上述佐劑結合，相較於單純佐劑或氫氧化鋁與YDRPVQPDR-CRM197共軛物結合。 Figure 1B shows the use of alternative adjuvants, including TLR4 and less saponin or oil-in-water emulsifier, to promote specific immunity of the preferred injection peptide, when YDRPVQPDR-CRM197 conjugate and the above The agent binds to the YDRPVQPDR-CRM197 conjugate as compared to a simple adjuvant or aluminum hydroxide.

第1C圖表示利用可交替之佐劑，包含TLR4但無水包油乳化劑或皂素，可促進較佳注入式胜肽之專一性免疫力，當KNDEGAP-CRM197共軛物與上述佐劑結合，相較於單純佐劑或氫氧化鋁與KNDEGAP-CRM197共軛物結合。 Figure 1C shows that the use of an alternative adjuvant comprising TLR4 but an anhydrous oil-in-water emulsifier or saponin promotes the specific immunity of a preferred injectable peptide when the KNDEGAP-CRM197 conjugate is combined with the above adjuvant, Binding to the KNDEGAP-CRM197 conjugate compared to a simple adjuvant or aluminum hydroxide.

第2A圖表示利用可交替之佐劑，包含水包油乳化劑及TLR4或皂素，可促進較佳注入式胜肽之專一性免疫力，當DQPVLPD-KLH共軛物與上述佐劑結合，相較於單純佐劑或氫氧化鋁與DQPVLPD-KLH共軛物結合。 Figure 2A shows that the use of an alternative adjuvant, including an oil-in-water emulsifier and TLR4 or saponin, promotes the specific immunity of a preferred injectable peptide when the DQPVLPD-KLH conjugate is combined with the above adjuvant, Binding to the DQPVLPD-KLH conjugate compared to a simple adjuvant or aluminum hydroxide.

第2B及2D圖表示利用可交替之佐劑，包含TLR4或水包油乳化劑，但無皂素，可促進較佳注入式胜肽之專一性免疫力，當YDRPVQPDR-KLH(B)及DHPVHPDS-KLH(D)共軛物與上述佐劑結合，相較於單純佐劑或氫氧化鋁分別與YDRPVQPDR-KLH(B)及DHPVHPDS-KLH(D)共軛物結合。 Figures 2B and 2D show the use of alternative adjuvants, including TLR4 or oil-in-water emulsifiers, but without saponin, which promotes the specific immunity of better injected peptides, when YDRPVQPDR-KLH(B) and DHPVHPDS The -KLH(D) conjugate is bound to the above adjuvant and is bound to the YDRPVQPDR-KLH (B) and DHPVHPDS-KLH (D) conjugates, respectively, compared to the adjuvant alone or aluminum hydroxide.

第2C圖表示利用可交替之佐劑，包含TLR4及較少之水包油乳化劑或皂素，可促進較佳注入式胜肽之專一性免疫力，當KNDEGAP-KLH共軛物與上述佐劑結合，相較於單純佐劑或氫氧化鋁與KNDEGAP-KLH共軛物結合。 Figure 2C shows the use of alternative adjuvants, including TLR4 and less oil-in-water emulsifier or saponin, to promote the specific immunity of the preferred injectable peptide, when the KNDEGAP-KLH conjugate and the above The agent binds to the KNDEGAP-KLH conjugate as compared to a simple adjuvant or aluminum hydroxide.

第3A圖表示利用可交替之佐劑，包含皂素及較少之TLR4 或水包油乳化劑，可促進較佳之單核細胞/巨噬細胞活化，係根據單核球趨化蛋白-1細胞介素(MCP-1 cytokine)濃度，當DQPVLPD-CRM197共軛物與佐劑結合，相較於單純佐劑或氫氧化鋁與DQPVLPD-CRM197共軛物結合。惟需注意的是，單獨Quil-A已似乎可促進單核細胞/巨噬細胞激化，雖於相對低劑量。 Figure 3A shows the use of alternative adjuvants, including saponin and less TLR4 Or an oil-in-water emulsifier that promotes better monocyte/macrophage activation based on the concentration of mononuclear chemokine-1 interleukin (MCP-1 cytokine) when DQPVLPD-CRM197 conjugate The agent binds to the DQPVLPD-CRM197 conjugate as compared to a simple adjuvant or aluminum hydroxide. It should be noted that Quil-A alone appears to promote monocyte/macrophage activation, albeit at relatively low doses.

第3B圖表示利用可交替之佐劑，包含皂素、水包油乳化劑或TLR4，可促進較佳單核細胞/巨噬細胞活化，根據單核球趨化蛋白-1細胞介素(MCP-1 cytokine)濃度，當YDRPVQPDR-CRM197共軛物與佐劑結合，相較於單純佐劑或氫氧化鋁與YDRPVQPDR-CRM197共軛物結合。惟需注意的是，單獨Quil-A已似乎可促進單核細胞/巨噬細胞激化，雖為相對低劑量。 Figure 3B shows that the use of alternative adjuvants, including saponin, oil-in-water emulsifier or TLR4, promotes better monocyte/macrophage activation, according to mononuclear chemokine-1 interleukin (MCP) -1 cytokine) concentration, when the YDRPVQPDR-CRM197 conjugate is bound to an adjuvant, binds to the YDRPVQPDR-CRM197 conjugate as compared to a simple adjuvant or aluminum hydroxide. It should be noted that Quil-A alone appears to promote monocyte/macrophage intensification, albeit at relatively low doses.

第3C圖 表示利用可交替之佐劑，包含皂素或水包油乳化劑或TLR4，可促進較佳單核細胞/巨噬細胞活化，根據單核球趨化蛋白-1細胞介素(MCP-1 cytokine)濃度，當KNDEGAP-CRM197共軛物與佐劑結合，相較於單純佐劑或氫氧化鋁與KNDEGAP-CRM197共軛物結合。單獨Quil-A已似乎可促進單核細胞/巨噬細胞激化，雖為相對低劑量。 Figure 3C shows that the use of alternative adjuvants, including saponin or oil-in-water emulsifier or TLR4, promotes better monocyte/macrophage activation, according to mononuclear chemokine-1 interleukin (MCP) -1 cytokine) concentration, when the KNDEGAP-CRM197 conjugate is bound to the adjuvant, binds to the KNDEGAP-CRM197 conjugate as compared to the adjuvant alone or aluminum hydroxide. Quil-A alone appears to promote monocyte/macrophage activation, albeit at relatively low doses.

第3D圖 表示利用可交替之佐劑，包含皂素、TLR4或水包油乳化劑，可促進較佳單核細胞/巨噬細胞活化，根據單核球趨化蛋白-1細胞介素(MCP-1 cytokine)濃度，當DHPVHPDS-CRM197共軛物與佐劑結合，相較於單純佐劑或氫氧化鋁與DHPVHPDS-CRM197共軛物結合。單獨Quil-A已似乎可促進單核細胞/巨噬細胞激化，雖為相對低劑量。 Figure 3D shows the use of alternative adjuvants, including saponin, TLR4 or oil-in-water emulsifiers, to promote better monocyte/macrophage activation, according to mononuclear chemokine-1 interleukin (MCP) -1 cytokine) concentration, when the DHPVHPDS-CRM197 conjugate is bound to an adjuvant, binds to the DHPVHPDS-CRM197 conjugate as compared to a simple adjuvant or aluminum hydroxide. Quil-A alone appears to promote monocyte/macrophage activation, albeit at relatively low doses.

第4A圖 表示利用可交替之佐劑，包含TLR4、皂素或水包油乳化劑，可促進較佳單核細胞/巨噬細胞活化，根據單核球趨化蛋白-1細胞介素(MCP-1 cytokine)濃度，當DQPVLPD-KLH共軛物與佐劑結合，相較於單純佐劑或氫氧化鋁與DQPVLPD-KLH共軛物。 Figure 4A shows the use of alternative adjuvants, including TLR4, saponin or oil-in-water emulsifiers, to promote better monocyte/macrophage activation, according to mononuclear chemokine-1 interleukin (MCP) -1 cytokine) concentration when the DQPVLPD-KLH conjugate is bound to the adjuvant compared to the adjuvant alone or the aluminum hydroxide and DQPVLPD-KLH conjugate.

第4B及4D圖表示利用可交替之佐劑，包含TLR4、水包油 乳化劑或皂素，可促進較佳單核細胞/巨噬細胞活化，根據單核球趨化蛋白-1細胞介素(MCP-1 cytokine)濃度，當YDRPVQPDR-KLH(B)及DHPVHPDS-KLH(D)共軛物與佐劑結合，相較於單純佐劑或氫氧化鋁分別於與YDRPVQPDR-KLH(B)及DHPVHPDS-KLH(D)共軛物結合。單獨Quil-A已似乎可促進單核細胞/巨噬細胞激化，雖為相對低劑量。 Figures 4B and 4D show the use of alternative adjuvants, including TLR4, oil-in-water An emulsifier or saponin that promotes better monocyte/macrophage activation, depending on the concentration of mononuclear chemokine-1 interleukin (MCP-1 cytokine), when YDRPVQPDR-KLH(B) and DHPVHPDS-KLH (D) The conjugate is bound to an adjuvant and is bound to the YDRPVQPDR-KLH (B) and DHPVHPDS-KLH (D) conjugates, respectively, compared to the adjuvant alone or aluminum hydroxide. Quil-A alone appears to promote monocyte/macrophage activation, albeit at relatively low doses.

第4C圖 表示利用可交替之佐劑，包含水包油乳化劑或皂素，但無TLR4，可促進較佳單核細胞/巨噬細胞活化，根據單核球趨化蛋白-1細胞介素(MCP-1 cytokine)濃度，當KNDEGAP-KLH共軛物與佐劑結合，相較於單純佐劑或氫氧化鋁與KNDEGAP-KLH共軛物結合。單獨Quil-A已似乎可促進單核細胞/巨噬細胞激化，雖為相對低劑量。 Figure 4C shows the use of an alternative adjuvant, including an oil-in-water emulsifier or saponin, but without TLR4, which promotes better monocyte/macrophage activation, according to mononuclear chemokine-1 interleukin (MCP-1 cytokine) concentration, when the KNDEGAP-KLH conjugate is bound to the adjuvant, binds to the KNDEGAP-KLH conjugate as compared to the adjuvant alone or aluminum hydroxide. Quil-A alone appears to promote monocyte/macrophage activation, albeit at relatively low doses.

第5A及5B圖表示比較不同之佐劑與CRM197-共軛物(A)及KLH-共軛物(B)結合，關於其作用於週邊血液之單核細胞餾分多寡。在所有樣本中，單核細胞百分比於生理範圍內，雖顯示QuilA僅降低單核細胞數目之趨勢及所有擬抗原決定位-共軛物組合之測試。絕對性差異反應分析之變異性。 Figures 5A and 5B show the binding of different adjuvants to CRM197-conjugate (A) and KLH-conjugate (B), and the number of monocyte fractions acting on peripheral blood. In all samples, the percentage of monocytes was within the physiological range, although QuilA showed only a trend to reduce the number of monocytes and all of the quasi-antigenic epitope-conjugate combinations tested. Absolute differential response analysis for variability.

第6A及6D圖表示具有協同效果之替代性佐劑與KNDEGAP-CRM197(A)及DHPVHPDS-KLH(D)結合，在活體內周邊血液單核細胞吞噬Aβ情形，相較於氫氧化鋁分別與KNDEGAP-CRM197及DHPVHPDS-KLH共軛物結合。 Figures 6A and 6D show that the synergistic effect of the alternative adjuvant combined with KNDEGAP-CRM197 (A) and DHPVHPDS-KLH (D), in the peripheral blood mononuclear cells phagocytosis of Aβ, compared with aluminum hydroxide and KNDEGAP-CRM197 and DHPVHPDS-KLH conjugates were combined.

第6B圖 表示具有協同效果之包含TLR4或水包油乳化劑佐劑，但無皂素，與DHPVHPDS-CRM197結合，在活體內周邊血液單核細胞吞噬Aβ情形，相較於氫氧化鋁分別與DHPVHPDS-CRM197共軛物結合。 Figure 6B shows a synergistic effect of TLR4 or an oil-in-water emulsifier adjuvant, but no saponin, combined with DHPVHPDS-CRM197, in the peripheral blood mononuclear cells phagocytose Aβ, compared with aluminum hydroxide respectively DHPVHPDS-CRM197 conjugate binding.

第6C圖 表示具有協同效果之包含TLR4，但無水包油乳化劑或皂素，與KNDEGAP-KLH結合，在活體內周邊血液單核細胞吞噬Aβ情形，相較於氫氧化鋁分別與KNDEGAP-KLH共軛物結合。 Figure 6C shows a synergistic effect of TLR4, but no oil-in-water emulsifier or saponin, combined with KNDEGAP-KLH, in the peripheral blood mononuclear cells phagocytose Aβ in vivo, compared to aluminum hydroxide and KNDEGAP-KLH, respectively Conjugate binding.

實例Instance

材料及方法：擬抗原決定位-疫苗候選物之活體內特徵：共軛物生產：利用異雙功能性(heterobifunctional)之交聯劑(crosslinking agent)GMBS，使擬抗原決定位胜肽片段與攜帶蛋白CRM-197或KLH結合。簡言之，CRM-197/KLH與過量之GMBS於室溫下混合，以便活化，接著利用透析移除多餘之GMBS。過量之擬抗原決定位胜肽片段加入已活化之攜帶蛋白。擬抗原決定位CRM-197/KLH共軛物使用於疫苗製劑。 MATERIALS AND METHODS: In vivo features of the antigen-determinant-vaccine candidate: conjugate production: using a heterobifunctional cross-linking agent GMBS to enable the antigenic epitope peptide fragment to be carried Protein CRM-197 or KLH binds. Briefly, CRM-197/KLH was mixed with excess GMBS at room temperature for activation, followed by dialysis to remove excess GMBS. An excess of the antigenic epitope peptide is added to the activated carrier protein. The pseudo epitope CRM-197/KLH conjugate was used in a vaccine formulation.

利用不同之佐劑所製成之疫苗投予動物。每隻小鼠注射相同劑量之已共軛連結之擬抗原決定位胜肽片段，此時CRM-197/KLH疫苗相較於其他疫苗或相較於不同之佐劑。 Animals are administered with vaccines made with different adjuvants. Each mouse was injected with the same dose of the conjugated antigenic epitope peptide, at which point the CRM-197/KLH vaccine was compared to other vaccines or to different adjuvants.

動物實驗：Animal experiment:

雌性BALB/c小鼠，每組6隻，利用擬抗原決定位-CRM-197/KLH與不同佐劑共軛物，以接種小鼠。控制組使用CRM-197/KLH分別加上佐劑及/或PBS及/或單獨佐劑。 Female BALB/c mice, 6 in each group, were vaccinated with the antigen-determinant-CRM-197/KLH and different adjuvant conjugates. The control group used CRM-197/KLH plus adjuvant and/or PBS and/or separate adjuvant.

動物在固定時間間隔內(2週為一間隔)接種三次，且每次皆採取血漿樣本(接種前一天)。 Animals were inoculated three times at regular intervals (two weeks apart) and plasma samples were taken each time (one day prior to inoculation).

實例1：不同之佐劑系統對擬抗原決定位-CRM-197共軛物之效益：致免疫性(Immunogenicity)(第1圖)Example 1: Benefits of different adjuvant systems for the quasi-antigenic epitope-CRM-197 conjugate: Immunogenicity (Figure 1)

在許多平行的實驗中，雌性BALB/c小鼠重複性接種相同劑量之AFFITOPE胜肽(在此揭露之擬抗原決定位)，包含較佳為C或N端為半胱胺酸殘基，與CRM-197結合(每次接種10 μg胜肽)。不同之製劑使用相同共軛物之AFFITOPE，與合適之控制組比較(如：單獨PBS或單獨佐劑或CRM-197加上佐劑)。 In many parallel experiments, female BALB/c mice were repeatedly vaccinated with the same dose of AFFITOPE peptide (the antigenic epitope disclosed herein), preferably containing a C or N-terminal cysteine residue, CRM-197 binding (10 μg peptide per inoculation). Different formulations use the same conjugate of AFFITOPE compared to a suitable control group (eg, PBS alone or adjuvant alone or CRM-197 plus adjuvant).

下列之胜肽共軛物或共軛物之組合被使用於： The following peptide conjugates or combinations of conjugates are used in:

˙DQPVLPD結合於CRM197 ̇DQPVLPD is combined with CRM197

˙YDRPVQPDR結合於CRM197 ̇YDRPVQPDR is combined with CRM197

˙DHPVHPDS結合於CRM197 ̇DHPVHPDS combined with CRM197

˙KNDEGAP結合於CRM197 ̇KNDEGAP combined with CRM197

在本實例中，使用之佐劑為：氫氧化鋁、氫氧化鋁與TLR作用劑MPLA、鯊烯為基礎、水包油乳化劑(=Assavax)、含皂素之佐劑(=QuilA)。 In this example, the adjuvant used was: aluminum hydroxide, aluminum hydroxide and TLR agent MPLA, squalene based, oil-in-water emulsifier (=Assavax), saponin-containing adjuvant (=QuilA).

試管內ELISA分析決定抗體效價(titer)，接著加入每隻小鼠之血漿，進行免疫作用(參閱方法詳述於後)。 In vitro ELISA assays determine antibody titers, which are then added to the plasma of each mouse for immunization (see method for details).

胜肽片段ELISA：Peptide Fragment ELISA:

為了偵測已被接種動物之免疫反應而進行ELISA，從小鼠抽取周邊血液，並使用肝素(heparin)為抗凝劑，且血漿也從這些樣本製備而來。稀釋後之血漿使用ELISA分析。為此目的，ELISA盤(Nunc Maxisorb)上之孔洞(wells)覆蓋胜肽-牛血清白蛋白(BSA)共軛物。接著，加入稀釋後之血漿，加入生物素化之抗小鼠免疫球蛋白G(biotinylated anti-mouse IgG,Southern Biotech)抗體，接著利用鏈球菌卵白素-POD(Streptavidin-POD)及ABTS進行呈色反應，以偵測專一性抗體胜肽片段。 In order to detect the immune response of the vaccinated animals, ELISA was performed, peripheral blood was taken from the mice, and heparin was used as an anticoagulant, and plasma was also prepared from these samples. The diluted plasma was analyzed by ELISA. For this purpose, wells on ELISA plates (Nunc Maxisorb) cover the peptide-bovine serum albumin (BSA) conjugate. Next, the diluted plasma was added, biotinylated anti-mouse IgG (Southern Biotech) antibody was added, and then stained with Streptavidin-POD and ABTS. Reaction to detect specific antibody peptide fragments.

實例2：不同之佐劑系統對擬抗原決定位-KLH共軛物之效益：致免疫性(Immunogenicity)(第2圖)Example 2: Benefits of different adjuvant systems for the quasi-antigenic epitope-KLH conjugate: Immunogenicity (Fig. 2)

在許多平行的實驗中，雌性BALB/c小鼠重複性接種相同劑量之擬抗原決定位胜肽片段與KLH結合(如每次接種10μg胜肽)。利用相同之擬抗原決定位共軛物製成不同之製劑，與合適之控制組比較(如：單獨 PBS或單獨佐劑或KLH加上佐劑)。 In many parallel experiments, female BALB/c mice were repeatedly vaccinated with the same dose of the pseudo epitope determinant peptide to bind to KLH (eg, 10 [mu]g peptide per vaccination). Use the same pseudo-epitope conjugate to make different preparations, compare with the appropriate control group (eg: separate PBS or adjuvant alone or KLH plus adjuvant).

下列之胜肽共軛物或共軛物之組合被使用於： The following peptide conjugates or combinations of conjugates are used in:

˙DQPVLPD結合於KLH ̇DQPVLPD is combined with KLH

˙YDRPVQPDR結合於KLH ̇YDRPVQPDR is combined with KLH

˙DHPVHPDS結合於KLH ̇DHPVHPDS is combined with KLH

˙KNDEGAP結合於KLH ̇KNDEGAP combined with KLH

在本實例中，使用之佐劑為(同實例1)：氫氧化鋁、氫氧化鋁與TLR作用劑MPLA、Assavax及含QuilA。試管內ELISA分析決定抗體效價(titer)，接著加入每隻小鼠之血漿，進行免疫作用(參閱方法詳述於實例1)。 In this example, the adjuvant used was (same as Example 1): aluminum hydroxide, aluminum hydroxide and the TLR agent MPLA, Assavax and containing QuilA. In vitro ELISA assays determined antibody titers, followed by plasma from each mouse for immunization (see Method 1 for details).

實例3：不同之佐劑系統對擬抗原決定位-CRM-197共軛物之效益：周邊單核細胞/巨噬細胞之作用(第3圖)Example 3: Benefits of different adjuvant systems for the quasi-antigenic epitope-CRM-197 conjugate: the role of peripheral monocytes/macrophages (Fig. 3)

為了分析是否擬抗原決定位-CRM-197與相異於如前所述之佐劑佐劑化，其可改變細胞介素(cytokine)周圍環境，進而影響周邊單核細胞/巨噬細胞活化，係測定已知可活化單核細胞/巨噬細胞或顯示單核細胞/巨噬細胞之活性化(如CCL2/MCP1等)的細胞介素(cytokine)/化學增活素(Chemokines)之濃度。在注射不同之疫苗後2小時，測定血漿中細胞介素(cytokine)/化學增活素(Chemokines)之濃度。 In order to analyze whether the epitope-CRM-197 is different from the adjuvant adjuvant as described above, it can alter the surrounding environment of cytokine, thereby affecting peripheral monocyte/macrophage activation. The concentration of cytokine/Chemokines known to activate monocytes/macrophages or to demonstrate activation of monocytes/macrophages (eg, CCL2/MCP1, etc.). The concentration of cytokine/Chemokines in plasma was measured 2 hours after the injection of different vaccines.

細胞介素(cytokine)之測定：Determination of cytokine:

為了測定已接種疫苗動物中血液循環內之細胞介素(cytokine)之濃度，在動物施打疫苗2小時後收集血液。接著，從血液樣本中製造血漿，且每一樣本中細胞介素濃度使用FlowCytomix磁珠陣列系統(eBioscience)及流式細胞分析來偵測。 To determine the concentration of cytokine in the blood circulation in vaccinated animals, blood was collected 2 hours after the animals were vaccinated. Next, plasma was prepared from blood samples, and the interleukin concentration in each sample was detected using FlowCytomix Magnetic Bead Array System (eBioscience) and flow cytometry.

實例4：不同之佐劑系統對擬抗原決定位-KLH共軛物之效益：周邊單核細胞/巨噬細胞之作用(第4圖)Example 4: Benefits of Different Adjuvant Systems for Quasi-Antigenic Site-KLH Conjugates: Role of Peripheral Monocytes/Macrophages (Figure 4)

為了分析是否擬抗原決定位-CRM-197與相異於如前所述之佐劑佐劑化，其可改變細胞介素(cytokine)周圍環境，進而影響周邊單核細胞/巨噬細胞活化，係測定已知可活化單核細胞/巨噬細胞或顯示單核細胞/巨噬細胞之活性化(如CCL2/MCP1等)的細胞介素(cytokine)/化學增活素(Chemokines)之濃度。在注射不同之疫苗後2小時，測定血漿中細胞介素(cytokine)/化學增活素(Chemokines)之濃度。(詳細內容參閱實例3之方法)。 In order to analyze whether the epitope-CRM-197 is different from the adjuvant adjuvant as described above, it can alter the surrounding environment of cytokine, thereby affecting peripheral monocyte/macrophage activation. The concentration of cytokine/Chemokines known to activate monocytes/macrophages or to demonstrate activation of monocytes/macrophages (eg, CCL2/MCP1, etc.). The concentration of cytokine/Chemokines in plasma was measured 2 hours after the injection of different vaccines. (See the method of Example 3 for details).

實例5：單核細胞及巨噬細胞吞噬甲型共核蛋白之免疫治療效益(第5圖)Example 5: Immunotherapeutic benefits of monocyte and macrophage phagocytosis of alpha-nuclear protein (Figure 5)

新穎之疫苗製劑具有改變周邊CD11b+單核細胞數目之能力，且在活體內亦確認可改變單核細胞吞噬甲型共核蛋白。 Novel vaccine formulations have the ability to alter the number of peripheral CD11b+ monocytes, and are also confirmed in vivo to alter monocyte phagocytosis of the alpha-nuclear protein.

如前所述，單核細胞被認定為腦部小神經膠質之週邊血液前驅細胞(Rezaie,P.,et al 1999.Dev.Brain Res.115：71-81；Mildner et al Nat Neurosci.2007 Dec；10(12)：1544-53)。如CD11b及Ly6C標示物(marker)為免疫標示物(immunological marker)，其呈現於週邊血液單核細胞，且當這些細胞滲透入腦部時，亦續存。(Mildner et al.,2007,Lebson L,et al.J Neurosci.2010 Jul 21；30(29)：9651-8)。 As mentioned earlier, monocytes are identified as peripheral blood precursor cells of the brain microglia ( Rezaie, P., et al 1999. Dev. Brain Res. 115:71-81; Mildner et al Nat Neurosci. 2007 Dec ;10(12):1544-53). For example, CD11b and Ly6C markers are immunological markers that are present in peripheral blood mononuclear cells and also persist when these cells penetrate into the brain. (Mildner et al., 2007, Lebson L, et al. J Neurosci. 2010 Jul 21; 30(29): 9651-8).

為證明是否TLR作用劑包含佐劑或相關物質作用於改變周邊血液中之單核細胞，實施如前所述之共軛物製劑比較分析。 To demonstrate whether the TLR agent contains an adjuvant or related substance to act on monocytes that alter peripheral blood, a comparative analysis of the conjugate preparation as described above was carried out.

本結果再度證明擬抗原決定位-疫苗與一TLR作用劑作為佐劑之協同作用，可誘發免疫反應(抗體)。 This result reaffirms the synergistic effect of the pseudo epitope-vaccine and a TLR agent as an adjuvant to induce an immune response (antibody).

流式細胞儀分析：Flow cytometry analysis:

在分別注射最後一劑疫苗及抗體後24小時，從小鼠抽取周邊血液，並加予K2-EDTA抗凝劑。利用BD Pharm Lyse^TM(BD Pharmingen) 加入每一個動物樣本，以溶解紅血球。剩餘之週邊血液細胞與大鼠抗小鼠(Rat anti-Mouse)CD16/CD32(BD Biosciences之BD Fc Block^TM)抗體一起培養，細胞進一步與混合之直接結合抗體一同培養，如Mildner et al.,2007所述，或相似抗體：PE-共軛結合倉鼠抗-小鼠CD3，大鼠抗-小鼠CD45R/B220，大鼠抗-小鼠Ly-6G，小鼠抗-小鼠NK1.1；APC-共軛結合大鼠抗-小鼠CD11b；PE-Cy7-共軛結合倉鼠抗-小鼠CD11c，FITC-大鼠抗-小鼠Ly-6C及一合適的大鼠抗-小鼠CD62L(BD Biosciences)。 Peripheral blood was drawn from the mice 24 hours after the last dose of the vaccine and antibody, respectively, and K2-EDTA anticoagulant was added. Using BD Pharm Lyse ^TM (BD Pharmingen) was added to each sample of an animal, to dissolve erythrocytes. The remaining peripheral blood cells and rat anti-mouse (Rat anti-Mouse) CD16 / CD32 (BD Biosciences the BD Fc Block ^TM) incubated with antibodies, cells are further mixed with direct binding of the antibody with culture, as Mildner et al., 2007, or similar antibodies: PE-conjugated binding to hamster anti-mouse CD3, rat anti-mouse CD45R/B220, rat anti-mouse Ly-6G, mouse anti-mouse NK1.1; APC-conjugated binding to rat anti-mouse CD11b; PE-Cy7-conjugated to hamster anti-mouse CD11c, FITC-rat anti-mouse Ly-6C and a suitable rat anti-mouse CD62L ( BD Biosciences).

樣本由流式細胞儀分析(BD FACSCanto II)所收集及資料由FACSDiva軟體(BD Biosciences)分析，包含使用螢光通道之自動補償程式。 Samples were collected by flow cytometry analysis (BD FACSCanto II) and analyzed by FACSDiva software (BD Biosciences), including an automatic compensation program using a fluorescent channel.

單核細胞經由前向/側向分散器特性被辨識，收集到CD3-/CD45R/B220-/Ly-6G-/NK1.1-(Lineage-)/CD11b+細胞。CD11b+單核細胞經常被報導佔全部細胞的1百分比(排除碎片)。 Monocytes were identified via forward/lateral disperser characteristics and CD3-/CD45R/B220-/Ly-6G-/NK1.1-(Lineage-)/CD11b+ cells were harvested. CD11b+ monocytes are often reported to account for 1% of all cells (excluding debris).

甲型共核蛋白吞噬分析(第6圖)：為了證實周邊血液之單核細胞功能，測試這些單核細胞吞噬重組人類甲型共核蛋白的能力。使用螢光重組人類甲型共核蛋白(1-140；HiLyte Fluor^TM488標示，Anaspec Inc.)以測量吞噬的活性。 Phagocytosis analysis of alpha-nuclear proteins (Fig. 6): To demonstrate the monocyte function of peripheral blood, the ability of these monocytes to phagocytose recombinant human alpha-type nuclear proteins was tested. Using fluorescent recombinant human alpha-synuclein (1-140; HiLyte Fluor ^TM 488 Flag, Anaspec Inc.) to measure the activity of phagocytosis.

為了此分析，小鼠注射螢光重組人類甲型共核蛋白，注射後2小時抽取血液。由流式細胞儀測定樣品中甲型共核蛋白吞噬活性，且資料由FACSDiva軟體(BD Biosciences)分析。 For this analysis, mice were injected with fluorescent recombinant human alpha-nuclear protein and blood was drawn 2 hours after injection. The alpha-nuclear protein phagocytic activity in the samples was determined by flow cytometry and the data was analyzed by FACSDiva software (BD Biosciences).

單核細胞經由前向/側向分散器特性被辨識，排除碎片且收集到CD3-/CD45R/B220-/Ly-6G-/NK1.1-(Lineage-)/CD11b+細胞。利用全部所收集到之單核細胞中，偵測HiLyte fluor^TM 488甲型共核蛋白陽性細胞百分比分析而得甲型共核蛋白吞噬(Alpha synuclein uptake)。 Monocytes were identified via forward/lateral disperser characteristics, debris was removed and CD3-/CD45R/B220-/Ly-6G-/NK1.1-(Lineage-)/CD11b+ cells were harvested. Using all of the collected mononuclear cells, the detection of influenza HiLyte fluor ^TM 488 synuclein percentage of positive cells derived from alpha-synuclein phagocytosis analysis (Alpha synuclein uptake).

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<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 19 <400> 19

<210> 20 <210> 20

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 20 <400> 20

<210> 21 <210> 21

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 21 <400> 21

<210> 22 <210> 22

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 22 <400> 22

<210> 23 <210> 23

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 23 <400> 23

<210> 24 <210> 24

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 24 <400> 24

<210> 25 <210> 25

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 25 <400> 25

<210> 26 <210> 26

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 26 <400> 26

<210> 27 <210> 27

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 27 <400> 27

<210> 28 <210> 28

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 28 <400> 28

<210> 29 <210> 29

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 29 <400> 29

<210> 30 <210> 30

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 30 <400> 30

<210> 31 <210> 31

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 31 <400> 31

<210> 32 <210> 32

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 32 <400> 32

<210> 33 <210> 33

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 33 <400> 33

<210> 34 <210> 34

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 34 <400> 34

<210> 35 <210> 35

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 35 <400> 35

<210> 36 <210> 36

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 36 <400> 36

<210> 37 <210> 37

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 37 <400> 37

<210> 38 <210> 38

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 38 <400> 38

<210> 39 <210> 39

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 39 <400> 39

<210> 40 <210> 40

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 40 <400> 40

<210> 41 <210> 41

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 41 <400> 41

<210> 42 <210> 42

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 42 <400> 42

<210> 43 <210> 43

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 43 <400> 43

<210> 44 <210> 44

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 44 <400> 44

<210> 45 <210> 45

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 45 <400> 45

<210> 46 <210> 46

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 46 <400> 46

<210> 47 <210> 47

<211> 10 <211> 10

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 47 <400> 47

<210> 48 <210> 48

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 48 <400> 48

<210> 49 <210> 49

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 49 <400> 49

<210> 50 <210> 50

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 50 <400> 50

<210> 51 <210> 51

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 51 <400> 51

<210> 52 <210> 52

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 52 <400> 52

<210> 53 <210> 53

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 53 <400> 53

<210> 54 <210> 54

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 54 <400> 54

<210> 55 <210> 55

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 55 <400> 55

<210> 56 <210> 56

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列胜肽 <223> Artificial sequence peptide

<400> 56 <400> 56

<210> 57 <210> 57

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 共同序列 <223> Common sequence

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(任何胺基酸殘基)n，其中n=0或大於0之整數 <223> Xaa = (any amino acid residue) n, where n = 0 or an integer greater than 0

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (2)..(2) <222> (2)..(2)

<223> Xaa=一胺基酸殘基選自由天冬胺酸(aspartic acid,D)及麩胺酸(glutamic acid, E)所組成之群組 <223> Xaa = monoamino acid residue is selected from the group consisting of aspartic acid (D) and glutamic acid (glutamic acid, E) group

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (3)..(3) <222> (3)..(3)

<223> Xaa=任何胺基酸殘基 <223> Xaa = any amino acid residue

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (6)..(6) <222> (6)..(6)

<223> Xaa=任何胺基酸殘基 <223> Xaa = any amino acid residue

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (7)..(7) <222> (7)..(7)

<223> Xaa=一胺基酸殘基選自由脯胺酸(proline,P)及丙胺酸(alanine,A)所組成之群組 <223> Xaa=monoamino acid residue is selected from the group consisting of proline (P) and alanine (A)

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (8)..(8) <222> (8)..(8)

<223> Xaa=一胺基酸殘基選自由天冬胺酸(aspartic acid,D)及麩胺酸(glutamic acid, E)所組成之群組 <223> Xaa = monoamino acid residue is selected from the group consisting of aspartic acid (D) and glutamic acid (glutamic acid, E) group

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(任何胺基酸殘基)n，其中n=0或大於0之整數 <223> Xaa = (any amino acid residue) n, where n = 0 or an integer greater than 0

<400> 57 <400> 57

<210> 58 <210> 58

<211> 140 <211> 140

<212> PRT <212> PRT

<213> Homo sapiens <213> Homo sapiens

<400> 58 <400> 58

<210> 59 <210> 59

<211> 134 <211> 134

<212> PRT <212> PRT

<213> 人類 <213> Human

<400> 59 <400> 59

<210> 60 <210> 60

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人類甲型共核蛋白片段 <223> Human A-type nuclear protein fragment

<400> 60 <400> 60

<210> 61 <210> 61

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 61 <400> 61

<210> 62 <210> 62

<211> 10 <211> 10

<212> PRT <212> PRT

<213> 人工序列e <213> Artificial sequence e

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 62 <400> 62

<210> 63 <210> 63

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 63 <400> 63

<210> 64 <210> 64

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 64 <400> 64

<210> 65 <210> 65

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 65 <400> 65

<210> 66 <210> 66

<211> 6 <211> 6

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 66 <400> 66

<210> 67 <210> 67

<211> 10 <211> 10

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 67 <400> 67

<210> 68 <210> 68

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 68 <400> 68

<210> 69 <210> 69

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 69 <400> 69

<210> 70 <210> 70

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 70 <400> 70

<210> 71 <210> 71

<211> 6 <211> 6

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 71 <400> 71

<210> 72 <210> 72

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 72 <400> 72

<210> 73 <210> 73

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 73 <400> 73

<210> 74 <210> 74

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 74 <400> 74

<210> 75 <210> 75

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 75 <400> 75

<210> 76 <210> 76

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 76 <400> 76

<210> 77 <210> 77

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 77 <400> 77

<210> 78 <210> 78

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 78 <400> 78

<210> 79 <210> 79

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 79 <400> 79

<210> 80 <210> 80

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 80 <400> 80

<210> 81 <210> 81

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 81 <400> 81

<210> 82 <210> 82

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 82 <400> 82

<210> 83 <210> 83

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 83 <400> 83

<210> 84 <210> 84

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 84 <400> 84

<210> 85 <210> 85

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 85 <400> 85

<210> 86 <210> 86

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 86 <400> 86

<210> 87 <210> 87

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 87 <400> 87

<210> 88 <210> 88

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 88 <400> 88

<210> 89 <210> 89

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 89 <400> 89

<210> 90 <210> 90

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 90 <400> 90

<210> 91 <210> 91

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 91 <400> 91

<210> 92 <210> 92

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 92 <400> 92

<210> 93 <210> 93

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 93 <400> 93

<210> 94 <210> 94

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 94 <400> 94

<210> 95 <210> 95

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 95 <400> 95

<210> 96 <210> 96

<211> 13 <211> 13

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 96 <400> 96

<210> 97 <210> 97

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 97 <400> 97

<210> 98 <210> 98

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 98 <400> 98

<210> 99 <210> 99

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 99 <400> 99

<210> 100 <210> 100

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 100 <400> 100

<210> 101 <210> 101

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 101 <400> 101

<210> 102 <210> 102

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 102 <400> 102

<210> 103 <210> 103

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 103 <400> 103

<210> 104 <210> 104

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 104 <400> 104

<210> 105 <210> 105

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 105 <400> 105

<210> 106 <210> 106

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 106 <400> 106

<210> 107 <210> 107

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 107 <400> 107

<210> 108 <210> 108

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 108 <400> 108

<210> 109 <210> 109

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 109 <400> 109

<210> 110 <210> 110

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 110 <400> 110

<210> 111 <210> 111

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 111 <400> 111

<210> 112 <210> 112

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 112 <400> 112

<210> 113 <210> 113

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 113 <400> 113

<210> 114 <210> 114

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 114 <400> 114

<210> 115 <210> 115

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 115 <400> 115

<210> 116 <210> 116

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 116 <400> 116

<210> 117 <210> 117

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 117 <400> 117

<210> 118 <210> 118

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 118 <400> 118

<210> 119 <210> 119

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 119 <400> 119

<210> 120 <210> 120

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 120 <400> 120

<210> 121 <210> 121

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 121 <400> 121

<210> 122 <210> 122

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 122 <400> 122

<210> 123 <210> 123

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 123 <400> 123

<210> 124 <210> 124

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 124 <400> 124

<210> 125 <210> 125

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 125 <400> 125

<210> 126 <210> 126

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 126 <400> 126

<210> 127 <210> 127

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 127 <400> 127

<210> 128 <210> 128

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 128 <400> 128

<210> 129 <210> 129

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 129 <400> 129

<210> 130 <210> 130

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 130 <400> 130

<210> 131 <210> 131

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 131 <400> 131

<210> 132 <210> 132

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 132 <400> 132

<210> 133 <210> 133

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 133 <400> 133

<210> 134 <210> 134

<211> 8 <211> 8

<212> PRT <212> PRT

<212> 人工序列 <212> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<400> 134 <400> 134

<210> 135 <210> 135

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (2)..(2) <222> (2)..(2)

<223> Xaa係一胺基酸，選自由離胺酸(lysine,K)，精胺酸(arginine,R)， 丙胺酸(alanine,A)及組胺酸(histidine,H)所組成之群組 <223> Xaa is an amino acid selected from the group consisting of lysine (K) and arginine (R). a group consisting of alanine (A) and histidine (H)

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (3)..(3) <222> (3)..(3)

<223> Xaa係一胺基酸，選自由天冬醯胺酸(asparagine,N)，麩醯胺酸 (glutamine,Q)，絲胺酸(serine,S)，甘胺酸(glycine,G)及 丙胺酸(alanine,A)所組成之群組 <223> Xaa is an amino acid selected from asparagine (N), glutamic acid (glutamine, Q), serine (S), glycine (Glycine, G) and Group of alanine (A)

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (4)..(4) <222> (4)..(4)

<223> Xaa係一胺基酸，選自由 麩胺酸(glutamic acid,E)，天冬胺酸(aspartic acid,D)及丙胺酸 (alanine,A)所組成之群組 <223> Xaa is an amino acid selected from Glutamic acid (E), aspartic acid (D) and alanine Group of (alanine, A)

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (5)..(5) <222> (5)..(5)

<223> Xaa係一胺基酸殘基，選自由麩胺酸(glutamic acid,E)及天冬胺酸 (aspartic acid,D)所組成之群組 <223> Xaa is an amino acid residue selected from the group consisting of glutamic acid (E) and aspartic acid Group of (aspartic acid, D)

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (7)..(7) <222> (7)..(7)

<223> Xaa係一胺基酸殘基，選自由 丙胺酸(alanine,A)及酪胺酸(tyrosine,Y)所組成之群組 <223> Xaa is an amino acid residue selected from Group of alanine (A) and tyrosine (Y)

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 135 <400> 135

<210> 136 <210> 136

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 136 <400> 136

<210> 137 <210> 137

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列Sequence <213> Artificial Sequence Sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 137 <400> 137

<210> 138 <210> 138

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 138 <400> 138

<210> 139 <210> 139

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 139 <400> 139

<210> 140 <210> 140

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 140 <400> 140

<210> 141 <210> 141

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 141 <400> 141

<210> 142 <210> 142

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 142 <400> 142

<210> 143 <210> 143

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 143 <400> 143

<210> 144 <210> 144

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 144 <400> 144

<210> 145 <210> 145

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 145 <400> 145

<210> 146 <210> 146

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 146 <400> 146

<210> 147 <210> 147

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 147 <400> 147

<210> 148 <210> 148

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 148 <400> 148

<210> 149 <210> 149

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 149 <400> 149

<210> 150 <210> 150

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 150 <400> 150

<210> 151 <210> 151

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n,w其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n,w wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 151 <400> 151

<210> 152 <210> 152

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 152 <400> 152

<210> 153 <210> 153

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列Sequence <213> Artificial Sequence Sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 153 <400> 153

<210> 154 <210> 154

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 154 <400> 154

<210> 155 <210> 155

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 155 <400> 155

<210> 156 <210> 156

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 156 <400> 156

<210> 157 <210> 157

<211> 14 <211> 14

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任何胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> misc_feature <221> misc_feature

<222> (14)..(14) <222> (14)..(14)

<223> Xaa可為任何天然發生之胺基酸 <223> Xaa can be any naturally occurring amino acid

<400> 157 <400> 157

<210> 158 <210> 158

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 158 <400> 158

<210> 159 <210> 159

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 159 <400> 159

<210> 160 <210> 160

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 160 <400> 160

<210> 161 <210> 161

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 161 <400> 161

<210> 162 <210> 162

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 162 <400> 162

<210> 163 <210> 163

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 163 <400> 163

<210> 164 <210> 164

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 164 <400> 164

<210> 165 <210> 165

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 165 <400> 165

<210> 166 <210> 166

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 166 <400> 166

<210> 167 <210> 167

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 167 <400> 167

<210> 168 <210> 168

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 168 <400> 168

<210> 169 <210> 169

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 169 <400> 169

<210> 170 <210> 170

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 170 <400> 170

<210> 171 <210> 171

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 171 <400> 171

<210> 172 <210> 172

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 172 <400> 172

<210> 173 <210> 173

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 173 <400> 173

<210> 174 <210> 174

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 174 <400> 174

<210> 175 <210> 175

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 175 <400> 175

<210> 176 <210> 176

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 176 <400> 176

<210> 177 <210> 177

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 177 <400> 177

<210> 178 <210> 178

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 178 <400> 178

<210> 179 <210> 179

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 179 <400> 179

<210> 180 <210> 180

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 180 <400> 180

<210> 181 <210> 181

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 181 <400> 181

<210> 182 <210> 182

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 182 <400> 182

<210> 183 <210> 183

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 183 <400> 183

<210> 184 <210> 184

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 184 <400> 184

<210> 185 <210> 185

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 185 <400> 185

<210> 186 <210> 186

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 186 <400> 186

<210> 187 <210> 187

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 187 <400> 187

<210> 188 <210> 188

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 188 <400> 188

<210> 189 <210> 189

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 189 <400> 189

<210> 190 <210> 190

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 190 <400> 190

<210> 191 <210> 191

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 191 <400> 191

<210> 192 <210> 192

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 192 <400> 192

<210> 193 <210> 193

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 193 <400> 193

<210> 194 <210> 194

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 194 <400> 194

<210> 195 <210> 195

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 擬抗原決定位 <223> pseudo antigenic epitope

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (1)..(1) <222> (1)..(1)

<223> Xaa=(Xaa)n，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)n, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<220> <220>

<221> MISC_FEATURE <221> MISC_FEATURE

<222> (9)..(9) <222> (9)..(9)

<223> Xaa=(Xaa)m，其中Xaa係任一胺基酸殘基，較佳為 半胱胺酸(cysteine)，且n為0或大於0之整數，較佳為1或0 <223> Xaa=(Xaa)m, wherein Xaa is any amino acid residue, preferably Cysteine, and n is 0 or an integer greater than 0, preferably 1 or 0.

<400> 195 <400> 195

<210> 196 <210> 196

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人類甲型蛋白片段 <223> Human A-type protein fragment

<400> 196 <400> 196

Claims (16)

組成物包含一甲型共核蛋白抗原決定位之至少一擬抗原決定位，用於預防及/或治療共核蛋白病(synucleinopathies)之方法，其中，該至少一擬抗原決定位為結合或融合於醫藥學上可接受之攜帶蛋白，該攜帶蛋白選自由一無毒白喉毒素(non-toxic diphtheria toxin mutant)、血氰蛋白(keyhole limpet hemocyanin，簡稱KLH)、白喉毒素(diphtheria toxin，簡稱DT)、破傷風類毒素(tetanus toxid，簡稱TT)及流感嗜血桿菌共同蛋白D(Haemophilus influenzae protein D，簡稱protein D)所組成之群組。 The composition comprises at least one antigenic epitope of a alpha-nuclear protein epitope, for preventing and/or treating a method of synucleinopathies, wherein the at least one antigenic epitope is a binding or fusion a pharmaceutically acceptable carrier protein selected from the group consisting of a non-toxic diphtheria toxin mutant, a keyhole limpet hemocyanin (KLH), a diphtheria toxin (DT), A group consisting of tetanus toxin (TT) and Haemophilus influenzae protein D (protein D). 如申請專利範圍第1項所述之組成物，其中，該無毒白喉毒素(non-toxic diphtheria toxin mutant)係選自由CRM 197、CRM 176、CRM 228、CRM 45、CRM 9、CRM 102、CRM 103及CRM 107所組成之群組，特別是CRM 197。 The composition of claim 1, wherein the non-toxic diphtheria toxin mutant is selected from the group consisting of CRM 197, CRM 176, CRM 228, CRM 45, CRM 9, CRM 102, CRM 103 And a group of CRM 107, especially CRM 197. 如申請專利範圍第1或2項所述之組成物，其中，該至少一擬抗原決定位與至少一佐劑製成製劑。 The composition of claim 1 or 2, wherein the at least one antigenic epitope is formulated with at least one adjuvant. 如申請專利範圍第3項所述之組成物，其中，該至少一佐劑係刺激先天性免疫系統。 The composition of claim 3, wherein the at least one adjuvant stimulates the innate immune system. 如申請專利範圍第4項所述之組成物，其中，該至少一佐劑係刺激先天性免疫系統，包含或由一Toll-like接受體(TLR)作用劑所組成，較佳為一TLR1、TLR2、TLR3、TLR4、TLR5、TLR7、TLR8或TLR9作用劑，特別較佳為一TLR4作用劑。 The composition of claim 4, wherein the at least one adjuvant stimulates the innate immune system, comprises or consists of a Toll-like receptor (TLR) agent, preferably a TLR1. The TLR2, TLR3, TLR4, TLR5, TLR7, TLR8 or TLR9 agent is particularly preferably a TLR4 agent. 如申請專利範圍第5項所述之組成物，其中，該TLR作用劑係選自由單磷酸脂質A(monophosphoryl lipid A，MPL)、3-去-O-醯化單磷酸脂質A(3-de-O-acylated monophosphoryl lipid A，3D-MPL)、poly I：C、GLA、鞭毛蛋白(flagellin)、R848、imiquimod 及CpG所組成之群組。 The composition of claim 5, wherein the TLR agent is selected from the group consisting of monophosphoryl lipid A (MPL), 3-de-O-deuterated monophosphate lipid A (3-de) -O-acylated monophosphoryl lipid A, 3D-MPL), poly I: C, GLA, flagellin, R848, imiquimod And a group of CpGs. 如申請專利範圍第3至6項中任一項所述之組成物，其中，該至少一佐劑包含或由一皂素(saponin)，較佳為QS21，一油包水乳化劑(water in oil emulsion)及一微脂體(liposome)所組成。 The composition of any one of claims 3 to 6, wherein the at least one adjuvant comprises or consists of a saponin, preferably QS21, a water-in-oil emulsifier (water in Oil emulsion) and a liposome. 如申請專利範圍第3項所述之組成物，其中，該至少一佐劑選自由MF59、AS01、AS02、AS03、AS04、氫氧化鋁及磷酸鋁所組成之群組。 The composition of claim 3, wherein the at least one adjuvant is selected from the group consisting of MF59, AS01, AS02, AS03, AS04, aluminum hydroxide, and aluminum phosphate. 如申請專利範圍第1至8項中任一項所述之組成物，其中，該抗原決定位包含KNEEGAP或DMPVDPDN胺基酸序列。 The composition of any one of claims 1 to 8 wherein the epitope comprises a KNEEGAP or DMPVDPDN amino acid sequence. 如申請專利範圍第1至9項中任一項所述之組成物，其中，該至少一擬抗原決定位包含一胺基酸序列(X₁)_nX₂X₃X₄X₅GX₆P(X₇)_m (式I)，其中X₁ 為任何胺基酸殘基，X₂ 為一胺基酸殘基，選自由離胺酸(lysine，K)、精安酸(arginine，R)、丙胺酸(alanine，A)及組胺酸(histidine，H)所組成之群組，X₃ 為一胺基酸殘基，選自由天冬醯胺酸(asparagine，N)、麬醯胺酸(glutamine，Q)、絲胺酸(serine，S)、甘胺酸(glycine，G)及丙胺酸(alanine，A)所組成之群組，較佳為選自由天冬醯胺酸(asparagine，N)、絲胺酸(serine，S)、甘胺酸(glycine，G)及丙胺酸(alanine，A)所組成之群組， X₄ 為一胺基酸殘基，選自由麩胺酸(glutamic acid，E)、天冬胺酸(aspartic acid，D)及丙胺酸(alanine，A)所組成之群組，X₅為一胺基酸殘基，選自由麩胺酸(glutamic acid，E)及天冬胺酸(aspartic acid，D)所組成之群組，X₆ 為一胺基酸殘基，選自由丙胺酸(alanine，A)及酪胺酸(tyrosine，Y)所組成之群組，X₇為任何胺基酸殘基，n及m分別為0或大於0之整數，其中，式I之胺基酸序列並不完全相同於，或不包含甲型共核蛋白之7-基體(7-mer)多胜肽片段KNEEGAP，且其中該至少一擬抗原決定位(mimotope)包含式I之胺基酸序列具有與一抗體結合之能力，該抗體係對一甲型共核蛋白抗原決定位具專一性，包含該胺基酸序列KNEEGAP。 The composition according to any one of claims 1 to 9, wherein the at least one pseudo epitope comprises an amino acid sequence (X ₁ ) _n X ₂ X ₃ X ₄ X ₅ GX ₆ P (X ₇ ) _m (Formula I), wherein X ₁ is any amino acid residue and X ₂ is an amino acid residue selected from the group consisting of lysine (K) and arginine (R) a group consisting of alanine (A) and histidine (H), X ₃ is an amino acid residue selected from asparagine (N), proline a group consisting of (glutamine, Q), serine (S), glycine (G), and alanine (A), preferably selected from asparagine (asparagine, N), a group consisting of serine (S), glycine (G), and alanine (A), X ₄ is an amino acid residue selected from the group consisting of glutamic acid ( Glutamic acid, E), aspartic acid (D) and alanine (A), X ₅ is an amino acid residue selected from glutamic acid (E) ) and the group consisting of aspartic acid (aspartic acid, D), X 6 is an amino acid residue selected from By the alanine (alanine, A) groups, and tyrosine (tyrosine, Y) composed of, X ₇ is any amino acid residue, n and m are each an integer of 0 or greater than 0, the wherein Formula I The amino acid sequence is not identical to or does not comprise a 7-mer (7-mer) polypeptide fragment KNEEGAP of the alpha-nuclear protein, and wherein the at least one mitope comprises an amine of formula I The acid sequence has the ability to bind to an antibody that is specific for the alpha-nuclear epitope, including the amino acid sequence KNEEGAP. 如申請專利範圍第10項所述之組成物，其中，該擬抗原決定位包含一胺基酸序列，其選自由(X₁)_nKNDEGAP(X₇)_m、(X₁)_nANEEGAP(X₇)_m、(X₁)_nKAEEGAP(X₇)_m、(X₁)_nKNAEGAP(X₇)_m、(X₁)_nRNEEGAP(X₇)_m、(X₁)_nHNEEGAP(X₇)_m、(X₁)_nKNEDGAP(X₇)_m、(X₁)_nKQEEGAP(X₇)_m、(X₁)_nKSEEGAP(X₇)_m、(X₁)_nKNDDGAP(X₇)_m、(X₁)_nRNDEGAP(X₇)_m、(X₁)_nRNEDGAP(X₇)_m、(X₁)_nRQEEGAP(X₇)_m、(X₁)_nRSEEGAP(X₇)_m、(X₁)_nANDEGAP(X₇)_m、(X₁)_nANEDGAP(X₇)_m、(X₁)_nHSEEGAP(X₇)_m、(X₁)_nASEEGAP(X₇)_m、(X₁)_nHNEDGAP(X₇)_m、(X₁)_nHNDEGAP(X₇)_m、(X₁)_nRNAEGAP(X₇)_m、 (X₁)_nHNAEGAP(X₇)_m、(X₁)_nKSAEGAP(X₇)_m、(X₁)_nKSDEGAP(X₇)_m、(X₁)_nKSEDGAP(X₇)_m、(X₁)_nRQDEGAP(X₇)_m、(X₁)_nRQEDGAP(X₇)_m、(X₁)_nHSAEGAP(X₇)_m、(X₁)_nRSAEGAP(X₇)_m、(X₁)_nRSDEGAP(X₇)_m、(X₁)_nRSEDGAP(X₇)_m、(X₁)_nHSDEGAP(X₇)_m、(X₁)_nHSEDGAP(X₇)_m、(X₁)_nRQDDGAP(X₇)_m所組成之群組，較佳為(X₁)_nKNDEGAP(X₂)_m、(X₁)_nRNEEGAP(X₂)_m、(X₁)_nRNDEGAP(X₂)_m、(X₁)_nKNAEGAP(X₂)_m、(X₁)_nKSDEGAP(X₂)_m、(X₁)_nRNAEGAP(X₂)_m或(X₁)_nRSEEGAP(X₂)_m。 The composition of claim 10, wherein the pseudo epitope comprises an amino acid sequence selected from the group consisting of (X ₁ ) _n KNDEGAP(X ₇ ) _m , (X ₁ ) _n ANEEGAP (X) ₇ ) _m , (X ₁ ) _n KAEEGAP(X ₇ ) _m , (X ₁ ) _n KNAEGAP(X ₇ ) _m , (X ₁ ) _n RNEEGAP(X ₇ ) _m , (X ₁ ) _n HNEEGAP(X ₇ ) _m , (X ₁ ) _n KNEDGAP(X ₇ ) _m , (X ₁ ) _n KQEEGAP(X ₇ ) _m , (X ₁ ) _n KSEEGAP(X ₇ ) _m , (X ₁ ) _n KNDDGAP(X ₇ ) _m , (X ₁ ) _n RNDEGAP(X ₇ ) _m , (X ₁ ) _n RNEDGAP(X ₇ ) _m , (X ₁ ) _n RQEEGAP(X ₇ ) _m , (X ₁ ) _n RSEEGAP(X ₇ ) _m , (X ₁ ) _n ANDEGAP(X ₇ ) _m , (X ₁ ) _n ANEDGAP(X ₇ ) _m , (X ₁ ) _n HSEEGAP(X ₇ ) _m , (X ₁ ) _n ASEEGAP(X ₇ ) _m , (X ₁ ) _n HNEDGAP(X ₇ ) _m , (X ₁ ) _n HNDEGAP(X ₇ ) _m , (X ₁ ) _n RNAEGAP(X ₇ ) _m , (X ₁ ) _n HNAEGAP(X ₇ ) _m , (X ₁ ) _n KSAEGAP (X ₇ ) _m , (X ₁ ) _n KSDEGAP(X ₇ ) _m , (X ₁ ) _n KSEDGAP(X ₇ ) _m , (X ₁ ) _n RQDEGAP(X ₇ ) _m , (X ₁ ) _n RQEDGAP(X ₇ ) _m , (X ₁ ) _n HSAEGAP(X ₇ ) _m , (X ₁ ) _n RSAEGAP(X ₇ ) _m , (X ₁ ) _n RSDEGAP(X ₇ ) _m , (X ₁ ) _n RSEDGAP(X ₇ ) _m , (X ₁ ) _n HSD a group consisting of EGAP(X ₇ ) _m , (X ₁ ) _n HSEDGAP(X ₇ ) _m , (X ₁ ) _n RQDDGAP(X ₇ ) _m , preferably (X ₁ ) _n KNDEGAP(X ₂ ) _m , (X ₁ ) _n RNEEGAP(X ₂ ) _m , (X ₁ ) _n RNDEGAP(X ₂ ) _m , (X ₁ ) _n KNAEGAP(X ₂ ) _m , (X ₁ ) _n KSDEGAP(X ₂ ) _m , ( X ₁ ) _n RNAEGAP(X ₂ ) _m or (X ₁ ) _n RSEEGAP(X ₂ ) _m . 如申請專利範圍第1至11項中任一項所述之組成物，其中，該至少一擬抗原決定位包括一胺基酸序列，選自由(X₁)_nQASFAME(X₇)_m、(X₁)_nTASWKGE(X₇)_m、(X₁)_nQASSKLD(X₇)_m、(X₁)_nTPAWKGE(X₇)_m、(X₁)_nTPSWAGE(X₇)_m、(X₁)_nTPSWKGE(X₇)_m所組成之群組，其中，X₁為任一胺基酸殘基，X₇為任一胺基酸殘基，n及m分別為0或大於0之整數，上述之至少一擬抗原決定位(minotope)具有與一抗體結合之能力，該抗體係對一甲型共核蛋白抗原決定位具專一性，包含該胺基酸序列KNEEGAP使用於預防及/或治療共核蛋白病(synucleinopathies)。 The composition according to any one of claims 1 to 11, wherein the at least one pseudo epitope comprises an amino acid sequence selected from (X ₁ ) _n QASFAME (X ₇ ) _m , ( X ₁ ) _n TASWKGE(X ₇ ) _m , (X ₁ ) _n QASSKLD(X ₇ ) _m , (X ₁ ) _n TPAWKGE(X ₇ ) _m , (X ₁ ) _n TPSWAGE(X ₇ ) _m , (X _{1 n} TPSWKGE(X ₇ ) _m is a group wherein X ₁ is any amino acid residue, X ₇ is any amino acid residue, and n and m are each 0 or an integer greater than 0. The at least one minotope has the ability to bind to an antibody, and the anti-system has specificity for the alpha-nuclear protein epitope, and the amino acid sequence KNEEGAP is used for prevention and/or treatment. Synucleinopathies (synucleinopathies). 如申請專利範圍第1至12項中任一項所述之組成物，其中，該至少一擬抗原決定位包含該胺基酸序列 (X_1’)_n’X_2’X_3’PVX_4’X_5’X_6’(X_7’)_m’ (式II)，其中，X_1’ 為任何胺基酸殘基，X_2’ 為一胺基酸殘基，選自由天冬胺酸(aspartic acid，D)及麩胺酸(glutamic acid，E)所組成之群組，X_3’ 為任何胺基酸殘基，X_4’ 為任何胺基酸殘基，X_5’ 為一胺基酸殘基，選自由脯胺酸(proline，P)及丙胺酸(alanine，A)所組成之群組，X_6’ 為一胺基酸殘基，選自由天冬胺酸(aspartic acid，D)及麩胺酸(glutamic acid，E)所組成之群組，X_7’ 為任何胺基酸殘基，n’及m’分別為0或大於0之整數，其中，式II之胺基酸序列並不完全相同於，或不包含該甲型共核蛋白之8-基體(8-mer)多胜肽片段DMPVDPDN，且其中該至少一擬抗原決定位(mimotope)包含式II之胺基酸序列具有與一抗體結合之能力，該抗體係對一甲型共核蛋白抗原決定位具專一性，包含該胺基酸序列DMPVDPDN。 The composition of any one of claims 1 to 12, wherein the at least one quasi-antigenic epitope comprises the amino acid sequence (X _{1 '} ) _n' X _2' X _3' PVX _4' X _5' X _6' (X _7' ) _m' (Formula II), wherein X _{1 '} is any amino acid residue and X _{2 '} is an amino acid residue selected from aspartic acid (aspartic) Group of acid, D) and glutamic acid (E), X _{3 '} is any amino acid residue, X _{4 '} is any amino acid residue, and X _{5 '} is an amino acid a residue selected from the group consisting of proline (P) and alanine (A), X _{6 '} is an amino acid residue selected from aspartic acid (D) And a group consisting of glutamic acid (E), X _{7 '} is any amino acid residue, n ' and m ' are each an integer of 0 or greater than 0, wherein the amino acid sequence of formula II Is not identical to, or does not comprise, the 8-mer (8-mer) polypeptide fragment DMPVDPDN of the alpha-nuclear protein, and wherein the at least one mitope comprises an amino acid sequence of formula II Has the ability to bind to an antibody that determines the alpha-nuclear protein Specificity, including the amino acid sequence DMPVDPDN. 如申請專利範圍第3項所述之組成物，其中，擬抗原決定位具有一胺基酸序列，選自由(C)DQPVLPD、(C)DMPVLPD、(C)DSPVLPD、(C)DSPVWAE、(C)DTPVLAE、(C)DQPVLPDN、(C)DMPVLPDN、(C)DSPVLPDN、(C)DQPVTAEN、(C)DSPVWAEN、(C)DTPVLAEN、(C)HDRPVTPD、 (C)DRPVTPD、(C)DVPVLPD、(C)DTPVYPD、(C)DTPVIPD、(C)HDRPVTPDN、(C)DRPVTPDN、(C)DNPVHPEN、(C)DVPVLPDN、(C)DTPVYPDN、(C)DTPVIPDN、(C)DQPVLPDG、(C)DMPVLPDG、(C)DSPVLPDG、(C)DSPVWAEG、(C)DRPVAPEG、(C)DHPVHPDS、(C)DMPVSPDR、(C)DSPVPPDD、(C)DQPVYPDI、(C)DRPVYPDI、(C)DHPVTPDR、(C)EYPVYPES、(C)DTPVLPDS、(C)DMPVTPDT、(C)DAPVTPDT、(C)DSPVVPDN、(C)DLPVTPDR、(C)DSPVHPDT、(C)DAPVRPDS、(C)DMPVWPDG、(C)DAPVYPDG、(C)DRPVQPDR、(C)YDRPVQPDR、(C)DMPVDPEN、(C)DMPVDADN、DQPVLPD(C)、DMPVLPD(C)、(C)EMPVDPDN及(C)DNPVHPE所組成之群組。 The composition of claim 3, wherein the pseudo epitope has an amino acid sequence selected from the group consisting of (C) DQPVLPD, (C) DMVPLPD, (C) DSPVLPD, (C) DSPVWAE, (C) )DTPVLAE, (C)DQPVLPDN, (C)DMPVLPDN, (C)DSPVLPDN, (C)DQPVTAEN, (C)DSPVWAEN, (C)DTPVLAEN, (C)HDRPVTPD, (C) DRPVTPD, (C) DVPVLPD, (C) DTPVYPD, (C) DTPVIPD, (C) HDRPVTPDN, (C) DRPVTPDN, (C) DNPVHPEN, (C) DVPVLPDN, (C) DTPVYPDN, (C) DTPVIPDN, (C) DQPVLPDG, (C) DMPVLPDG, (C) DSPVLPDG, (C) DSPVWAEG, (C) DRPVAPEG, (C) DHPVHPDS, (C) DMPVSPDR, (C) DSPVPPDD, (C) DQPVYPDI, (C) DRPVYPDI, (C) DHPVTPDR, (C) EYPVYPES, (C) DTPVLPDS, (C) DMPVTPDT, (C) DAPVTPDT, (C) DSPVVPDN, (C) DLPVTPDR, (C) DSPVHPDT, (C) DAPVRPDS, (C) DMPVWPDG, (C) A group consisting of DAPVYPDG, (C) DRPVQPDR, (C) YDRPVQPDR, (C) DMPVDPEN, (C) DMPVDADN, DQPVLPD (C), DMVPLPD (C), (C) EMPVDPDN, and (C) DNPVHPE. 如申請專利範圍第10至14項中任一項所述之組成物，其特徵在於，n’及/或m’為1，及X_1’及/或X_7’為半胱胺酸(cysteine，C)。 The composition according to any one of claims 10 to 14, wherein n' and/or m' is 1, and X _{1 '} and/or X _{7 '} is cysteine (cysteine) , C). 如申請專利範圍第1至15項中任一項所述之組成物，其中，該至少一擬抗原決定位選自由DQPVLPD、DSPVLPD、DVPVLPD、DSPVLPDG、YDRPVQPDR、DHPVHPDS、DAPVRPDS、KNDEGAP、KQEEGAP及KSEEGAP所組成之群組，特別是選自由DQPVLPD及YDRPVQPDR所組成之群組。 The composition of any one of claims 1 to 15, wherein the at least one antigenic epitope is selected from the group consisting of DQPVLPD, DSPVLPD, DVPVLPD, DSPVLPDG, YDRPVQPDR, DHPVHPDS, DAPVRPDS, KNDEGAP, KQEEGAP, and KSEEGAP The group consisting, in particular, is selected from the group consisting of DQPVLPD and YDRPVQPDR.