CN1946424A - 真菌感染的治疗 - Google Patents
真菌感染的治疗 Download PDFInfo
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- CN1946424A CN1946424A CNA2005800127088A CN200580012708A CN1946424A CN 1946424 A CN1946424 A CN 1946424A CN A2005800127088 A CNA2005800127088 A CN A2005800127088A CN 200580012708 A CN200580012708 A CN 200580012708A CN 1946424 A CN1946424 A CN 1946424A
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- antibody
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- antifungal
- fab
- aspergillus
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Abstract
本发明提供了一种组合物,其包含特异于来自曲霉属(Aspergillusgenus)生物体的hsp90的至少一个表位的抗体或其抗原结合片段,以及至少一种选自伊曲康唑和伏立康唑的抗真菌剂。
Description
本发明涉及新的组合物和制剂,其包含有效的抗真菌剂以及可掺入所述组合物和制剂中的抗体。
真菌感染是重症监护病房中造成患者死亡的一个主要原因,且更常见于免疫缺陷和体弱患者(Gold,J.W.M.M.,1984,Am.J.Med.76:458-463;Klein,R.S.et al.,1984,N.Engl.J.Med.311:354-357;Burnie,J.P.,1997,Current Anaesthesia & Critical Care 8:180-183)。真菌感染的发生和持久性可归因于广谱抗真菌剂的选择压力、患者频繁长时间在医疗设施如重症监护病房中停留、在诊断感染中的问题、以及治疗中使用的抗真菌剂缺乏功效。虽然严格的卫生控制可在医院或其它环境中对真菌感染有一定程度的预防,但是感染爆发仍然是一个严重的问题,需要加以解决。
尽管真菌病的大多数临床表现主要是由烟曲霉(Aspergillusfumigatus)引起的,其它曲霉种如黄曲霉(A.flavas)、土曲霉(A.terreus)和黑曲霉(A.niger)也与免疫缺陷的宿主的急性感染有关(Espinel-Ingroff,A.,2003,J.Clin.Microbiol.41:403-409)。
检测和诊断造成感染的真菌病原体对于后续治疗是至关重要的,因为这样可以使抗真菌剂更有效地对抗某些菌株。GB2240979和EP0406029(在此通过引用将其全文合并入本发明中)公开了可用于检测真菌病原体的敏感性和高特异性检验中的真菌应激蛋白及其抗体。
传统上,采用抗真菌剂两性霉素B治疗由曲霉(Aspergillus)和假丝酵母(Candida)种引起的真菌感染,这被认为是全身性抗真菌治疗的“黄金标准”(Burnie,J.P.,1997,supra)。不过,两性霉素B自身是高毒性的,其使用受到副作用(包括寒战、发热、肌痛或血栓静脉炎)的影响。其它抗真菌剂包括口服唑类药物(霉康唑、酮康唑、伊曲康唑、氟康唑、伏立康唑)和5-氟胞嘧啶。然而,许多真菌变得对抗真菌剂如氟康唑具有抗性,而且这些真菌经常出现在预防性施用该药的患者中。尽管最近在治疗药物(如氟康唑、伊曲康唑以及基于脂质体的两性霉素B的全身性施用的变体)上取得了进展(Burnie,J.P.,1997,supra),为了应对耐抗真菌剂菌株日益盛行,对用于治疗真菌感染的有效试剂的需求仍很迫切。
上述需求在WO 01/76627中得以解决,该发明公开了一种用于治疗人或动物真菌感染的组合物。该组合物包含一种特异于真菌应激蛋白hsp90的一个保守表位的抗体,该抗体与已知的多烯抗真菌剂特别是两性霉素B组合在一起。特别地,该抗体(在下文中称为Mycograb(RTM))识别具有SEQ ID NO:1的序列的肽所展示的表位,该表位在许多真菌种中都是保守的。令人惊讶地,当该抗体存在时,两性霉素B抗各种病理上重要的真菌菌株(如假丝酵母种)的功效得到显著增强,从而允许使用更低的治疗剂量或使得使用相同剂量时的治疗更有效,进而减少不需要的副作用。此外,WO 01/76627中公开的组合物使得能对该组合物中使用的抗真菌剂天然耐药的真菌感染进行有效治疗。
重要的是,氟康唑(一种口服唑类抗真菌剂)与Mycograb(RTM)抗体的组合对假丝酵母菌株几乎没有协同作用。
所有唑类抗真菌剂都通过共同的作用模式起作用,即通过抑制依赖真菌细胞色素P450的酶羊毛固醇14-α-脱甲基酶来阻止真菌质膜上主要的固醇成分-麦角固醇的合成。结果,麦角固醇的消耗和伴随的14-α-甲基化前体的蓄积影响了真菌膜上麦角固醇的大量功能,并同时改变了膜的流动性和一些膜结合酶的活性。最终的净效应是抑制真菌生长和复制(Maertens,J.A.,2004,Clin.Microbiiol.Infect.10(Suppl.1):1-10)。
由于氟康唑与Mycograb(RTM)抗体的组合对假丝酵母菌株几乎没有协同作用,且口服唑类抗真菌剂的作用模式是共同的,那么其它口服唑类抗真菌剂例如霉康唑、酮康唑、伊曲康唑和伏立康唑与Mycograb(RTM)抗体的组合也将显示出没有协同作用,这是合乎逻辑的。
本发明人现已发现,尽管先前发现在治疗由曲霉或假丝酵母菌株引起的感染时唑类抗真菌剂与WO 01/76627中公开的Mycograb(RTM)组合表现出很小的协同作用或无协同作用,口服唑类抗真菌剂伊曲康唑和伏立康唑与Mycograb(RTM)抗体组合却存在治疗性协同作用。下面的试验表明了这种协同作用目前为止仅限于伊曲康唑和伏立康唑,不过其它未被检测或正在开发的口服唑类抗真菌剂也可能表现出与Mycograb(RTM)抗体的某些协同作用。
本发明提供了一种组合物,其包含特异于来自曲霉属(Aspergillusgenus)生物体的hsp90的至少一个表位的抗体或其抗原结合片段,以及至少一种选自伊曲康唑和伏立康唑的抗真菌剂。
本发明还提供了一种组合制剂例如一种药物包装,其包含特异于来自曲霉属生物体的hsp90的至少一个表位的抗体或其抗原结合片段,以及至少一种选自伊曲康唑和伏立康唑的抗真菌剂,以同时、单独或顺序用于治疗真菌感染。
本发明还提供了一种制备用于治疗人或动物体的真菌感染的药物的方法,其特征在于使用特异于来自曲霉属生物体的hsp90的至少一个表位的抗体或其抗原结合片段,以及至少一种选自伊曲康唑和伏立康唑的抗真菌剂。
本发明还提供了一种组合物在制备用于治疗真菌感染的药物中的应用,所述组合物包含特异于来自曲霉属生物体的hsp90的至少一个表位的抗体或其抗原结合片段,以及包含至少一种选自伊曲康唑和伏立康唑的抗真菌剂。
初步结果也表明泼康唑能取得相似的协同结果,因此本发明还延伸到泼康唑和特异于来自曲霉属生物体的hsp90的至少一个表位的抗体或其抗原结合片段的组合物、组合制剂、制备方法及应用。
所述抗体或其抗原结合片段可以特异于由包含SEQ ID NO:1的序列的肽展示的表位。
所述抗体或其抗原结合片段可以特异于由包含SEQ ID NO:2的序列的肽展示的表位。
对于抗体,其制备和应用众所周知,并公开于例如Harlow,E.andLane,D.,Antibodies:A Laboratory Manual,Cold Spring HarborLaboratory Press,Cold Spring Harbor,New York,1999。
可以利用本领域中已知的标准方法产生抗体。抗体的例子包括(但不限于)多克隆、单克隆、嵌合、单链、Fab片段、Fab表达文库生产的片段和抗体的抗原结合片段。
可以在一定范围内的宿主中生产抗体,例如山羊、兔、大鼠、小鼠、人和其它宿主。可通过注射真菌应激蛋白或其任何具有免疫原性特性的片段或寡肽对这些宿主进行免疫接种。根据宿主的物种,可利用不同的佐剂来增强免疫反应。这种佐剂包括但不限于弗氏佐剂、矿物凝胶如氢氧化铝、以及表面活性物质如溶血卵磷脂、多聚醇、聚阴离子、肽、油乳剂、匙孔血蓝蛋白和二硝基苯酚。在用于人的佐剂中,BCG(卡介苗)和小棒状杆菌菌苗尤其有用。
真菌应激蛋白或其任何片段或寡肽的单克隆抗体可通过培养传代细胞系生产抗体分子的任何技术加以制备。这些技术包括,但不限于,杂交瘤技术、人B细胞杂交瘤技术以及EBV-杂交瘤技术(Koehleret al.,1975,Nature,256:495-497;Kosber et al.,1983,Immunol.Today4:72;Cote et al.,1983,PNAS USA,80:2026-2030;Cole et al.,1985,Monoclonal Antibodies and Cancer Therapy,Alan R.Liss Inc.,New York,pp.77-96)。
此外,也可使用被开发用于制备“嵌合抗体”的技术,即将小鼠抗体基因拼接到人抗体基因上以获得一种具有适当的抗原特异性和生物学活性的分子(Morrison et al.,1984,PNAS USA,81:6851-6855;Neuberger et al.,1984,Nature,312:604-608;Takeda et al.,1985,Nature,314:452-454)。或者,可采用被描述用以生产单链抗体的技术,即利用本领域中已知的方法生产真菌应激蛋白特异性单链抗体。可以从随机组合的免疫球蛋白文库通过链改组生产具有相关特异性,但属于不同的独特型组合的抗体(Burton,D.R.,1991,PNAS USA,88:11120-11123)。
还可以通过体内诱导生产在淋巴细胞群中生产抗体或通过筛选重组免疫球蛋白文库或高特异性结合试剂板生产抗体(Orlandi et al.,1989,PNAS USA,86:3833-3837;Winter,G.et al.,1991,Nature,349:293-299)。
也可以产生抗原结合片段,例如F(ab’)2片段可通过胃蛋白酶消化抗体分子生产,Fab片段可通过还原F(ab’)2片段的二硫键产生。或者,可以构建Fab表达文库以快速和简单地鉴定具有所需特异性的单克隆Fab片段(Huse et al.,1989,Science,256:1275-1281)。
可以将各种免疫测定用于筛选以鉴定具有所需特异性的抗体。利用具有确定的特异性的多克隆或单克隆抗体进行竞争结合或放射免疫分析的许多方案在本领域中众所周知。这种免疫测定典型地包括对真菌应激蛋白或其任何片段或寡肽与其特异抗体之间复合体形成的测量。可以使用利用特异于互不干扰的两种真菌应激蛋白表位的单克隆抗体的基于单克隆的双位免疫测定方法,除此还可以使用竞争性结合测定(Maddox et al.,1983,J.Exp.Med.,158:1211-1216)。
例如,在所述组合物或组合制剂中使用的抗体可以包含SEQ IDNO:3的序列。
所述组合物或组合制剂可用于治疗真菌感染。该真菌感染可以是由曲霉属的生物体引起的。
所述真菌感染可以对所述抗真菌剂本身是具有抗性的。
所述组合物或组合制剂可用于治疗人或动物体的真菌感染的方法中。
所述组合物或制剂可以额外地包含一种药学上可接受的载体、稀释剂或赋形剂。同样,本发明的任何制备方法或相同方式的应用也包括药学上可接受的载体、稀释剂或赋形剂的使用。药学上可接受的载体、稀释剂和赋形剂的例子为本领域技术人员所熟知,例如参见Remington′s Pharmaceutical Sciences和US Pharmacopoeia(1984,MackPublishing Company,Easton,PA,USA)。
本发明还提供了一种治疗人和动物体的真菌感染的方法,该方法包括给有需要的患者施用治疗有效量的特异于来自曲霉属生物体的hsp90的至少一个表位的抗体或其抗原结合片段,以及至少一种选自伊曲康唑和伏立康唑的抗真菌剂。
所述组合物或组合制剂可口服施用。
本发明还提供了一种试剂盒,其包含特异于来自曲霉属生物体的hsp90的至少一个表位的抗体或其抗原结合片段,以及至少一种选自伊曲康唑和伏立康唑的抗真菌剂。
所述试剂盒可用于真菌感染的治疗。
可以用可检测标签对本发明的抗体或抗原结合片段进行标记,或者可以利用传统方法将其与效应分子(例如药物如抗真菌剂(如伊曲康唑或伏立康唑)、或毒素如篦麻毒素、或酶)缀合,因此本发明还延伸至这种被标记的抗体或抗体缀合物。
如需要,可将抗体混合物用于诊断或治疗,例如根据本发明的识别真菌应激蛋白的不同表位的两种或多种抗体的混合物,和/或不同类抗体的混合物(例如识别本发明的相同或不同表位的IgG和IgM抗体的混合物)。
本申请中讨论的各参考文献的内容,包括其中引用的参考文献,在此通过引用将其整体合并到本发明中。
通过以下描述本发明将更为清楚,以下描述只是通过实施例的方式对所述组合物的特定的具体实施方式及相关的试验进行说明。
实施例
下面描述的试验研究了结合抗真菌剂两性霉素B、卡泊芬净、伊曲康唑和伏立康唑使用的Mycograb(RTM)抗体的抗真菌效果。Mycograb(RTM)抗体识别具有SEQ ID Nos:1和2的序列的肽所展示的表位。结果表明,伏立康唑和伊曲康唑与Mycograb(RTM)抗体组合被证明对多种临床上重要的曲霉种表现出令人惊讶的强烈的协同效应。这一协同效应对于真菌感染的临床治疗具有重要启示。
材料与方法
抗真菌剂
根据国家委员会临床实验室标准(M38-A)在含有谷氨酰胺肉汤培养基的RPMI 1640中制备两性霉素B储存液(AMB,Sigma),卡泊芬净(Caspo)、伏立康唑(VOR)和伊曲康唑(ITZ),并用0.165mmol/L的吗啉代丙烷磺酸(MOPS)将pH值调至7.0。在100%二甲基亚砜(DMSO)中制备100倍(100×series)的AMB储存液,并将其稀释在介质中至0.03125-16μg/ml的浓度范围。在0.03125-1024μg/ml的浓度范围检测卡泊芬净、伏立康唑和伊曲康唑,在0.25-1024μg/ml的浓度范围检测Mycograb(RTM)(NeuTec Pharmaplc)。
测试分离株
烟曲霉(2)、黄曲霉(1)、土曲霉(1)和黑曲霉(1)的临床分离株获自英国曼彻斯特皇家医院微生物部(Department onMicrobiology,Manchester Royal Infirmary,Manchester,UK)。
抗体
对特异于具有SEQ ID NO:1的序列的真菌hsp90应激蛋白表位的Mycograb(RTM)抗体的DNA序列(如GB2240979和EP0406029中所公开)通过密码子优化进行遗传修饰用于在大肠杆菌(Escherichia coli)(Operon Technologies Inc.,Alameda,CA,USA)中表达,并将其插入大肠杆菌表达载体。本发明的Mycograb(RTM)的氨基酸序列包含SEQ ID NO:3的序列(包括重链、轻链和间隔结构域)。
在大肠杆菌宿主中表达Mycograb(RTM),并采用标准分子生物学方案(参见例如Harlow & Lane,supra;Sambrook,J.et al.,1989,Molecular Cloning:A Laboratory Manual,2nd Edition,Cold SpringHarbor Laboratory Press,Cold Spring Harbor,New York;Sambrook,J.&Russell,D.,2001,Molecular Cloning:A Laboratory Manual,3rd Edition,Cold Spring Harbor Laboratory Press,Cold Spring Harbor)通过使用咪唑交换柱的亲和层析进行纯化。将Mycograb(RTM)抗体分离至95%的纯度。
按照如下制备Mycograb(RTM)抗体的配制剂:将一支10mg纯Mycograb(RTM)抗体、150mg药用级(Ph Eur)尿素和174mg L-精氨酸(Ph Eur)在5mL水中进行重构。
Mycograb(RTM)抗体与曲霉种hsp90的交叉反应性
先前,已经将免疫印迹用以检测患有过敏性支气管肺曲霉病、曲霉肿及侵入性曲霉病患者体内对烟曲霉的抗体应答。该被鉴定的多抗原的分子量在18-92kDa范围变化。基于其与Mycograb(RTM)抗体的交叉反应,一个88kDa的抗原被鉴定为hsp90的同系物(Burnie.J.P.和R.C.Matthews.1991.J.Clin.Microbiol.29:2099-106)。表位作图已揭示Mycograb(RTM)抗体对具有SEQ ID NO:2的序列的肽所展示的表位具有反应性,该序列在烟曲霉和黑曲霉中都是保守的。
抗真菌易感性测试
根据国家委员会临床实验室标准文件M38-A,通过肉汤微稀释法对两性霉素B,卡泊芬净、伏立康唑和伊曲康唑、以及Mycograb(RTM)抗体的最小抑制浓度(MIC)进行测定。简言之,通过MIC终点和棋盘式滴定对AMB(0.03125-16μg/ml)、卡泊芬净、伏立康唑和伊曲康唑(0.03125-1024μg/ml)以及Mycograb(RTM)(0.25-1024μg/ml)的浓度进行单独和组合测定。通过从培养了7天的沙氏平板探测菌落,在具有谷氨酸酰胺的缓冲RPMI培养基中制备接种物悬浮液。将该悬浮液调节至适于曲霉的0.09-0.11(80%-82%的透光率)、0.15-0.17(68%-70%的透光率)。当被添加至试验中的抗真菌剂时,接种物进一步进行1∶2稀释(接种物终浓度(0.4×104-0.5×104))。对于AMB和Mycograb(RTM),单独地或组合在一起,其终点以其浓度下不再有生长加以确定(MIC-0)。将微量滴定板在不搅拌的情况下,于37℃温育48小时以培养曲霉种。对于卡泊芬净、伏立康唑和伊曲康唑,单独地或与Mycograb(RTM)抗体组合,将相对于生长对照组导致混浊度显著下降(≥50%的生长抑制,MIC-2)的浓度确定为MIC终点(Keele et al.2001;Espinel-ingroff2003)。用存在第二种药物时的MIC除以不存在第二种药物时的MIC计算每种药物的最终抑制浓度(FIC)。对于每种组合,产生两个级分,求和得到分级最终抑制浓度。将≤0.5的值定义为协同,将>0.5至<4.0之间的值定义为无差异,将≥4.0的值定义为拮抗作用(Matthews et al.,2003)。
结果
除识别由具有SEQ ID NO:1的序列的肽所展示的表位之外,Mycograb(RTM)抗体还能识别具有SEQ ID NO:2的序列的肽所展示的保守的曲霉种表位。
检测Mycograb(RTM)抗体与抗真菌剂组合的效果的体外试验如表1-4所示。
表1两性霉素B和Mycograb(RTM)抗体抗曲霉种的棋盘式滴定
菌株 | 试剂 | 每种试剂的MIC-0(μg/ml) | FIC(μg/ml) | FICI | 结果 | |
单独 | 组合 | |||||
烟曲霉烟曲霉CI2黑曲霉黄曲霉土曲霉 | AMBMycograbAMBMycograbAMBMycograbAMBMycograbAMBMycograb | 25122512251245124512 | 141161445124512 | 0.50.010.50.0310.50.011111 | 0.50.5310.522 | 无差异无差异无差异无差异无差异 |
表2卡泊芬净和Mycograb(RTM)抗体抗曲霉种的棋盘式滴定
菌株 | 试剂 | 每种试剂的MIC-2(μg/ml) | FIC(μg/ml) | FICI | 结果 | |
单独 | 组合 | |||||
烟曲霉烟曲霉CI2黑曲霉黄曲霉土曲霉 | CaspoMycograbCaspoMycograbCaspoMycograbCaspoMycograbCaspoMycograb | 0.12510240.1251024125615120.31251024 | 0.0625320.0625160.1250.06250.50.06250.07832 | 0.50.0620.50.0620.1250.00010.50.00010.250.031 | 0.5620.5620.1250.5000.312 | 无差异无差异协同无差异协同 |
表3伊曲康唑和Mycograb(RTM)抗体抗曲霉种的棋盘试式滴定
菌株 | 试剂 | 每种试剂的MIC-2(μg/ml) | FIC(μg/ml) | FICI | 结果 | |
单独 | 组合 | |||||
烟曲霉烟曲霉CI2黑曲霉黄曲霉土曲霉 | ITZMycograbITZMycograbITZMycograbITZMycograbITZMycograb | 0.510240.510240.125160.1255120.1251024 | 0.0312160.12580.015640.03120.250.031232 | 0.06250.0160.250.0080.1250.250.250.00050.250.031 | 0.07810.25780.3750.250.281 | 协同协同协同协同协同 |
表4伏立康唑和Mycograb(RTM)抗体抗曲霉种的棋盘式滴定
菌株 | 试剂 | 每种试剂的MIC-2(μg/ml) | FIC(μg/ml) | FICI | 结果 | |
单独 | 组合 | |||||
烟曲霉烟曲霉CI2黑曲霉黄曲霉土曲霉 | VORMycograbVORMycograbVORMycograbVORMycograbVORMycograb | 0.062510240.2510240.125160.255120.251024 | 0.03120.250.1250.250.125160.06250.250.1250.25 | 0.50.00020.50.0002110.250.00050.50.0002 | 0.50.520.250.5 | 协同协同无差异协同协同 |
总结
表1-4所示的结果表明,尽管Mycograb(RTM)抗体自身能够抑制某些曲霉生长,但是当该抗体与伊曲康唑联合使用时观察到其对所有检测菌种都表现出令人惊讶的高水平抗真菌活性,当该抗体与伏立康唑联合使用时观察到其对除黑曲霉外的所有检测菌种都表现出令人惊讶的高水平抗真菌活性。当其它口服唑类抗真菌剂(例如氟康唑、两性霉素B或卡泊芬净)与所述抗体结合时,并没有观察到该抗体与伊曲康唑/伏立康唑之间这一令人惊讶的协同作用。
结论
本发明的数据清晰地表明,Mycograb(RTM)抗体与抗真菌剂伊曲康唑和伏立康唑之间存在着令人惊讶的协同作用,该效应增强了对多种病理上重要的曲霉菌株的抗真菌活性。这些使得可以将包含伊曲康唑和伏立康唑中的任一种,以及Mycograb(RTM)抗体的组合物用于治疗人或动物真菌感染。本发明允许使用更低的治疗剂量或使得使用相同剂量时的治疗更有效,进而减少不需要的副作用。
本发明具有一些重要的临床应用。第一,伊曲康唑/伏立康唑和Mycograb(RTM)抗体协同性组合产品可成为治疗曲霉感染的选择。该将减少这些感染的死亡率和发病率。第二,伊曲康唑/伏立康唑与受药对象中的不需要的副作用有关。例如,伏立康唑十分常见地与发热、头痛、腹痛、恶心、呕吐、腹泻、外周水肿、皮疹以及视觉障碍有关。本发明所提供的所述协同作用意味着可以使用更低剂量的伊曲康唑或伏立康唑并同时保持药效,并伴随着毒性和副作用的减少。第三,鉴于Mycograb(RTM)抗体具有降低毒性的效应,因此可以探究更高剂量的伊曲康唑/伏立康唑的临床疗效,从而进一步改善临床效果。
序列表
<110>纽泰克医药有限公司
<120>真菌感染的治疗
<130>GDM/JAR-MP101019-UK
<160>3
<170>PatentIn version 3.2
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Claims (19)
1、一种组合物,其包含特异于来自曲霉属(Aspergillus genus)生物体的hsp90的至少一个表位的抗体或其抗原结合片段,以及至少一种选自伊曲康唑和伏立康唑的抗真菌剂。
2、一种组合制剂,其包含特异于来自曲霉属生物体的hsp90的至少一个表位的抗体或其抗原结合片段,以及至少一种选自伊曲康唑和伏立康唑的抗真菌剂,以同时、单独或顺序用于治疗真菌感染。
3、根据权利要求1的组合物或根据权利要求2的组合制剂,其中所述抗体或其抗原结合片段特异于具有SEQ ID NO:1的序列的肽所展示的表位。
4、根据权利要求1或3的组合物,或根据权利要求2或3的组合制剂,其中所述抗体或其抗原结合片段特异于具有SEQ ID NO:2的序列的肽所展示的表位。
5、根据权利要求3或4的组合物或组合制剂,其中所述抗体包含SEQ ID NO:3的序列。
6、根据权利要求1或3-5中任一项的组合物或者根据权利要求2-5中任一项的组合制剂,用于治疗真菌感染。
7、根据权利要求6的组合物或组合制剂,其中所述真菌感染由曲霉属生物体引起。
8、根据权利要求5或6的组合物或组合制剂,其中所述真菌感染对所述抗真菌剂本身具有抗性。
9、根据权利要求1或3-8中任一项的组合物或者根据权利要求2-8中任一项的组合制剂,用于治疗人或动物体的真菌感染的方法中。
10、一种制备用于治疗人或动物体的真菌感染的药物的方法,其特征在于使用特异于来自曲霉属生物体的hsp90的至少一个表位的抗体或其抗原结合片段,以及至少一种选自伊曲康唑和伏立康唑的抗真菌剂。
11、一种组合物在制备用于治疗真菌感染的药物的方法中的应用,所述组合物包含特异于来自曲霉属生物体的hsp90的至少一个表位的抗体或其抗原结合片段,以及包含至少一种选自伊曲康唑和伏立康唑的抗真菌剂的抗真菌剂。
12、根据权利要求11的组合物的应用,其中所述真菌感染对所述抗真菌剂本身具有抗性。
13、一种治疗人或动物体的真菌感染的方法,该方法包括给有需要的患者施用治疗有效量的根据权利要求1或3-8中任一项的组合物,或根据权利要求2-8中任一项的组合制剂。
14、根据权利要求13的方法,其中所述组合物或组合制剂经口服施用。
15、一种试剂盒,其包含特异于来自曲霉属生物体的hsp90的至少一个表位的抗体或其抗原结合片段,以及至少一种选自伊曲康唑和伏立康唑的抗真菌剂。
16、根据权利要求15的试剂盒,用于治疗真菌感染。
17、根据权利要求1或3-8中任一项的组合物,或根据权利要求2-8中任一项的组合制剂,其中所述抗体或抗原结合片段标记有可检测标签。
18、根据权利要求1或3-8中任一项的组合物,或根据权利要求2-8中任一项的组合制剂,其中所述抗体或抗原结合片段与效应分子相缀合。
19、在实施例中充分描述的发明。
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CN111116743A (zh) * | 2018-10-30 | 2020-05-08 | 迈威(上海)生物科技有限公司 | Hsp90抗体及其在抗真菌感染中的应用 |
CN113845591A (zh) * | 2018-10-30 | 2021-12-28 | 迈威(上海)生物科技股份有限公司 | Hsp90抗体及其在抗真菌感染中的应用 |
CN111116743B (zh) * | 2018-10-30 | 2022-01-28 | 迈威(上海)生物科技股份有限公司 | Hsp90抗体及其在抗真菌感染中的应用 |
CN113845591B (zh) * | 2018-10-30 | 2023-10-31 | 迈威(上海)生物科技股份有限公司 | Hsp90抗体及其在抗真菌感染中的应用 |
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