CN111491944A - 促转导素-d-改良的基因转移增强剂 - Google Patents
促转导素-d-改良的基因转移增强剂 Download PDFInfo
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- CN111491944A CN111491944A CN201880070990.2A CN201880070990A CN111491944A CN 111491944 A CN111491944 A CN 111491944A CN 201880070990 A CN201880070990 A CN 201880070990A CN 111491944 A CN111491944 A CN 111491944A
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Abstract
本发明涉及具有序列Z1‑Gln‑Ala‑Lys‑Ile‑Lys‑Gln‑Ile‑Ile‑Asn‑Met‑Trp‑Gln‑Z2的多肽。该多肽用于逆转录病毒转染/转导。
Description
本申请涉及改进的基因转移增强剂(即促转导素D(PTD-D),其是对转导增强剂PTD-A和PTD-B的改进),并且涉及其多肽,并且涉及其N末端保护的多肽,并且涉及包含所述多肽的药物,并且涉及所述多肽在基因治疗中的应用,并且涉及用于增强基因工程病毒构建体对细胞的感染的方法以及所述多肽用于转染或转导扩增的用途。
自克隆第一个人类基因并重组生产以来,用于改变特定细胞功能的遗传物质的引入已成为生物医学基础和应用研究中必不可少的工具。基因导入方法不断进步,促使基因转移的优化。
对转导增强剂的开发研究使得促转导素-A被发现,这是一种来自HIV病毒包膜蛋白的肽。令人惊讶的是,它适合于以前所未有的程度提高基因材料进入核内的慢病毒转导(Yolamanova等人,自然·纳米技术)。因此,可以证明,例如,与金标准“重组人纤维蛋白片段(retroectin)”相比,以不同浓度(1-100μg/ml)的促转导素-A(同义词:EF-C)预温育的HIV对报告细胞的感染率增加了十的几次方倍。作为作用机理,假定EF-C形成能够结合和浓缩病毒并因此放大病毒进入细胞的纤维结构。除感染病毒颗粒外,EF-C还可以在基因治疗中广泛应用的多种人类细胞类型(T细胞、胶质细胞、成纤维细胞、造血干细胞)中高效增强慢病毒和逆转录病毒颗粒的转导(Jan Münch等人,自然·纳米技术,第8卷,第2期,第130-136页)。EP 2452947A1也涉及促转导素A。
半胱氨酸属于极性中性氨基酸。此外,由于其独特的功能性硫醇基团,因此半胱氨酸是一种从未被考虑过修饰或甚至被另一种氨基酸,尤其是来自另一组氨基酸的取代的氨基酸。像Cys一样,Tyr、Asp、Ser、Gly、Gln、Thr是一部分极性但中性的氨基酸。但是,本领域技术人员会回避用其他组的氨基酸取代,因为这种取代对通过交换修饰的肽的二级结构的影响是难以预见的。因此,本领域技术人员不会考虑用非极性疏水性氨基酸组中的氨基酸取代促转导素的Cys。
然而,现在令人惊讶地发现,促转导素中的氨基酸Cys可以被丙氨酸取代,而不会导致修饰的多肽作为转导增强剂的有效性发生显著变化。
根据本发明,提供了一种修饰的促转导素,其一方面具有与PTD-A作为转导增强剂相当的功效,还具有更高的储存稳定性,并且确保了在其作为转导增强剂的应用中的操作更简单,这是GMP生产中的巨大优势。
本发明的多肽与如下序列具有至少80%或90%的序列同一性,尤其是95%的序列同一性
Z1-Gln-Ala-Lys-Ile-Lys-Gln-Ile-Ile-Asn-Met-Trp-Gln-Z2。
Z1彼此独立地是多肽的N末端,或彼此独立地是氨基酸Leu或Ser,或以下肽:
Ser-Asn、Ser-Asn-Asn、Ser-Asn-Asn-Ile、Ser-Asn-Asn-Ile-Thr、Thr-Leu、Ile-Thr-Leu、Asn-Ile-Thr-Leu、Asn-Asn-Ile-Thr-Leu、或Ser-Asn-Asn-Ile-Thr-Leu,
Z2彼此独立地为多肽的C末端,或彼此独立地为氨基酸Gly或Glu或以下肽:
Glu-Val、Glu-Val-Gly、Glu-Val-Gly-Lys、Glu-Val-Gly-Lys-Ala、Glu-Val-Gly-Lys-Ala-Met、Glu-Val-Gly-Lys-Ala-Met-Tyr、Glu-Val-Gly-Lys-Ala-Met-Tyr-Ala、Glu-Val-Gly-Lys-Ala-Met-Tyr-Ala-Pro、Glu-Val-Gly-Lys-Ala-Met-Tyr-Ala-Pro-Pro、Glu-Val-Gly-Lys-Ala-Met-Tyr-Ala-Pro-Pro-Ile、Glu-Val-Gly-Lys-Ala-Met-Tyr-Ala-Pro-Pro-Ile-Glu、Glu-Val-Gly-Lys-Ala-Met-Tyr-Ala-Pro-Pro-Ile-Glu-Gly、Glu-Gly、Ile-Glu-Gly、Pro-Ile-Glu-Gly、Pro-Pro-Ile-Glu-Gly、Ala-Pro-Pro-Ile-Glu-Gly、Tyr-Ala-Pro-Pro-Ile-Glu-Gly、Met-Tyr-Ala-Pro-Pro-Ile-Glu-Gly、Ala-Met-Tyr-Ala-Pro-Pro-Ile-Glu-Gly、Lys-Ala-Met-Tyr-Ala-Pro-Pro-Ile-Glu-Gly、Gly-Lys-Ala-Met-Tyr-Ala-Pro-Pro-Ile-Glu-Gly、Val-Gly-Lys-Ala-Met-Tyr-Ala-Pro-Pro-Ile-Glu-Gly、或Glu-Val-Gly-Lys-Ala-Met-Tyr-Ala-Pro-Pro-Ile-Glu-Gly。
通过本发明的多肽可以实现的提高涉及转导增强剂的增加的稳定性,其可以用于治疗用途。用于治疗应用的细胞中有效的基因转导可以减少例如用于基因转导的病毒颗粒的所需量。此外,可以减少有效转导所需的感染周期数。通过使用本发明的多肽作为转导增强剂,可以减少用于增殖基因修饰的细胞的体外培养的持续时间和要从患者中去除的细胞的量(例如,通过血细胞去除术),并且在某些情况下,可以通过减少体内病毒载量来实现有效且无毒的体内基因转导。此外,高效的转导增强剂的快速处理可减少待转导细胞的负荷。
由于其提高的稳定性,即使在物质的长时间储存之后,本发明的多肽也可以更好地预测转导增强剂的有效性。
由于其更高的稳定性,与PTD-A相比,本发明的多肽还可生产更大的肽批次,其可以被存储更长的时间。与PTD-A相比,本发明的多肽的反应性较低,使其具有较低的细胞毒活性。在转导中,这使得转导细胞具有更高产量。
具体地,本发明涉及与如下序列具有至少80%序列同一性,尤其是90%序列同一性的多肽
Gln-Ala-Lys-Ile-Lys-Gln-Ile-Ile-Asn-Met-Trp-Gln。
根据本发明,术语“本发明的多肽”还包括通过改变本发明的多肽的多肽链中的氨基酸而形成的,但是仍然具有相当的且足够的效力的那些相关多肽,其可以例如,在以下生物测定中确定。
可以例如通过使用富含原代活化的CD4+/CD8+的T细胞来测试转导效率,原代活化的CD4+/CD8+的T细胞与作为靶细胞的CD3/CD28珠子、以及编码绿色荧光蛋白(GFP)的慢病毒和逆转录病毒载体培养3天。可以例如针对作为转导增强剂的金标准的PTD-A和Retronectin测试PTD-D。
在测定中采用例如25μg/ml的PTD-A和PTD-D。靶细胞以特别是103至106细胞/ml的浓度使用。将混合物孵育8至16小时,然后洗涤细胞。然后,将细胞培养例如另外4天。然后,在第7天,通过流动离心确定GFP+T细胞的比例,并确定细胞计数和活力。
具体地,同源肽是与本发明的多肽的序列有关的多肽,其中氨基酸的替换或缺失以所述程度进行。具体地,可以交换具有相似性质,例如相似极性的氨基酸。因此,广泛存在精氨酸和赖氨酸,谷氨酸和天冬氨酸,谷氨酰胺、天冬酰胺和苏氨酸,甘氨酸、丙氨酸和脯氨酸,亮氨酸、异亮氨酸和缬氨酸,酪氨酸、苯丙氨酸和色氨酸以及丝氨酸和苏氨酸的交换。
在序列的位置1,优选氨基酸谷氨酰胺。在位置3和5,优选碱性氨基酸,优选赖氨酸。在1、4、6、7、8、9、10、11和12位上,大多数是中性氨基酸。该序列可以在N末端和/或C末端被延伸或截短。单体的序列可以在N-末端,由C-末端部分或整个氨基酸序列NH 2-Ser-Asn-Asn-Ile-Thr-Leu-COOH延伸。单体的序列可在C-末端,由N-末端部分或整个氨基酸序列NH2-Glu-Val-Gly-Lys-Ala-Met-Tyr-Ala-Pro-Pro-Ile-Glu-Gly-COOH延伸。本发明的多肽具有在水溶液中形成不溶性聚集体的共同特性。单体由4至25个氨基酸组成,优选由10至20个氨基酸组成。
此外,同源分子具有在水溶液中形成不溶性聚集物并增强慢病毒或逆转录病毒载体对靶细胞的转导的共同特性。
在本发明的一个实施方式中,构成本发明多肽的氨基酸链的N-末端被选自下组的化学基团修饰:一个或两个烷基,例如甲基、乙基、丙基或丁基,酰基,例如乙酰基或丙酰基,或氨基酸焦谷氨酸,其形成N末端。
本发明还涉及包含至少一种本发明的多肽的药物。
本发明还涉及多肽在用于治疗可通过基因治疗而治疗的疾病的基因治疗中的应用。
本发明还涉及增强病毒对细胞的感染的方法,包括以下步骤:
-提供溶解在有机溶剂中的权利要求1或2的多肽;
-将多肽添加到水溶液中以形成所述多肽的不溶性聚集体;
-混合前一步骤的溶液;和
-在至少一种本发明的多肽的存在下培养细胞。
本发明还涉及至少一种本发明的多肽在增强病毒对细胞的感染中的用途。
本发明还涉及包含至少一种本发明的多肽的试剂盒。
本发明的肽可以例如通过根据梅里菲尔德(Merrifield)的方法用Fmoc保护的氨基酸来制备。
该方法可根据梅里菲尔德(Merrifield)原理,在逐步固相合成中,用Fmoc保护的衍生物,即(9-芴基甲氧基羰基)保护的氨基酸,特别是在预装有Fmoc-L-谷氨酰胺(0.59mmol/g,例如100-200目)的Wang树脂上,作为合成器ABI-433的固体载体。
Fmoc-L-氨基酸的活化通常以十倍摩尔过量使用,它常温下在N-甲基-2-吡咯烷酮(NMP)中添加0.5M 1-羟基苯并三唑(HOBt)和2M二异丙基乙胺(DIEA)的[(2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸盐]进行。
各个酰化反应需要45分钟,而用20%哌啶进行Fmoc脱保护则需要15分钟。
下列氨基酸衍生物和相关的正交酸可裂解的侧链保护基团用于合成:
Fmoc-L-Asn(Trt)、Fmoc-L-Ala(Trt)、L-pGlu、Fmoc-L-Gln(Trt)、Fmoc-L-Ile、Fmoc-L-Lys(Boc)、Fmoc-L-Met和Fmoc-L-Trp(Boc)。
用94%的三氟乙酸(TFA)、3%的乙二硫醇(EDT)和3%的软化水从肽基树脂上裂解树脂载体后,将粗肽沉淀在冷的甲基叔丁基醚中,然后将粗肽离心分离为沉淀,弃去上清液。
粗肽的后续色谱纯化通过梯度洗脱的制备方法进行。
EP 2452947A1的促转导素A与促转导素D之间的差异在于,本发明的促转导素D被Cys2/丙氨酸取代。WO 2014/177635A1的促转导素B和促转导素D之间的差异在于,本发明的促转导素D被Cys2/丙氨酸取代,并且合成的L-焦谷氨酸(pGlu)插入N端,以换成合成的L-谷氨酰胺(Gln)。原始的谷氨酰胺通过闭环修饰而形成内酰胺。
实施例:
对激活的CD3+T细胞的转导效率进行检测。针对不同的对照和重组人纤维蛋白片段测试了五个不同的PTD批次。
为了进行转导,使用了冷冻保存的富含CD4+/CD8+的T细胞。将它们解冻,并与CD3/CD28珠一起培养3天。3天后除去珠子后,用GFP载体转导T细胞,该GFP载体是通过生产细胞系HG820#4E912#4.3获得的。使用了两种不同的MOI。然后将细胞再培养4天。在第7天,使用Nucleo计数器NC-200确定细胞计数和细胞活力。通过流动离心测定GFP+T细胞的比例。
预刺激,去除小珠,转导,扩增
在第0天,使用血液加温仪(Barkey Plasmatherm device)解冻CD4+/CD8+T细胞,并用1×PBS洗涤一次。通过添加细胞培养基无血清培养基(X-vivo)15+2mM谷氨酰胺(Glutamax)+5%CTS的“免疫细胞血清替换”使细胞以1×106个活细胞/ml的密度重悬,并加入的450IU/ml IL-7和50IU/ml IL-15。为了激活细胞,每个细胞添加3(三)个CD3/CD28磁珠,并培养至第3天。
在第3天,用来自艾本德的混匀小精灵(MixMate)和来自巴克斯特的MaxSep磁体除去珠。离心浓缩后,用浓度为MOI 2或MOI 4的GFP载体转导细胞。作为对照,用重组人纤维连接片段和病毒进行转导而无添加。非转导的对照用作阴性对照。
将不同的促转导素肽溶解在DMSO中至10mg/ml(原液)。将原液用1×PBS稀释至1mg/ml的浓度,并孵育至少10分钟,以便可以形成PTD原纤维。将病毒上清液与培养基和血清替代物混合以获得所需浓度。随后,添加不同的PTD,以获得50μg/ml的浓度。将混合物在室温温育最少5分钟。温育后,加入细胞,从而获得5×105细胞/ml的细胞密度和25μl/ml的最终PTD浓度。将细胞在6孔板中于37℃、5%CO2和高湿度下孵育16+/-4小时,直到第4天。
在第4天,测定细胞计数和活力,与先前的类似物相比,在PTD中产生改善的结果。将细胞转移到装有5ml细胞培养基的T-25培养瓶中,并在37℃、5%CO2和高湿度下孵育。
在第5天,加入10ml的新鲜细胞培养基。
在第7天,确定每个培养瓶的培养基的体积。随后,通过FACS分析确定细胞计数、活力和转导率。
测定细胞计数和活力
通过使用一次性Via1盒子的NucleoCounter NC-200测定细胞计数和活力。
通过流式细胞仪测定GFP的表达
GFP+T细胞(CD3+)的数量通过FACSVerse流式细胞仪测定。为了进行测定,用1×PBS洗涤1.5×106个活细胞。离心后,将细胞沉淀溶于300μl 1×PBS和3μl FVS780溶液中。每次测试,将两个FACS管染色:
管1:未染色的GFP/FVS 780/BV421(CD3-BV421的FMO对照)
管2:GFP/FVS 780/CD3-BV421[5μl]
对于每个管,添加1×106个细胞,并在室温下在黑暗中孵育15分钟。温育后,将细胞与染色缓冲液BSA混合,并离心。随后,将细胞溶解到350μl染色缓冲液BSA中,并在180分钟内通过流式细胞仪进行分析。为了计算T-25培养瓶中GFP+细胞的绝对数量,将结果相对于未转导的对照进行了校正。
序列表
<110> 法瑞斯生物技术有限公司
<120> 促转导素-D-改良的基因转移增强剂
<130> 182448WO
<150> EP17188384.6
<151> 2017-08-29
<160> 26
<170> SIPOSequenceListing 1.0
<210> 1
<211> 12
<212> PRT
<213> 智人(Homo sapiens)
<400> 1
Gln Ala Lys Ile Lys Gln Ile Ile Asn Met Trp Gln
1 5 10
<210> 2
<211> 4
<212> PRT
<213> 智人(Homo sapiens)
<400> 2
Ser Asn Asn Ile
1
<210> 3
<211> 5
<212> PRT
<213> 智人(Homo sapiens)
<400> 3
Ser Asn Asn Ile Thr
1 5
<210> 4
<211> 4
<212> PRT
<213> 智人(Homo sapiens)
<400> 4
Asn Ile Thr Leu
1
<210> 5
<211> 5
<212> PRT
<213> 智人(Homo sapiens)
<400> 5
Asn Asn Ile Thr Leu
1 5
<210> 6
<211> 6
<212> PRT
<213> 智人(Homo sapiens)
<400> 6
Ser Asn Asn Ile Thr Leu
1 5
<210> 7
<211> 4
<212> PRT
<213> 智人(Homo sapiens)
<400> 7
Glu Val Gly Lys
1
<210> 8
<211> 5
<212> PRT
<213> 智人(Homo sapiens)
<400> 8
Glu Val Gly Lys Ala
1 5
<210> 9
<211> 6
<212> PRT
<213> 智人(Homo sapiens)
<400> 9
Glu Val Gly Lys Ala Met
1 5
<210> 10
<211> 7
<212> PRT
<213> 智人(Homo sapiens)
<400> 10
Glu Val Gly Lys Ala Met Tyr
1 5
<210> 11
<211> 8
<212> PRT
<213> 智人(Homo sapiens)
<400> 11
Glu Val Gly Lys Ala Met Tyr Ala
1 5
<210> 12
<211> 9
<212> PRT
<213> 智人(Homo sapiens)
<400> 12
Glu Val Gly Lys Ala Met Tyr Ala Pro
1 5
<210> 13
<211> 10
<212> PRT
<213> 智人(Homo sapiens)
<400> 13
Glu Val Gly Lys Ala Met Tyr Ala Pro Pro
1 5 10
<210> 14
<211> 11
<212> PRT
<213> 智人(Homo sapiens)
<400> 14
Glu Val Gly Lys Ala Met Tyr Ala Pro Pro Ile
1 5 10
<210> 15
<211> 12
<212> PRT
<213> 智人(Homo sapiens)
<400> 15
Glu Val Gly Lys Ala Met Tyr Ala Pro Pro Ile Glu
1 5 10
<210> 16
<211> 13
<212> PRT
<213> 智人(Homo sapiens)
<400> 16
Glu Val Gly Lys Ala Met Tyr Ala Pro Pro Ile Glu Gly
1 5 10
<210> 17
<211> 4
<212> PRT
<213> 智人(Homo sapiens)
<400> 17
Pro Ile Glu Gly
1
<210> 18
<211> 5
<212> PRT
<213> 智人(Homo sapiens)
<400> 18
Pro Pro Ile Glu Gly
1 5
<210> 19
<211> 6
<212> PRT
<213> 智人(Homo sapiens)
<400> 19
Ala Pro Pro Ile Glu Gly
1 5
<210> 20
<211> 7
<212> PRT
<213> 智人(Homo sapiens)
<400> 20
Tyr Ala Pro Pro Ile Glu Gly
1 5
<210> 21
<211> 8
<212> PRT
<213> 智人(Homo sapiens)
<400> 21
Met Tyr Ala Pro Pro Ile Glu Gly
1 5
<210> 22
<211> 9
<212> PRT
<213> 智人(Homo sapiens)
<400> 22
Ala Met Tyr Ala Pro Pro Ile Glu Gly
1 5
<210> 23
<211> 10
<212> PRT
<213> 智人(Homo sapiens)
<400> 23
Lys Ala Met Tyr Ala Pro Pro Ile Glu Gly
1 5 10
<210> 24
<211> 11
<212> PRT
<213> 智人(Homo sapiens)
<400> 24
Gly Lys Ala Met Tyr Ala Pro Pro Ile Glu Gly
1 5 10
<210> 25
<211> 12
<212> PRT
<213> 智人(Homo sapiens)
<400> 25
Val Gly Lys Ala Met Tyr Ala Pro Pro Ile Glu Gly
1 5 10
<210> 26
<211> 13
<212> PRT
<213> 智人(Homo sapiens)
<400> 26
Glu Val Gly Lys Ala Met Tyr Ala Pro Pro Ile Glu Gly
1 5 10
Claims (8)
1.一种多肽,其特征在于,与如下序列具有至少80%或90%序列同一性,尤其是95%序列同一性
Z1-Gln-Ala-Lys-Ile-Lys-Gln-Ile-Ile-Asn-Met-Trp-Gln-Z2,
其中,
Z1代表多肽的N末端,或彼此独立的是氨基酸Leu或Ser,或以下肽:
Ser-Asn、Ser-Asn-Asn、Ser-Asn-Asn-Ile、Ser-Asn-Asn-Ile-Thr、Thr-Leu、Ile-Thr-Leu、Asn-Ile-Thr-Leu、Asn-Asn-Ile-Thr-Leu、或Ser-Asn-Asn-Ile-Thr-Leu,
Z2代表多肽的C末端,或彼此独立地是氨基酸Gly或Glu或以下肽:
Glu-Val、Glu-Val-Gly、Glu-Val-Gly-Lys、Glu-Val-Gly-Lys-Ala、Glu-Val-Gly-Lys-Ala-Met、Glu-Val-Gly-Lys-Ala-Met-Tyr、Glu-Val-Gly-Lys-Ala-Met-Tyr-Ala、Glu-Val-Gly-Lys-Ala-Met-Tyr-Ala-Pro、Glu-Val-Gly-Lys-Ala-Met-Tyr-Ala-Pro-Pro、Glu-Val-Gly-Lys-Ala-Met-Tyr-Ala-Pro-Pro-Ile、Glu-Val-Gly-Lys-Ala-Met-Tyr-Ala-Pro-Pro-Ile-Glu、Glu-Val-Gly-Lys-Ala-Met-Tyr-Ala-Pro-Pro-Ile-Glu-Gly、Glu-Gly、Ile-Glu-Gly、Pro-Ile-Glu-Gly、Pro-Pro-Ile-Glu-Gly、Ala-Pro-Pro-Ile-Glu-Gly、Tyr-Ala-Pro-Pro-Ile-Glu-Gly、Met-Tyr-Ala-Pro-Pro-Ile-Glu-Gly、Ala-Met-Tyr-Ala-Pro-Pro-Ile-Glu-Gly、Lys-Ala-Met-Tyr-Ala-Pro-Pro-Ile-Glu-Gly、Gly-Lys-Ala-Met-Tyr-Ala-Pro-Pro-Ile-Glu-Gly、Val-Gly-Lys-Ala-Met-Tyr-Ala Pro-Pro-Ile-Glu-Gly或Glu-Val-Gly-Lys-Ala-Met-Tyr-Ala-Pro-Pro-Ile-Glu-Gly。
2.如权利要求1所述的多肽,其特征在于,与如下序列具有至少90%的序列同一性,尤其是95%的同源性,
Gln-Ala-Lys-Ile-Lys-Gln-Ile-Ile-Asn-Met-Trp-Gln。
3.如权利要求1或2中的至少一项所述的多肽,其特征在于,所述N末端被选自下组的化学基团修饰形成N-末端:一个或两个烷基,例如甲基、乙基、丙基或丁基,酰基,例如乙酰基或丙酰基,或氨基酸焦谷氨酸。
4.一种药物,其特征在于,包含如权利要求1至3中至少一项所述的多肽。
5.如权利要求1-4中至少一项所述的多肽在用于治疗可通过基因治疗而治疗的疾病的基因治疗中的应用。
6.一种增强病毒感染细胞的方法,其特征在于,包括以下步骤:
-提供溶解在有机溶剂中的如权利要求1-5中至少一项所述的多肽;
-将所述多肽添加到水溶液中以形成多肽的不溶性聚集体;
-混合前一步骤的溶液;和
-在如权利要求1-3中至少一项所述的多肽的存在下培养细胞。
7.如权利要求1至6中至少一项所述的多肽在增强病毒对细胞的感染中的用途。
8.一种试剂盒,其特征在于,包含如权利要求1至7中至少一项所述的多肽。
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EP17188384.6 | 2017-08-29 | ||
EP17188384 | 2017-08-29 | ||
PCT/EP2018/073194 WO2019043037A1 (de) | 2017-08-29 | 2018-08-29 | Protransduzin-d - verbesserter enhancer des gentransfers |
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CN111491944A true CN111491944A (zh) | 2020-08-04 |
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US (1) | US20210154327A1 (zh) |
EP (1) | EP3676286A1 (zh) |
KR (1) | KR20200038532A (zh) |
CN (1) | CN111491944A (zh) |
AU (1) | AU2018326439A1 (zh) |
CA (1) | CA3080076A1 (zh) |
WO (1) | WO2019043037A1 (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1310626A (zh) * | 1998-05-20 | 2001-08-29 | 特莱默里斯公司 | 具有增强药物动力特性的杂合肽 |
EP2452947A1 (en) * | 2010-11-16 | 2012-05-16 | Münch, Jan | Viral infection enhancing peptide |
CN105209480A (zh) * | 2013-05-02 | 2015-12-30 | 法瑞斯生物技术有限公司 | 促转导素B(Protransduzin B)-基因转移的增强剂 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US6656906B1 (en) * | 1998-05-20 | 2003-12-02 | Trimeris, Inc. | Hybrid polypeptides with enhanced pharmacokinetic properties |
-
2018
- 2018-08-29 CA CA3080076A patent/CA3080076A1/en not_active Abandoned
- 2018-08-29 EP EP18769599.4A patent/EP3676286A1/de not_active Withdrawn
- 2018-08-29 AU AU2018326439A patent/AU2018326439A1/en not_active Abandoned
- 2018-08-29 US US16/641,841 patent/US20210154327A1/en not_active Abandoned
- 2018-08-29 CN CN201880070990.2A patent/CN111491944A/zh active Pending
- 2018-08-29 KR KR1020207007923A patent/KR20200038532A/ko not_active Application Discontinuation
- 2018-08-29 WO PCT/EP2018/073194 patent/WO2019043037A1/de unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1310626A (zh) * | 1998-05-20 | 2001-08-29 | 特莱默里斯公司 | 具有增强药物动力特性的杂合肽 |
EP2452947A1 (en) * | 2010-11-16 | 2012-05-16 | Münch, Jan | Viral infection enhancing peptide |
CN105209480A (zh) * | 2013-05-02 | 2015-12-30 | 法瑞斯生物技术有限公司 | 促转导素B(Protransduzin B)-基因转移的增强剂 |
Also Published As
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KR20200038532A (ko) | 2020-04-13 |
US20210154327A1 (en) | 2021-05-27 |
AU2018326439A1 (en) | 2020-04-16 |
EP3676286A1 (de) | 2020-07-08 |
WO2019043037A8 (de) | 2020-01-16 |
CA3080076A1 (en) | 2019-03-07 |
WO2019043037A1 (de) | 2019-03-07 |
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