CN111565736B - 猪g-csf变体和其用途 - Google Patents
猪g-csf变体和其用途 Download PDFInfo
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- CN111565736B CN111565736B CN201880066531.7A CN201880066531A CN111565736B CN 111565736 B CN111565736 B CN 111565736B CN 201880066531 A CN201880066531 A CN 201880066531A CN 111565736 B CN111565736 B CN 111565736B
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Abstract
本发明涉及猪粒细胞集落刺激因子(pG‑CSF)的变体。该pG‑CSF变体能够用于治疗、预防或降低猪细菌感染的发生率。公开了治疗猪的方法。
Description
本申请要求2017年10月11日提交的美国临时专利申请序列号62/570,877的优先权权益，其内容通过引用全文纳入本文。
本发明涉及包含合成氨基酸的变体猪粒细胞集落刺激因子(pG-CSF)多肽。合成氨基酸通过连接聚(乙二醇)(PEG)分子进行修饰。PEG化的pG-CSF变体用于治疗猪细菌感染。当猪是临产母猪时，细菌感染可能是乳腺炎、子宫炎和无乳(MMA)综合征。减少怀孕母猪细菌感染可以改善仔猪存活。
食用动物生产中传染病的经济影响是有据可查的。传染病会减少利润，增加生产成本并危害食品，以及影响动物的状态，健康和福祉。疾病可导致新生，幼小(例如，后备家畜)或成年动物的发病和死亡，从而对食用动物的生产造成毁灭性的影响。
在猪中，一种这类疾病可能是乳腺炎、子宫炎和无乳(MMA)综合征。乳腺炎是乳房的细菌感染。可以只感染一个腺体或者感染两个腺体，或者感染可以扩散到多个腺体。子宫炎是泌尿生殖道的细菌感染，有时表现为外阴分泌物。无乳是母猪乳汁产生减少或完全丧失。MMA综合征可以变化很大，并且可能不会出现上述所有症状。因此，MMA综合征可能难以检测和诊断，并且只有在哺乳仔猪出现饥饿，体重减轻甚至死亡的迹象时才可以被检测到。
因为MMA综合征难以检测，所以预防性治疗是优选的。不鼓励在食品动物中使用抗生素，尤其是广谱(shared class)抗生素，因此在猪的治疗中优选非抗生素疗法。细胞因子如pG-CSF可以增加动物中的嗜中性粒细胞数量，从而引发先天免疫系统对细菌感染的快速反应。使用PEG修饰pG-CSF变体可以延长细胞因子的药代动力学和稳定性，从而增强其作用。
PEG化的牛G-CSF可用于治疗奶牛的乳腺炎(WO2010/011735)。也已经描述了PEG化的人G-CSF(WO2000/044785)。已经提出了PEG化的野生型猪G-CSF，用于治疗呼吸道感染，如病毒感染(WO2005/025593)。如本文各个方面所公开的，PEG化的pG-CSF变体提高了猪血液嗜中性粒细胞数量，降低了临产母猪MMA综合征的发生率，和/或改善了仔猪存活率。
本发明提供了猪粒细胞集落刺激因子(pG-CSF)变体，其具有下述共有序列：
X1PLSPASSLPQSFLLKX2LEQVRKIQADGAELQERLCATHKLCX3PQELVLLGHSLGLPQASLSSCSSQALQLTGCLNQLHGGLVLYQGLLQALAGISPELAPALDILQLDVTDLATNIWLQX4EDLRX4APASLPTQGTVPTFTSAFQRRAGGVLVVSQLQSFLELAYRVLRYLAEP(SEQ ID NO:13)。可变X1可以为二肽甲硫氨酸丙氨酸，如SEQ ID NO:2和9中，二肽正亮氨酸丙氨酸，如SEQ ID NO:7和10中，丙氨酸，如SEQ IDNO:4和11中，或不存在，如SEQ ID NO:8和12中。可变X2可以为半胱氨酸，如SEQ ID NO:2、4、7和8，或者X2可以为丝氨酸，如SEQ ID NO:9、10、11和12。可变X3可以为合成氨基酸。该合成氨基酸可以存在于位置43(相对于如SEQ ID NO:3中所给出的成熟野生型pG-CSF的位置)，如SEQ ID NO:13中所示。合成氨基酸可为对乙酰基苯丙氨酸(pAF)。可变X4可以为甲硫氨酸，如SEQ ID NO:2、4、8、9、11和12，或者X4可以为正亮氨酸，如SEQ ID NO:7和10中。pAF合成氨基酸可以与聚(乙二醇)(PEG)分子共价连接。PEG可以具有约20kD至约50kD的分子量，或约30kD的分子量。优选地，PEG是线性PEG分子。
本发明提供了猪粒细胞集落刺激因子(pG-CSF)变体，其具有下述序列：MAPLSPASSLPQSFLLKCLEQVRKIQADGAELQERLCATHKLC[pAF]PQELVLLGHSLGLPQASLSSCSSQALQLTGCLNQLHGGLVLYQGLLQALAGISPELAPALDILQLDVTDLATNIWLQMEDLRMAPASLPTQGTVPTFTSAFQRRAGGVLVVSQLQSFLELAYRVLRYLAEP(SEQ ID NO:2)，其中存在于位置43的对乙酰基苯丙氨酸(pAF)合成氨基酸与30kD的线性PEG分子共价连接。
本发明提供了药物组合物，其包含本文所述的任何pG-CSF变体，和至少一种药学上可接受的运载体、稀释剂或赋形剂。
本发明提供了用于治疗猪细菌感染的方法，其包括向有此需要的猪给予治疗有效量的本文所述的任何pG-CSF变体。细菌感染可以是乳腺炎、子宫炎和无乳(MMA)综合征。需要治疗的猪可以是临产母猪。治疗有效量的pG-CSF变体可以为约10-100μg/kg动物体重，或约30-50μg/kg动物体重，或约40μg/kg动物体重。本文所述任何pG-CSF变体的给药可以分娩前7天或更短的时间(即，妊娠的第107天或之后)进行至少一次，或在分娩时进行。在一些方面中，治疗猪细菌感染的方法可以包括在分娩后14天更短的时间内(即，在分娩后1、2、3、4、5、6、7、8、9、10、11、12、13或14天内)第二次给予本文所述的任何pG-CSF变体。
本发明提供了用于刺激猪先天免疫应答的方法，其包括向有此需要的猪给予治疗有效量的本文所述的任何pG-CSF变体。需要刺激的猪可以是临产母猪。在其他方面中，需要刺激的猪可以是免疫系统受损或减弱的猪。在其他方面中，需要刺激的猪可以是具有感染或处于发展出感染风险的猪，包括例如细菌感染或病毒感染。在一些方面中，该方法可以刺激细胞因子(例如，干扰素(IFN)，肿瘤坏死因子(TNF)，集落刺激因子(CSF)和/或白介素(IL))的产生，和/或激活或增加免疫细胞的水平，所述免疫细胞如树突细胞(DC)，淋巴细胞(例如，B细胞，T细胞和自然杀伤(NK)细胞)和髓细胞(例如，肥大细胞，成髓细胞(例如，嗜碱性粒细胞，嗜酸性粒细胞，嗜中性粒细胞，单核细胞和巨噬细胞))。在这些方面的一些实施方案中，该方法可以通过例如增加嗜中性粒细胞髓过氧化物酶-过氧化氢-卤化物介导的抗菌功能来刺激或增强嗜中性粒细胞抗菌功能。
在刺激先天免疫应答的方法中，治疗有效量的pG-CSF变体可以为约10-100μg/kg动物体重，或约30-50μg/kg动物体重，或约40μg/kg动物体重。本文所述任何pG-CSF变体的给药可以分娩前7天或更短的时间(即，妊娠的第107天或之后)进行至少一次，或在分娩时进行。在一些方面中，治疗猪细菌感染的方法可以包括在分娩后14天更短的时间内(即，在分娩后1、2、3、4、5、6、7、8、9、10、11、12、13或14天内)第二次给予本文所述的任何pG-CSF变体。
本发明提供了用于降低仔猪死亡率的方法，其包括向临产母猪给予治疗有效量的本文所述的任何pG-CSF变体。治疗有效量的pG-CSF变体可以为约10-100μg/kg动物体重，或约30-50μg/kg动物体重，或约40μg/kg动物体重。本文所述任何pG-CSF变体的给药可以分娩前7天或更短的时间(即，妊娠的第107天或之后)进行至少一次，或在分娩时进行。在一些方面中，降低仔猪死亡率的方法可以包括在分娩后14天更短的时间内(即，在分娩后1、2、3、4、5、6、7、8、9、10、11、12、13或14天内)第二次给予临产母猪本文所述的任何pG-CSF变体。
本发明提供了本文所述的任何pG-CSF变体在制备用于猪细菌感染的药物中的用途。细菌感染可以是MMA综合征。猪可以是临产母猪。本发明提供了本文所述的任何pG-CSF变体在制备用于降低仔猪死亡率的药物中的用途。
本发明提供了本文所述的任何pG-CSF变体，用于疗法。该疗法可以是对猪中的细菌感染的综合征的治疗。细菌感染可以是MMA综合征。猪可以是临产母猪。疗法可以是仔猪死亡率的降低。可以将pG-CSF变体以约10-100μg/kg动物体重，或约30-50μg/kg动物体重，或约40μg/kg动物体重给予临产母猪。该pG-CSF变体可以在分娩前7天或更短的时间(即，妊娠的第107天或之后)给予至少一次，或在分娩时给予。在分娩后14天或更短的时间对临产母猪进行第二次给药
“细菌感染”是指一种或多种细菌在动物皮肤，粘膜，腺体，眼，耳，泌尿生殖道，消化道，肺，血液或器官上或内部的生长。细菌可以是分类为下述属内的任何种：无色杆菌(Achromobacter)，放线杆菌(Actinobacillus)，放线菌(Actinomyces)，芽孢杆菌(Bacillus)，博达氏菌(Bordatella)，布鲁氏菌(Brucella)，梭菌(Clostridium)，棒状杆菌(Corynebacterium)，丹毒丝菌(Erysipelothrix)，埃希氏杆菌(Escherichia)，(Haemophilus)，(Klebsiella)，(Leptospira)，李斯特菌(Listeria)，支原菌(Mycoplasma)，巴斯德菌(Pasteurella)，变形杆菌(Proteus)，假单胞菌(Pseudomonas)，沙门氏菌(Salmonella)，球状菌(Sphaerophorus)，葡萄球菌(Staphylococcus)，链球菌(Streptococcus)或弧菌(Vibrio)。
如本文所用术语“猪(porcine)”是指猪(pig)，尤其是家猪(驯化的家猪(Susscrofa domesticus)或(Sus domesticus))，并且可以包括小型猪以及作为肉类生产而饲养的那些猪。述及“猪”意指包括所有猪品种。
临产母猪定义为在妊娠最后几周至分娩后头几周内的妊娠雌猪。分娩或产仔通常发生在妊娠的约114天。临产母猪可能是从妊娠约100天至分娩后约14天的雌猪。仔猪是从出生到大约3周龄时断奶的猪。
“合成氨基酸”是指不是20种常见氨基酸之一或吡咯赖氨酸或硒代半胱氨酸的氨基酸。这类合成氨基酸的实例包括但不限于，对乙酰基苯丙氨酸(pAF)，乙酰葡萄糖胺基-L-丝氨酸和N-乙酰葡萄糖胺基-L-苏氨酸。WO2010/011735和WO2005/074650中描述了一些合成氨基酸及其在多肽中的纳入和后续修饰。
本文所用术语“治疗”、“处理”或“疗法”包括抑制、减慢、停止、降低，改善或逆转症状、紊乱、病症或疾病的进展或严重程度。在一些方面中，本公开提供了对在这样的动物中未观察到或未检测到的症状、紊乱、病症或疾病的预防性治疗具有特异性的方法，所述动物可能处于发展一种或多种这类症状、紊乱、病症疾病的风险。在一些方面中，将治疗性地施用治疗。
所用术语“有效量”是指所给予的pG-CSF变体的量，其将具有所需作用，诸如预防，治疗或减少猪细菌感染。当猪是临产母猪时，治疗母猪中的细菌感染可以提高仔猪的存活率。有效量可能随着诸如母猪重量等因素而变化。
述及“给予”意指注射治疗有效量的化合物和包含所公开的所述化合物的组合物。例如但不限于，给药可以是肌内(i.m)或皮下(s.c.)。
术语“约”将为本领域普通技术人员所理解，并且在某种程度上取决于其使用的上下文而变化。如本文所用，“约”意在涵盖±10％、±5％或±1％(即，±10％、±9％、±8％、±7％、±6％、±5％、±4％、±3％、±2％或±1％)的变化。
本发明的pG-CSF变体可以容易地在多种细胞中产生，包括哺乳动物细胞，细菌细胞，诸如大肠杆菌，枯草芽孢杆菌(Bacillus subtilis)或荧光假单胞菌荧光(Pseudomonasfluorescence)，和/或在真菌或酵母细胞中。可以使用本领域所熟知的技术培养宿主细胞。可以通过熟知的方法将含有感兴趣的多核苷酸序列(例如，pG-CSF的变体和表达控制序列)的载体转移到宿主细胞中，这将根据细胞宿主的类型而变化。例如，氯化钙转化法通常用于原核细胞，而磷酸钙处理或电穿孔可用于其他真核宿主细胞。可以采用各种蛋白质纯化方法，并且这些方法是本领域已知的，并且描述于例如Deutscher，《酶学方法》
(Methods in Enzymology)182:83-89(1990)和Scopes，《蛋白质纯化：原理和实践》(Protein Purification:Principles and Practice)，第三版，纽约州斯普林格出版社(Springer)(1994)。
可以根据已知方法配制PEG化的pG-CSF变体以制备药学上有用的组合物。在一些方面中，制剂是稳定冻干产品(其能用适当稀释剂重建)，或高纯度的水性溶液，其具有任选的药学上可接受的运载体，防腐剂，赋形剂或稳定剂(参见，《雷明顿药物科学和实践》(Remington,The Science and Practice of Pharmacy)，第19版，Gennaro编著,马克出版公司(Mack Publishing Co.),宾夕法尼亚州伊斯顿1995)。
PEG化的pG-CSF变体可以用药学上可接受的缓冲剂配制，并调节pH以提供可接受的稳定性，和对于给药可接受的pH。在一些非限制性实例中，给药可接受的pH值可以在约5至约8的范围内(即，约5、约6、约7或约8)。此外，可以将本发明的PEG化的pG-CSF组合物置于容器中，如小瓶，筒，笔递送装置，注射器，静脉内给药管或静脉内给药袋。
以下实验性实施例说明了pG-CSF变体及其在治疗猪细菌感染如临产母猪MMA综合征中的用途。降低母猪细菌感染的发生率也降低仔猪死亡率。应当理解的是，其他实施方式和用途对于本领域技术人员将是显而易见的，并且本发明不限于这些具体说明性实施例或优选实施方式。
实施例1
通过定点PCR诱变在选定位置引入TAG终止密码子产生猪粒细胞集落刺激因子(pG-CSF)cDNA(GenBank登录号U68481.1)的不同变体。此外，编码信号序列的cDNA部分被单个甲硫氨酸密码子(即ATG)所替代。例如，编码具有改变的信号序列的野生型成熟pG-CSF的cDNA可以是：
(SEQ ID NO:5)。该变体将编码下述多肽：
(SEQ ID NO:1)。如果希望TAG终止密码子替代H43残基，那么cDNA序列可以是：
(SEQ ID NO:6)。所得多肽将是：
(SEQ ID NO：2)，其中“x”表示H43残基被合成氨基酸替代，如下所述。
将编码变体的质粒转化至含有有扩增的遗传密码系统组件的大肠杆菌细胞中，用于纳入合成氨基酸对-乙酰苯丙氨酸(pAF)。转化的细胞在补充有pAF的培养基中生长，并经诱导以表达具有纳入指定位点的pAE的pG-CSF。已经描述了表达系统，例如，于WO 2010/011735中(通过引用方式纳入本文)，并且这是为本领域通常已知的。
用阿拉伯糖诱导转染的cDNA变体的表达，收获细胞，并通过反相高压液相色谱法(RP-HPLC)分离和纯化靶pG-CSF pAF位点变体。将活化的30kD线性氨基氧基-PEG与纳入的pAF位点特异性偶联。通过色谱从过量的PEG和未偶联的pG-CSF变体纯化PEG-pG-CSF偶联物。
实施例2
通过变体诱导M-NSF-60细胞(ATCC CRL-1838)增殖的能力测量PEG化的PG-CSF(PEG-PG-CSF)变体的体外生物活性。通过与用野生型(WT)pG-CSF产生的标准曲线比较，确定能够实现50％最大增殖的变体浓度(EC50)。基于实施例1中所述表达的结果和本文所述的生物学试验，选择PEG-pG-CSF变体用于进一步研究。
在啮齿动物模型中测试选定的候选PEG-PG-CSF变体的体内活性。以0.25mg/kg体重用PEG-pG-CSF变体处理Sprague Dawley大鼠(3只/组)。在0(给药前)、1、3、6、24、48、56、72、96、144、192和264小时采集血样，用于药代动力学(PK)分析，并在24、48、72和96小时采集血样，用于全血细胞计数(CBC分析)。CBC分析中的主要测量值是存在的嗜中性粒细胞数量。H43变体比测试的其他变体刺激更高水平的嗜中性粒细胞发育。所有变体都具有相似的PK概况。
实施例3
如下所述制备PEG-pG-CSF H43pAF。如实施例1所述，使用阿拉伯糖诱导转染的cDNA变体的表达，收获细胞，并将pG-CSF H43pAF位点变体分离，变性和再折叠，并通过阳离子交换液相色谱(CEX)纯化，使用CAPTO Adhere Impres(GE健康生命科学公司(GEHealthcare Lifesciences))。简言之，将未PEG化的pG-CSF H43pAF变体上样至色谱柱至1-5mg/mL树脂的浓度。用5个柱体积(CV)pH 4.5的30mM乙酸钠洗涤柱。pG-CSF H43pAF变体的洗脱使用线性梯度的洗脱缓冲液(30mM乙酸钠，0.5M NaCl，Ph 4.5)，通过使用0-100％洗脱缓冲液洗涤20个CV来进行。
基于对pG-CSF H43pAF的质谱(MS)分析，分离的肽包括由SEQ ID NO：2所表示的主峰和几种不同的污染物。污染物包括N末端甲硫氨酸的缺失(SEQ ID NO：4)，N末端甲硫氨酸和丙氨酸的缺失(SEQ ID NO:8)，以及正亮氨酸替代N末端甲硫氨酸(SEQ ID NO:7)。在使用大肠杆菌的高密度发酵中，已知正亮氨酸被误纳入，而非氨基酸甲硫氨酸。通过使用下述步骤中的一个或多个减少正亮氨酸纳入：向发酵溶液中供给甲硫氨酸；使用复杂培养基而非成分限定培养基发酵(复杂培养基中含有一种或多种非限定成分，其包括但不限于甘油，盐，氨基酸，维生素，酵母提取物，动植物水解产物，蛋白胨和色氨酸)；和/或在诱导后降低发酵反应混合物的温度。
在使用Capto SP Impres色谱后，从阳离子交换色谱池中获得pG-CSFH43pAF变体，并使用10kDa MWCO切向流过滤盒缓冲液交换到30mM乙酸钠，4％蔗糖，pH 4.0中。然后根据制造商的说明，使用Amicon Ultra离心滤器将pG-CSF H43pAF变体浓缩至约8.0mg/mL。浓缩后，将30K线性PEG(例如，PEG可以商购自NOF美国公司或EMD Merck公司)以PEG与pG-CSFH43pAF变体6：1摩尔比添加。然后将PEG/pG-CSF变体混合物在约28℃下孵育至少21小时。该方法导致＞98％的与PEG偶联的pG-CSF变体。然后可以如上所述通过CEX纯化PEG化的变体。当在M-NSF-60细胞生物试验(实施例2)中进行测试时，PEG-pG-CSF H43pAF变体的EC50为至少0.40ng/mL，这证明了良好的结合和效力特性。
通过在1.5mL试管中于0℃冷冻并在室温水浴中解冻，将样品冻融五个循环。在五个冻融循环期间，未观察到对高分子量(HMW)蛋白谱的显著影响，这证明了该变体在溶液中的稳定性。
另生成了两个pG-CSF H43pAF变体，以试图改善该变体在50℃下的再折叠效率和热稳定性。半胱氨酸17变为丙氨酸(C17A)或丝氨酸(C17S，SEQ ID NO：9-12)。这些突变并不改善再折叠产量，但是C17A降低热稳定性。PEG-pG-CSF H43pAF/C17S的EC50略有改善，为0.26ng/mL。
实施例4
将PEG-pG-CSF H43pAF变体给予母猪以表征血液嗜中性粒细胞的变化。通过在颈侧进行肌肉内注射，将40μg/kg的PEG-pG-CSF H43pAF变体给予1.5–5岁且平均体重为269.7kg的6只母猪。将PEG-pG-CSF H43pAF变体以8.2mg/mL的浓度悬浮于30mM柠檬酸钠，250mM精氨酸，pH 6.0中。开始治疗后，动物不接受任何伴随用药。没有观测到不良事件。
在给药前第0天和给药后第2、7、10、14、17和21天采集血液。确定各只母猪的嗜中性粒细胞计数，并确定每天的治疗平均值。使用单剂量的PEG-pG-CSF H43pAF变体进行治疗导致三周的周期内血液中性粒细胞计数增加(表1)。可以预期附加剂量将刺激维持更高的嗜中性粒细胞水平。
表1.EG-pG-CSF H43pAF变体对平均每日血液嗜中性粒细胞计数的影响。
实施例5
将PEG-pG-CSF H43pAF变体给予临产母猪以表征其对乳腺炎、子宫炎和无乳(MMA)综合征以及对仔猪存活的影响。
将妊娠95–100天的母猪置于分娩笼，并遵循卫生饲养管理直到每只母猪妊娠的第107天。在第107天，收集血液，然后如实施例4所述使用40μg/kg的PEG-pG-CSF H43pAF变体或以氯化钠溶液作为阴性对照处理母猪(每组25只)。然后将母猪置于不卫生的条件下以刺激MMA的发展。不卫生的条件包括在分娩笼的栅格地板上放一块垫子以使草垫和废物堆积。此外，水、粪便和松木屑(2：1：1)的混合物也用于污染猪笼。没有给予母猪催产素或皮质类固醇药物。从妊娠的第107天开始每天早晨从每只母猪收集一次临床观察结果和直肠温度，一直持续到诊断为MMA为止，在那时母猪经历了的所有取样，然后从研究中移出，进行处理，并恢复卫生条件。收集的样品包括血液，直肠温度和受感染腺体的拭子。
分娩通常在妊娠的第114天发生。在出生后12小时内，将仔猪称重并贴标签。对仔猪进行每天两次临床观察，并在出生后第3、7和21天测量体重。
使用各疾病方案定义，两组之间几乎没有观测到差异。然而，当将外阴分泌物由疾病定义中去除时，PEG-pG-CSF治疗组的疾病发生率降低了50％以上。治疗组相较于与对照组的断奶仔猪数量也更多(表2)。
表2.PEG-pG-CSF对MMA发生率和仔猪存活率的作用。
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序列表
<110> 礼蓝美国股份有限公司（Elanco US Inc.）
安布罗克斯股份有限公司（Ambrx Inc.）
<120> 猪G-CSF变体及其用途
<130> X21439_WO
<150> US 62/570,877
<151> 2017-10-11
<160> 13
<170> PatentIn version 3.5
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Gln Arg Arg Ala Gly Gly Val Leu Val Val Ser Gln Leu Gln Ser Phe
145 150 155 160
Leu Glu Leu Ala Tyr Arg Val Leu Arg Tyr Leu Ala Glu Pro
165 170
<210> 5
<211> 528
<212> DNA
<213> 人工序列
<220>
<223> cDNA (人工)编码SEQ ID NO: 1和3
<400> 5
atggcccctc tcagccctgc cagctccctg ccccagagct tcctgctcaa gtgcttagag 60
caagtgagga aaatccaggc tgatggcgcc gagctgcagg agaggctgtg tgccacccac 120
aagctgtgcc acccccagga gctggtgctg ctcgggcact ctctgggcct cccccaggct 180
tccctgagca gctgctccag ccaggccctg cagctgactg gctgcctgaa ccaactgcat 240
ggcggcctcg tcctctacca gggcctcctg caggccctgg cgggcatctc cccagagctg 300
gcccccgccc tggacatact gcagctggat gtcaccgact tagccaccaa catctggctg 360
cagatggaag acctgaggat ggccccggcc tcgcttccca cccagggcac cgtgccgacc 420
ttcacctcgg ccttccagcg ccgggcagga ggggtcctgg ttgtctccca gctgcagagc 480
ttcctggagc tggcgtaccg tgtcctgcgc tacctcgccg agccctga 528
<210> 6
<211> 528
<212> DNA
<213> 人工序列
<220>
<223> cDNA (人工)编码SEQ ID NO: 2和4
<400> 6
atggcccctc tcagccctgc cagctccctg ccccagagct tcctgctcaa gtgcttagag 60
caagtgagga aaatccaggc tgatggcgcc gagctgcagg agaggctgtg tgccacccac 120
aagctgtgct agccccagga gctggtgctg ctcgggcact ctctgggcct cccccaggct 180
tccctgagca gctgctccag ccaggccctg cagctgactg gctgcctgaa ccaactgcat 240
ggcggcctcg tcctctacca gggcctcctg caggccctgg cgggcatctc cccagagctg 300
gcccccgccc tggacatact gcagctggat gtcaccgact tagccaccaa catctggctg 360
cagatggaag acctgaggat ggccccggcc tcgcttccca cccagggcac cgtgccgacc 420
ttcacctcgg ccttccagcg ccgggcagga ggggtcctgg ttgtctccca gctgcagagc 480
ttcctggagc tggcgtaccg tgtcctgcgc tacctcgccg agccctga 528
<210> 7
<211> 175
<212> PRT
<213> 人工序列
<220>
<223> 人工
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa = 正亮氨酸或甲硫氨酸
<220>
<221> MISC_FEATURE
<222> (44)..(44)
<223> Xaa = pAF
<220>
<221> MISC_FEATURE
<222> (122)..(122)
<223> Xaa = 正亮氨酸或甲硫氨酸
<220>
<221> MISC_FEATURE
<222> (127)..(127)
<223> Xaa = 正亮氨酸或甲硫氨酸
<400> 7
Xaa Ala Pro Leu Ser Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu
1 5 10 15
Lys Cys Leu Glu Gln Val Arg Lys Ile Gln Ala Asp Gly Ala Glu Leu
20 25 30
Gln Glu Arg Leu Cys Ala Thr His Lys Leu Cys Xaa Pro Gln Glu Leu
35 40 45
Val Leu Leu Gly His Ser Leu Gly Leu Pro Gln Ala Ser Leu Ser Ser
50 55 60
Cys Ser Ser Gln Ala Leu Gln Leu Thr Gly Cys Leu Asn Gln Leu His
65 70 75 80
Gly Gly Leu Val Leu Tyr Gln Gly Leu Leu Gln Ala Leu Ala Gly Ile
85 90 95
Ser Pro Glu Leu Ala Pro Ala Leu Asp Ile Leu Gln Leu Asp Val Thr
100 105 110
Asp Leu Ala Thr Asn Ile Trp Leu Gln Xaa Glu Asp Leu Arg Xaa Ala
115 120 125
Pro Ala Ser Leu Pro Thr Gln Gly Thr Val Pro Thr Phe Thr Ser Ala
130 135 140
Phe Gln Arg Arg Ala Gly Gly Val Leu Val Val Ser Gln Leu Gln Ser
145 150 155 160
Phe Leu Glu Leu Ala Tyr Arg Val Leu Arg Tyr Leu Ala Glu Pro
165 170 175
<210> 8
<211> 173
<212> PRT
<213> 人工序列
<220>
<223> 人工
<220>
<221> MISC_FEATURE
<222> (42)..(42)
<223> Xaa = pAF
<400> 8
Pro Leu Ser Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys Cys
1 5 10 15
Leu Glu Gln Val Arg Lys Ile Gln Ala Asp Gly Ala Glu Leu Gln Glu
20 25 30
Arg Leu Cys Ala Thr His Lys Leu Cys Xaa Pro Gln Glu Leu Val Leu
35 40 45
Leu Gly His Ser Leu Gly Leu Pro Gln Ala Ser Leu Ser Ser Cys Ser
50 55 60
Ser Gln Ala Leu Gln Leu Thr Gly Cys Leu Asn Gln Leu His Gly Gly
65 70 75 80
Leu Val Leu Tyr Gln Gly Leu Leu Gln Ala Leu Ala Gly Ile Ser Pro
85 90 95
Glu Leu Ala Pro Ala Leu Asp Ile Leu Gln Leu Asp Val Thr Asp Leu
100 105 110
Ala Thr Asn Ile Trp Leu Gln Met Glu Asp Leu Arg Met Ala Pro Ala
115 120 125
Ser Leu Pro Thr Gln Gly Thr Val Pro Thr Phe Thr Ser Ala Phe Gln
130 135 140
Arg Arg Ala Gly Gly Val Leu Val Val Ser Gln Leu Gln Ser Phe Leu
145 150 155 160
Glu Leu Ala Tyr Arg Val Leu Arg Tyr Leu Ala Glu Pro
165 170
<210> 9
<211> 175
<212> PRT
<213> 人工序列
<220>
<223> 人工
<220>
<221> MISC_FEATURE
<222> (44)..(44)
<223> Xaa = pAF
<400> 9
Met Ala Pro Leu Ser Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu
1 5 10 15
Lys Ser Leu Glu Gln Val Arg Lys Ile Gln Ala Asp Gly Ala Glu Leu
20 25 30
Gln Glu Arg Leu Cys Ala Thr His Lys Leu Cys Xaa Pro Gln Glu Leu
35 40 45
Val Leu Leu Gly His Ser Leu Gly Leu Pro Gln Ala Ser Leu Ser Ser
50 55 60
Cys Ser Ser Gln Ala Leu Gln Leu Thr Gly Cys Leu Asn Gln Leu His
65 70 75 80
Gly Gly Leu Val Leu Tyr Gln Gly Leu Leu Gln Ala Leu Ala Gly Ile
85 90 95
Ser Pro Glu Leu Ala Pro Ala Leu Asp Ile Leu Gln Leu Asp Val Thr
100 105 110
Asp Leu Ala Thr Asn Ile Trp Leu Gln Met Glu Asp Leu Arg Met Ala
115 120 125
Pro Ala Ser Leu Pro Thr Gln Gly Thr Val Pro Thr Phe Thr Ser Ala
130 135 140
Phe Gln Arg Arg Ala Gly Gly Val Leu Val Val Ser Gln Leu Gln Ser
145 150 155 160
Phe Leu Glu Leu Ala Tyr Arg Val Leu Arg Tyr Leu Ala Glu Pro
165 170 175
<210> 10
<211> 175
<212> PRT
<213> 人工序列
<220>
<223> 人工
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa = 正亮氨酸或甲硫氨酸
<220>
<221> MISC_FEATURE
<222> (44)..(44)
<223> Xaa = pAF
<220>
<221> MISC_FEATURE
<222> (122)..(122)
<223> Xaa = 正亮氨酸或甲硫氨酸
<220>
<221> MISC_FEATURE
<222> (127)..(127)
<223> Xaa = 正亮氨酸或甲硫氨酸
<400> 10
Xaa Ala Pro Leu Ser Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu
1 5 10 15
Lys Ser Leu Glu Gln Val Arg Lys Ile Gln Ala Asp Gly Ala Glu Leu
20 25 30
Gln Glu Arg Leu Cys Ala Thr His Lys Leu Cys Xaa Pro Gln Glu Leu
35 40 45
Val Leu Leu Gly His Ser Leu Gly Leu Pro Gln Ala Ser Leu Ser Ser
50 55 60
Cys Ser Ser Gln Ala Leu Gln Leu Thr Gly Cys Leu Asn Gln Leu His
65 70 75 80
Gly Gly Leu Val Leu Tyr Gln Gly Leu Leu Gln Ala Leu Ala Gly Ile
85 90 95
Ser Pro Glu Leu Ala Pro Ala Leu Asp Ile Leu Gln Leu Asp Val Thr
100 105 110
Asp Leu Ala Thr Asn Ile Trp Leu Gln Xaa Glu Asp Leu Arg Xaa Ala
115 120 125
Pro Ala Ser Leu Pro Thr Gln Gly Thr Val Pro Thr Phe Thr Ser Ala
130 135 140
Phe Gln Arg Arg Ala Gly Gly Val Leu Val Val Ser Gln Leu Gln Ser
145 150 155 160
Phe Leu Glu Leu Ala Tyr Arg Val Leu Arg Tyr Leu Ala Glu Pro
165 170 175
<210> 11
<211> 174
<212> PRT
<213> 人工序列
<220>
<223> 人工
<220>
<221> MISC_FEATURE
<222> (43)..(43)
<223> Xaa = pAF
<400> 11
Ala Pro Leu Ser Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys
1 5 10 15
Cys Leu Glu Gln Val Arg Lys Ile Gln Ala Asp Gly Ala Glu Leu Gln
20 25 30
Glu Arg Leu Cys Ala Thr His Lys Leu Cys Xaa Pro Gln Glu Leu Val
35 40 45
Leu Leu Gly His Ser Leu Gly Leu Pro Gln Ala Ser Leu Ser Ser Cys
50 55 60
Ser Ser Gln Ala Leu Gln Leu Thr Gly Cys Leu Asn Gln Leu His Gly
65 70 75 80
Gly Leu Val Leu Tyr Gln Gly Leu Leu Gln Ala Leu Ala Gly Ile Ser
85 90 95
Pro Glu Leu Ala Pro Ala Leu Asp Ile Leu Gln Leu Asp Val Thr Asp
100 105 110
Leu Ala Thr Asn Ile Trp Leu Gln Met Glu Asp Leu Arg Met Ala Pro
115 120 125
Ala Ser Leu Pro Thr Gln Gly Thr Val Pro Thr Phe Thr Ser Ala Phe
130 135 140
Gln Arg Arg Ala Gly Gly Val Leu Val Val Ser Gln Leu Gln Ser Phe
145 150 155 160
Leu Glu Leu Ala Tyr Arg Val Leu Arg Tyr Leu Ala Glu Pro
165 170
<210> 12
<211> 173
<212> PRT
<213> 人工序列
<220>
<223> 人工
<220>
<221> MISC_FEATURE
<222> (42)..(42)
<223> Xaa = pAF
<400> 12
Pro Leu Ser Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys Ser
1 5 10 15
Leu Glu Gln Val Arg Lys Ile Gln Ala Asp Gly Ala Glu Leu Gln Glu
20 25 30
Arg Leu Cys Ala Thr His Lys Leu Cys Xaa Pro Gln Glu Leu Val Leu
35 40 45
Leu Gly His Ser Leu Gly Leu Pro Gln Ala Ser Leu Ser Ser Cys Ser
50 55 60
Ser Gln Ala Leu Gln Leu Thr Gly Cys Leu Asn Gln Leu His Gly Gly
65 70 75 80
Leu Val Leu Tyr Gln Gly Leu Leu Gln Ala Leu Ala Gly Ile Ser Pro
85 90 95
Glu Leu Ala Pro Ala Leu Asp Ile Leu Gln Leu Asp Val Thr Asp Leu
100 105 110
Ala Thr Asn Ile Trp Leu Gln Met Glu Asp Leu Arg Met Ala Pro Ala
115 120 125
Ser Leu Pro Thr Gln Gly Thr Val Pro Thr Phe Thr Ser Ala Phe Gln
130 135 140
Arg Arg Ala Gly Gly Val Leu Val Val Ser Gln Leu Gln Ser Phe Leu
145 150 155 160
Glu Leu Ala Tyr Arg Val Leu Arg Tyr Leu Ala Glu Pro
165 170
<210> 13
<211> 174
<212> PRT
<213> 人工序列
<220>
<223> 人工
<220>
<221> misc_feature
<222> (1)..(1)
<223> Xaa可以是任何天然产生的氨基酸
<220>
<221> misc_feature
<222> (17)..(17)
<223> Xaa可以是任何天然产生的氨基酸
<220>
<221> MISC_FEATURE
<222> (43)..(43)
<223> Xaa = pAF
<220>
<221> misc_feature
<222> (121)..(121)
<223> Xaa可以是任何天然产生的氨基酸
<220>
<221> misc_feature
<222> (126)..(126)
<223> Xaa可以是任何天然产生的氨基酸
<400> 13
Xaa Pro Leu Ser Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys
1 5 10 15
Xaa Leu Glu Gln Val Arg Lys Ile Gln Ala Asp Gly Ala Glu Leu Gln
20 25 30
Glu Arg Leu Cys Ala Thr His Lys Leu Cys Xaa Pro Gln Glu Leu Val
35 40 45
Leu Leu Gly His Ser Leu Gly Leu Pro Gln Ala Ser Leu Ser Ser Cys
50 55 60
Ser Ser Gln Ala Leu Gln Leu Thr Gly Cys Leu Asn Gln Leu His Gly
65 70 75 80
Gly Leu Val Leu Tyr Gln Gly Leu Leu Gln Ala Leu Ala Gly Ile Ser
85 90 95
Pro Glu Leu Ala Pro Ala Leu Asp Ile Leu Gln Leu Asp Val Thr Asp
100 105 110
Leu Ala Thr Asn Ile Trp Leu Gln Xaa Glu Asp Leu Arg Xaa Ala Pro
115 120 125
Ala Ser Leu Pro Thr Gln Gly Thr Val Pro Thr Phe Thr Ser Ala Phe
130 135 140
Gln Arg Arg Ala Gly Gly Val Leu Val Val Ser Gln Leu Gln Ser Phe
145 150 155 160
Leu Glu Leu Ala Tyr Arg Val Leu Arg Tyr Leu Ala Glu Pro
165 170
Claims (17)
1.一种猪粒细胞集落刺激因子变体，其由下述序列组成：
X1PLSPASSLPQSFLLKX2LEQVRKIQADGAELQERLCATHKLC(pAF)PQELVLLGHSLGLPQASLSSCSSQALQLTGCLNQLHGGLVLYQGLLQALAGISPELAPALDILQLDVTDLATNIWLQX3EDLRX3APASLPTQGTVPTFTSAFQRRAGGVLVVSQLQSFLELAYRVLRYLAEP (SEQ ID NO: 13)；
其中X1选自二肽甲硫氨酸丙氨酸，二肽正亮氨酸丙氨酸，仅丙氨酸和无氨基酸；
其中X2是半胱氨酸或丝氨酸；
其中X3是甲硫氨酸或正亮氨酸；和
其中存在于位置43的对乙酰基苯丙氨酸（pAF）合成氨基酸与聚乙二醇（PEG）共价连接。
2. 如权利要求1所述的猪粒细胞集落刺激因子变体，其中，所述PEG的分子量为20 kD至50 kD。
3. 如权利要求1所述的猪粒细胞集落刺激因子变体，其中，所述PEG的分子量为30 kD。
4.如权利要求1所述的猪粒细胞集落刺激因子变体，其中，所述PEG是线性的。
5.一种猪粒细胞集落刺激因子变体，其由下述氨基酸序列组成：
MAPLSPASSLPQSFLLKCLEQVRKIQADGAELQERLCATHKLC(pAF)PQELVLLGHSLGLPQASLSSCSSQALQLTGCLNQLHGGLVLYQGLLQALAGISPELAPALDILQLDVTDLATNIWLQMEDLRMAPASLPTQGTVPTFTSAFQRRAGGVLVVSQLQSFLELAYRVLRYLAEP (SEQ ID NO: 2)，
其中存在于位置43的对乙酰基苯丙氨酸（pAF）合成氨基酸与30 kD的线性PEG共价连接。
6.一种药物组合物，其包含权利要求1-5中任一项所述的猪粒细胞集落刺激因子变体和至少一种药学上可接受的运载体、稀释剂或赋形剂。
7.权利要求1-5中任一项所述的猪粒细胞集落刺激因子变体或权利要求6所述的药物组合物的用途，其特征在于，所述用途为用于制备预防或治疗猪中的乳腺炎、子宫炎和无乳综合征(MMA)的药物。
8.如权利要求7所述的用途，所述药物给予临产母猪，从而降低仔猪死亡率。
9.如权利要求7所述的用途，其中所述药物刺激猪中的先天免疫应答。
10.如权利要求9所述的用途，其中，所述先天免疫应答包括增加嗜中性粒细胞抗菌功能，细胞因子水平，激活或增加树突细胞水平，激活或增加淋巴细胞水平，或激活或增加骨髓细胞水平，或其任何组合。
11.如权利要求7所述的用途，其中，所述猪是临产母猪。
12.如权利要求7所述的用途，其中，猪粒细胞集落刺激因子的量为10 - 100 μg/kg动物体重。
13.如权利要求7所述的用途，其中，猪粒细胞集落刺激因子的量为30 - 50 μg/kg动物体重。
14.如权利要求7所述的用途，其中，猪粒细胞集落刺激因子的量为40 μg/kg动物体重。
15.如权利要求7所述的用途，其中，所述药物在分娩前7天内给予至少一次。
16.如权利要求7所述的用途，其中，所述药物在分娩时给予。
17.如权利要求7所述的用途，所述药物还在不迟于分娩后14天的第二次给予。
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| US201762570877P | 2017-10-11 | 2017-10-11 | |
| US62/570,877 | 2017-10-11 | ||
| PCT/US2018/055203 WO2019075053A1 (en) | 2017-10-11 | 2018-10-10 | PORCINE G-CSF VARIANTS AND USES THEREOF |
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2021
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Also Published As
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| KR102619071B1 (ko) | 2023-12-27 |
| CN111565736A (zh) | 2020-08-21 |
| CA3077215A1 (en) | 2019-04-18 |
| KR20220150432A (ko) | 2022-11-10 |
| KR20200066628A (ko) | 2020-06-10 |
| BR112020007037A2 (pt) | 2020-11-17 |
| AU2021204727A1 (en) | 2021-08-05 |
| KR102461760B1 (ko) | 2022-10-31 |
| EP3694535A4 (en) | 2021-07-28 |
| MX2020003742A (es) | 2020-10-28 |
| AU2021204727B2 (en) | 2023-02-09 |
| AU2018348138A1 (en) | 2020-04-23 |
| US20210054039A1 (en) | 2021-02-25 |
| TW201928058A (zh) | 2019-07-16 |
| US11578111B2 (en) | 2023-02-14 |
| AR113756A1 (es) | 2020-06-10 |
| JP7046173B2 (ja) | 2022-04-01 |
| US20230340051A1 (en) | 2023-10-26 |
| EP3694535A1 (en) | 2020-08-19 |
| TWI820046B (zh) | 2023-11-01 |
| WO2019075053A1 (en) | 2019-04-18 |
| JP2020536935A (ja) | 2020-12-17 |
| RU2020113060A3 (zh) | 2021-12-27 |
| RU2020113060A (ru) | 2021-11-12 |
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