CN118382454A - 一种免疫球蛋白降解酶IdeE的突变体的用途 - Google Patents
一种免疫球蛋白降解酶IdeE的突变体的用途 Download PDFInfo
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Abstract
提供一种免疫球蛋白降解酶IdeE的突变体、包含所述突变体的蛋白、组合物和试剂盒在制备用于降低受试者中的IgG水平的药物中的用途;其中所述突变体在SEQ ID NO:2所示的氨基酸序列的位置8、10、24、59、97和280中的一位或者多位具有氨基酸取代、N端截短和/或C端截短,所述的突变体具备免疫球蛋白降解酶IdeE的功能,并具有高于野生型IdeE的活性和热稳定性。
Description
本发明涉及生物技术领域,具体涉及一种免疫球蛋白的降解酶的突变体及包含其的组合物用于降低IgG水平的应用。
化脓链球菌是人畜常见的病原菌之一,广泛存在于自然界及人或动物的口咽腔、呼吸道及肠道中。链球菌感染会引发相关疾病,较轻的病症如化脓性皮炎、咽炎,比较严重的疾病如败血症、坏死性筋膜炎和中毒性休克综合症。来自酿脓链球菌的免疫球蛋白G降解酶(Immunoglobulin G-degrading enzyme of Streptococcus pyogenes,IdeS),是一种常见的A型链球菌(Group A Streptococcus pyogenes,GAS)半胱氨酸蛋白酶,具有水解IgG的肽链内肽酶活性(Agniswamy J,Lei B,Musser J M等,J Biol Chem,2004,279:52789-52796.Lei B,DeLeo F R,Reid S D等,Infect Immun,2002,70:6880-6890.Von Pawel-Rammingen U,Johansson B P,Bjorck L..EMBO J,2002,21:1607-1615.)。作为一种致病菌的毒力因子,它可以识别抗体下铰链区CH1和CH2结构域并特异性降解IgG,获得同质的F(ab)
2和Fc片段,帮助GAS逃避抗体介导的吞噬及细胞毒作用,从而减弱宿主免疫系统对GAS的杀伤(Von Pawel-Rammingen U.J Innate Immunity,2012,4:132-140.Su,Y.-F.等,Molecular Immunology,2011,49:134-142.)。
免疫球蛋白G(Immunoglobulin G,IgG),是血清主要的抗体成分,约占血清免疫球蛋白的75%,在机体免疫中主要起保护作用,能有效预防感染性疾病。除了具有保护性作用之外,IgG也和疾病相关。在一些自身免疫性疾病中,IgG抗体与人体自身分子发生反应,在器官移植中IgG会引起急性移植排斥反应。IdeS特异性降解IgG,从而使IgG失去其应有功能从而实现免疫抑制。
目前应用于临床的IdeS存在活性不佳,人体预存抗体高的问题。IdeS是人类病原菌的毒力因子,临床研究发现正常人在正常生理条件下接近100%检 出抗IdeS抗体,导致IdeS的使用方式给药效率不高,同时存在安全性问题。
因此,需要一种更高安全性同时保持活性的免疫球蛋白降解酶用于相关疾病的临床药物制备。
发明内容
本发明的第一方面涉及免疫球蛋白降解酶IdeE的突变体的用途,优选在制备用于治疗受试者中的自身抗体介导的病症的药物中的用途,所述的免疫球蛋白降解酶IdeE包含如序列表中SEQ ID NO:2所示的氨基酸序列或由所述氨基酸序列组成;所述突变选自下组:
(1)对所述氨基酸序列的位置8、10、24、59、97和280中的一位或者多位进行替换后得到所述突变体;和/或,
(2)对所述免疫球蛋白降解酶IdeE进行截短,删除其N端的前1个、前2个、前3个、前4个、前5个、前6个、前7个、前8个、前9个,前10个、前11个、前12个、前13个、前14个、前15个、前16个、前17个、前18个或者前19个氨基酸序列;和/或,
(3)对所述免疫球蛋白降解酶IdeE进行截短,删除其C端的最后1个、最后2个、最后3个、最后4个、最后5个、最后6个、最后7个、最后8个、最后9个或者最后10个氨基酸序列;
其中所述突变体具有高于或等于所述免疫球蛋白降解酶IdeE的活性和/或热稳定性。
本发明的第一方面还涉及包含本发明的突变体的蛋白在制备用于治疗受试者中的自身抗体介导的病症的药物中的用途。优选地所述蛋白在所述突变体的N末端连接有分泌信号序列和/或甲硫氨酸;和/或所述蛋白在所述突变体的C末端连接有组氨酸标签。本发明的第一方面还涉及包含本发明的突变体或蛋白的组合物或者包含本发明的突变体或蛋白的试剂盒在制备用于治疗受试者中的自身抗体介导的病症的药物中的用途,优选地所述组合物进一步包含任选的药学上可接受的载体或赋形剂和/或另外的治疗剂,所述另外的治疗剂选自下组:(a)抗体或者含有Fc的蛋白,优选地所述抗体的靶点选自下组:细胞表面蛋白、细胞因子、激素、酶、胞内信使、胞间信使和免疫检查点;(b)病毒载体药物,优选地所述病毒载体药物选自下组:溶瘤病毒、基因治疗病毒和病毒载体疫苗;和(c)能降低血液IgG水平的药物,优选地所 述降低血液IgG水平的药物选自下组:FcRn抗体、与FcRn高亲和力的Fc片段变体。
本发明的第二方面涉及本发明的突变体、包含所述突变体的蛋白、或者包含所述突变体或所述蛋白的组合物或试剂盒在制备用于降低受试者中的IgG水平的药物中的用途。
本发明的第三方面涉及本发明的突变体、包含所述突变体的蛋白、或者包含所述突变体或所述蛋白的组合物或试剂盒在制备用于预防和/或治疗受试者中的实体器官移植后自身抗体介导的器官排斥的药物中的用途。
本发明的第四方面涉及本发明的突变体、包含所述突变体的蛋白、或者包含所述突变体或所述蛋白的组合物或试剂盒在制备用于基因治疗的药物中的用途、以及在制备用于在病毒载体为基础的基因治疗前清除体内预存的抗病毒载体的中和抗体之药物中的用途。
本发明的第五方面涉及本发明的突变体、包含所述突变体的蛋白、或者包含所述突变体或所述蛋白的组合物或试剂盒在制备用于治疗受试者中的肿瘤的药物中的用途。
本发明的第六方面涉及本发明的突变体、包含所述突变体的蛋白、或者包含所述突变体或所述蛋白的组合物或试剂盒在制备用于清除受试者中的自身抗体以使得含Fc剂更好发挥疗效的药物中的用途。
本发明的第七方面涉及本发明的突变体、包含所述突变体的蛋白、或者包含所述突变体或所述蛋白的组合物或试剂盒在制备用于在已施用含Fc剂的受试者中降低所述含Fc剂的血清水平的药物中的用途。
图1为7个单点突变体及野生型IdeE切割人IgG1产生的切割产物SDS-PAGE凝胶电泳图(酶:底物=1:1000)。
图2为7个单点突变体及野生型IdeE切割人IgG1产生的切割产物SDS-PAGE凝胶电泳图(酶:底物=1:2000)。
图3为5个N端截短突变体切割人IgG1产生的切割产物SDS-PAGE凝胶电泳图(酶:底物=1:1000)。
图4为50℃条件下保温1h后5个N端截短突变体及野生型IdeE切割人IgG1产生的切割产物SDS-PAGE凝胶电泳图(酶:底物=1:1000)。
图5为2个C截短突变体切割人IgG1产生的切割产物SDS-PAGE凝胶 电泳图(酶:底物=1:1000)。
图6为5个组合突变体切割人IgG1产生的切割产物SDS-PAGE凝胶电泳图(酶:底物=1:2000)。
图7为50℃条件下保温1h后5个组合突变体切割人IgG1产生的切割产物SDS-PAGE凝胶电泳图(酶:底物=1:2000)。
图8为不同浓度的E97D_del18突变体和IdeS切割人IgG1产生的切割产物SDS-PAGE凝胶电泳图。
图9为不同浓度的E97D_del18突变体和IdeZ切割人IgG1产生的切割产物SDS-PAGE凝胶电泳图。
图10为E97D_del18突变体在小鼠血清和血浆中切割人IVIg产生的切割产物SDS-PAGE凝胶电泳图。
图11为E97D_del18突变体在小鼠和人血清中产生的切割产物SDS-PAGE凝胶电泳图。
图12A-12D为不同浓度的E97D_del18在比格犬、大鼠、小鼠、兔、猴和猪血清中切割IgG产生的切割产物SDS-PAGE凝胶电泳图。
图13为E97D_del18在小鼠体内不同时间内切割人IVIg产生的切割产物SDS-PAGE凝胶电泳图。
图14A和14B为具有不同突变组合的突变体和IdeE切割人IgG1产生的切割产物SDS-PAGE凝胶电泳图(酶:底物=1:2000)。
图15A为IDEEV2活性检测图谱,泳道1~5分别为未酶切IgG1,IdeZ、IdeS、IdeE、IDEEV2酶切后的IgG1(非还原电泳)。
图15B为IDEEV2突变体热稳定性生物学活性检测图谱。泳道1~3分别为IDEEV2、E97D_del18、IdeE酶切后的IgG1(非还原电泳)。
图16A为IDEEV2突变体和IdeS切割人IgG1~4产生的切割产物的SDS-PAGE凝胶电泳图(酶:底物=1:200)。泳道1~12分别为依次IgG1、IgG2、IgG3、IgG4的非酶切对照及IDEEV2:底物为1:200的酶切(非还原电泳)
图16B为IDEEV2突变体和IdeS切割人不同免疫球蛋白产生的切割产物的SDS-PAGE凝胶电泳图(酶:底物=1:200)。泳道1~12分别为依次IgG、IgM、IgA、IgE、IgD的非酶切对照及IDEEV2:底物为1:200的酶切(还原电泳)。
图17为IDEEV2突变体和不同动物种属纯化IgG酶切图谱。泳道1~12 依次分别为兔IgG、犬IgG、大鼠IgG、小鼠IgG、猴IgG、人IgG、人IgG1的非酶切及IDEEV2对应的酶切图。(IDEEV2:底物为1:200)。
图18A为IDEEV2静脉输注给予新西兰兔,每周给药1次,给药2次,2mg/kg剂量组动物体内IgG含量随时间变化情况(SDS-PAGE检测结果)。
图18B为IDEEV2静脉输注给予新西兰兔,每周给药1次,给药2次,2mg/kg剂量组动物体内IgG含量随时间变化情况(ELISA检测结果)。
图19A为IDEEV2静脉输注给予Beagle犬,每周给药1次,给药2次,各剂量组动物体内IgG含量随时间变化情况(SDS-PAGE检测结果)a.0.2mg/kg剂量组动物;b.2mg/kg剂量组动物;c.20mg/kg剂量组动物。
图19B为IDEEV2静脉输注给予Beagle犬,每周给药1次,给药2次,各剂量组动物体内IgG含量随时间变化情况(ELISA检测结果)。
图20A为IDEEV2腹腔注射抗血小板抗体造模动物,期间各组动物血小板计数变化。
图20B为IDEEV2腹腔注射抗血小板抗体造模动物,期间各组动物存活率结果。
图21为免疫球蛋白降解酶突变体可排除免疫球蛋白对单抗抗肿瘤效果的负面影响。
图22A为AAV9-Fluc感染小鼠后的全身转导效果图。从左至右分别为1)荧光对照组(AAV9-Fluc);2)模型组(IVIg+AAV9-Fluc);3)供试品组(IVIg+E97D_del18+AAV9-Fluc)。图22B显示AAV9-Fluc感染小鼠后的全身转导效果。
图23显示AAV9-Fluc感染小鼠后的心脏、肝脏转导效果。
发明详述
I.免疫球蛋白降解酶IdeE的突变体
与IdeS序列同源性为70%左右的IdeE蛋白酶来源于马链球菌兽疫亚种Streptococcus equi ssp.equi,是一种马的致病菌(Jonas
Bengt Guss.FEMS Microbiol Lett,2006,262:230-235)。IdeE与IdeS这两种酶在完全相同的位置切断IgG,切割具有高度可重复性和特异性,并且有着非常类似的底物范围。由于IdeE来自马致病菌,推测其在人体内预先存在的抗体可能远低于IdeS,更适合开发用于治疗和预防由IgG抗体介导疾病的免疫抑制剂。 但野生型IdeE和IdeS一样,也存在活性低的问题。
因此,本发明涉及一种免疫球蛋白降解酶IdeE的突变体,所述突变体具有免疫球蛋白降解酶活性并选自下组:
(1)在SEQ ID NO:2的第8、10、24、59、97和280中的一位或者多位氨基酸进行替换后得到突变体;和/或,
(2)SEQ ID NO:2的N端的截短突变体,选自删除其N端的前1个、前2个、前3个、前4个、前5个、前6个、前7个、前8个、前9个、前10个、前11个、前12个、前13个、前14个、前15个、前16个、前17个、前18个或者前19个氨基酸序列;和/或,
(3)SEQ ID NO:2的C端的截短突变体,选自删除其C端的最后1个、最后2个、最后3个、最后4个、最后5个、最后6个、最后7个、最后8个、最后9个或者最后10个氨基酸序列。
本发明的突变体具有所述免疫球蛋白降解酶IdeE的功能,优选地还具有提高的IgG切割活性和热稳定性。
本发明中的术语“具有高于或等于免疫球蛋白降解酶IdeE的活性”指的是所述突变体降解免疫球蛋白的能力优于或等于野生型免疫球蛋白降解酶IdeE。
本发明中的术语“比IdeE具有更高的热稳定性“指的是所述突变体在某温度下维持一段时间后,降解免疫球蛋白的能力优于同等条件下的野生型免疫球蛋白降解酶IdeE。
本发明的突变体优选通过基因工程重组方式生产得到。
优选地,所述突变体与SEQ ID NO:2所示序列具有至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%的同一性。
更优选地,对所述位置8、10、24、59、97或者280的氨基酸进行替换,例如所得突变体的氨基酸序列如SEQ ID NO:3~17、SEQ ID NO:35中任一所示;
或者删除所述免疫球蛋白降解酶IdeE N端的前15个、前16个、前17个、前18个或者前19个氨基酸,所得突变体的氨基酸序列如SEQ ID NO:18~22中任一所示;
或者删除所述免疫球蛋白降解酶IdeE C端的最后1个、最后5个、最后8个或者最后10个氨基酸,例如所得突变体的氨基酸序列如SEQ ID NO:23~24中任一所示;
或者对所述位置8、10、24、59、97或者280进行替换并同时删除所述免疫球蛋白降解酶IdeE N端的前15个、前16个、前17个、前18个或者前19个氨基酸,优选删除前18个氨基酸,例如所得突变体的氨基酸序列如SEQ ID NO:25~29中任一所示。
或者对所述位置8、10、24、59、97或者280进行替换并同时删除所述免疫球蛋白降解酶IdeE N端的前15个、前16个、前17个、前18个或者前19个氨基酸并同时删除所述免疫球蛋白降解酶IdeE C端的最后1个、最后5个、最后8个或者最后10个氨基酸,优选删除前18个氨基酸,优选删除后5个氨基酸,例如所得突变体的氨基酸序列如SEQ ID NO:30~34中任一所示。
在本发明一个优选的实施方案中,所述氨基酸的替换选自下组:
(1)SEQ ID NO:2的位置8处的苏氨酸被替换成半胱氨酸、苯丙氨酸、色氨酸、酪氨酸、天冬氨酸、谷氨酸、丙氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、蛋氨酸、天冬酰胺、脯氨酸、谷氨酰胺、丝氨酸、缬氨酸、精氨酸和赖氨酸中的任意一种;
(2)SEQ ID NO:2的位置10处的丙氨酸被替换成半胱氨酸、天冬氨酸、谷氨酸、苯丙氨酸、甘氨酸、组氨酸、异亮氨酸、赖氨酸、亮氨酸、蛋氨酸、天冬酰胺、脯氨酸、谷氨酰胺、精氨酸、丝氨酸、苏氨酸、缬氨酸、色氨酸和酪氨酸中的任意一种;
(3)SEQ ID NO:2的位置24处的苏氨酸被替换成丙氨酸、半胱氨酸、天冬氨酸、天冬酰胺、谷氨酸、苯丙氨酸、甘氨酸、组氨酸、异亮氨酸、赖氨酸、亮氨酸、蛋氨酸、脯氨酸、谷氨酰胺、精氨酸、丝氨酸、缬氨酸、色氨酸和酪氨酸中的任意一种;
(4)SEQ ID NO:2的位置59处的丙氨酸被替换成半胱氨酸、天冬氨酸、谷氨酸、苯丙氨酸、甘氨酸、组氨酸、异亮氨酸、赖氨酸、亮氨酸、蛋氨酸、天冬酰胺、脯氨酸、谷氨酰胺、精氨酸、丝氨酸、苏氨酸、缬氨酸、色氨酸和酪氨酸中的任意一种;
(5)SEQ ID NO:2的位置97处的谷氨酸被替换成丙氨酸、半胱氨酸、天 冬氨酸、苯丙氨酸、甘氨酸、组氨酸、异亮氨酸、赖氨酸、亮氨酸、蛋氨酸、天冬酰胺、脯氨酸、谷氨酰胺、精氨酸、丝氨酸、苏氨酸、缬氨酸、色氨酸和酪氨酸中的任意一种;
(6)SEQ ID NO:2的位置280处的精氨酸被替换成丙氨酸、天冬氨酸、谷氨酸、半胱氨酸、丝氨酸、苯丙氨酸、组氨酸、异亮氨酸、赖氨酸、亮氨酸、蛋氨酸、天冬酰胺、脯氨酸、谷氨酰胺、苏氨酸、缬氨酸、色氨酸和酪氨酸中的任意一种。
在本发明一个更优选的实施方案中,所述氨基酸的替换选自下组:
(1)SEQ ID NO:2的位置8处的苏氨酸被替换成天冬氨酸、谷氨酸、色氨酸或酪氨酸;
(2)SEQ ID NO:2的位置10处的丙氨酸被替换成赖氨酸或精氨酸;
(3)SEQ ID NO:2的位置24处的苏氨酸被替换成丙氨酸、甘氨酸或丝氨酸;
(4)SEQ ID NO:2的位置59处的丙氨酸被替换成异亮氨酸、亮氨酸或缬氨酸;
(5)SEQ ID NO:2的位置97处的谷氨酸被替换成天冬酰胺;和/或
(6)SEQ ID NO:2的位置280处的精氨酸被替换成组氨酸或赖氨酸。
在另一优选的实施方案中,基于SEQ ID NO:9、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:1、SEQ ID NO:5和SEQ ID NO:16这5个经氨基酸替换得到的序列进一步删除其N端的前18个氨基酸,所得突变体的氨基酸序列如序列表中SEQ ID NO:25~29所示。
在另一优选的实施方案中,基于SEQ ID NO:26~29这5个经氨基酸替换得到的序列进一步删除其C端的5个或10氨基酸,所得突变体的氨基酸序列如序列表中SEQ ID NO:30~34所示。
在另一优选的实施方案中,基于SEQ ID NO:14~16这3个突变体进一步进行组合突变,所得突变体的氨基酸序列如序列表中SEQ ID NO:35所示。在另一优选的实施方案中,基于SEQ ID NO:9、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:1、SEQ ID NO:5和SEQ ID NO:16这5个经氨基酸替换得到的序列进一步删除其N端的前18个氨基酸,所得突变体的氨基酸序列如序列表中SEQ ID NO:25~29所示。
在另一优选的实施方案中,突变体的氨基酸序列如序列表中SEQ ID NO:36所示。
优选地,还可以对本发明中所述的突变体进行进一步的突变,进一步突变后所得的变体的序列与SEQ ID NO:2的序列具有至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%的同一性,同时具有免疫球蛋白降解酶IdeE的功能。
本发明使用的IdeE全序列作为GenBank登录号ABF57910.1是公众可获得的,其序列在本文中作为SEQ ID NO:1提供。该序列包括N末端甲硫氨酸,接着是33个氨基酸的分泌信号序列,接着是IdeE编码序列。N末端甲硫氨酸和信号序列通常被去除以形成成熟的IdeE蛋白,其序列在本文中作为SEQ ID NO:2提供。除非另有说明,对本文公开的免疫球蛋白降解酶序列中氨基酸位置的编号的所有提及均基于从N末端开始的SEQ ID NO:2中相应位置的编号。
本发明还涉及包含本发明的突变体的蛋白。
在一个优选的实施例中,所述蛋白为在上述突变体的N末端包含信号肽;优选地,所述蛋白在所述突变体的N末端连接有分泌信号序列并在所述分泌序列的N末端连接有甲硫氨酸和/或在所述突变体的C末端连接有组氨酸标签;更优选地,所述蛋白从N末端至C末端包含如下或由如下组成:甲硫氨酸、分泌信号序列和所述突变体。
II.药物组合物
本发明涉及一种组合物,其包括本发明的免疫球蛋白降解酶突变体或者包含所述突变体的蛋白,以及任选的药学上可接受的载体或赋形剂。
在一个具体的实施方案中,本发明的组合物进一步包含:抗体、小分子靶向药物和/或含有Fc的蛋白。
在一个具体的实施方案中,所述抗体的靶点选自下组:细胞表面蛋白、细胞因子、激素、酶、胞内信使、胞间信使和免疫检查点。
在一个具体的实施方案中,本发明的组合物进一步包含:病毒载体药物或基因治疗药物,优选地,所述病毒载体药物选自下组:溶瘤病毒、基因治疗病毒和病毒载体疫苗。
在一个具体的实施方案中,本发明的组合物进一步包含:能降低血液IgG水平的药物,优选的,所述降低血液IgG水平的药物选自下组:FcRn抗体、 与FcRn高亲和力的Fc片段变体。
2.1抗体
优选地,如上所述的组合物,其中,所述抗体的靶点可为细胞表面蛋白,包括但不限于:AFP、αv整联蛋白(integrin)、α4β7整联蛋白、BCMA、CD2、CD3、CD4、CD11a、CD19、CD20、CD22、CD25、CD30、CD32、CD33、CD36、CD38、CD40、CD46、CD47、CD52、CD56、CD64、CD70、CD74、CD79、CD80、CD86、CD105、CD121、CD123、CD133、CD138、CD174、CD205、CD227、CD326、CD340、CEA、c-Met、Cripto、CA1X、Claudin6、Claudin18.2、ED-B、EGFR、EpCAM、EphA2、EphB2、FAP、FOLR1、GD2、Globo H、GPC3、GPNMB、GPRC5D、HER-1、HER-2、HER-3、MAGE-A3、Mesothelin、MUC1、MUC4、MUC16、PSMA、TMEFF2、TAG-72、5T4、ROR-1、Sca-1、SP、Trop-2、CD38、CGRP、IGF-1R、Nectin-4、P-Selectin、vWF、KLK、CCR4、SLAMF7、PCSK9、GD2、VEGFR2、BLyS、RANKL、α4β1整联蛋白、VEGFR、血小板糖蛋白Iib/IIIa、IFNAR1、TSLP、VEGF或WT1。
所述抗体的靶点可为细胞因子中的一种或多种,包括但不限于:白介素IL-1至IL-13、IL-1β、IL15、IL17、IL-23p19、IL2R、IL-5R、IL-6R、IL-17R、IL-2R、肿瘤坏死因子α和β、干扰素α、β和γ、VEGF、PDGF-α、FGF-23、Sclerostin、肿瘤生长因子β(TGF-β)、集落刺激因子(CSF)或粒细胞单核细胞集落刺激因子(GM-CSF)。见Human Cytokines:Handbook for Basic&Clinical Research(Aggrawal等编,Blackwell Scientific,Boston,MA 1991)。
所述抗体的靶点可为激素、酶、胞内和胞间信使,例如:腺苷环化酶、鸟苷环化酶或磷脂酶C。
所述抗体的靶点可为免疫检查点中的一种或多种,包括但不限于:CTLA-4、PD-1、PD-L1、TIM-3、LAG3、Siglec7、Siglec9、Siglec15、4-1BB、GITR、OX40、CD40L、CD28、TIGIT、VISTA。
所述抗体的靶点可为IgE、RSV F、新冠病毒、Dabigatran、FIX/FX、艰难梭菌毒素B、C2、C5、炭疽菌的PA。
所述抗体可选自Satralizumab、Belantamab mafodotin、Tafasitamab、Inebilizumab、Sacituzumab govitecan、Isatuximab、Eptinezumab、Teprotumumab、Trastuzumab deruxtecan、Enfortumab Vedotin、Romosozumab、Crizanlizumab、 Brolucizumab、Polatuzumab、Risankizumab、Caplacizumab、Emapalumab、Ravulizumab、Cemiplimab、galcanezumab、Fremanezumab、Moxetumomab Pasudotox、Lanadelumab、Mogamulizumab、Erenumab、Burosumab、Tildrakizumab、Ibalizumab、Emicizumab、Benralizumab、inotuzumab ozogamicin、Sarilumab、Guselkumab、Durvalumab、Dupilumab、Ocrelizumab、Avelumab、Brodalumab、Daclizumab、Bezlotoxumab、Olaratumab、Atezolizumab、Obiltoxaximab、Ixekizumab、Reslizumab、Idarucizumab、Mepolizumab、Elotuzumab、Necitumumab、Evolocumab、Alirocumab、Daratumumab、Dinutuximab、Secukinumab、Blinatumomab、Pembrolizumab、Nivolumab、Vedolizumab、Siltuximab、Ramucirumab、Obinutuzumab、Ado-Trastuzumab emtansine、Raxibacumab、Pertuzumab、Brentuximab vedotin、Belimumab、Ipilimumab、Tocilizumab、Denosumab、Denosumab、Ofatumumab、Canakinumab、Golimumab、Ustekinumab、Certolizumab pegol、Eculizumab、Panitumumab、Ranibizumab、Natalizumab、Bevacizumab、Cetuximab、Efalizumab、Tositumomab、Omalizumab、Adalimumab、Ibritumomab tiuxetan、Alemtuzumab、Gemtuzumab Ozogamicin、Trastuzumab、Infliximab、palivizumab、Basiliximab、Daclizumab、Rituximab、Abciximab、Catumaxomab、Muromomab。
2.2小分子靶向药物
优选地,如上所述组合物,其中,所述组合物还包括靶向药物或化疗药物或免疫检查点阻断剂,所述靶向药物选自表观遗传学药物、靶向PI3K/Akt/mTOR信号通路的抑制剂和酪氨酸激酶抑制剂,所述化疗药物选自免疫抑制剂、蛋白酶体抑制剂、细胞毒药物和细胞周期非特异性药物;所述表观遗传学药物例如组蛋白去乙酰化酶抑制剂,所述靶向PI3K/Akt/mTOR信号通路的抑制剂例如Tricibine,所述酪氨酸激酶抑制剂例如舒尼替尼,所述免疫抑制剂例如环磷酰胺,所述蛋白酶体抑制剂例如硼替佐米,所述免疫抑制剂例如沙利度胺、泊马度胺,所述细胞毒药物例如吉西他滨、替莫唑胺,所述细胞周期非特异性药物例如米托蒽醌。
2.3能降低血液IgG水平的药物
优选地,如上所述的组合物,其中,所述能降低血液IgG水平的多肽药物能够阻断血液IgG和FcRn蛋白的结合。优选地,所述多肽与人FcRn蛋白的亲和力高于血液IgG和人FcRn蛋白的亲和力;所述IgG选自IgG1、 IgG2、IgG3、IgG4。优选地,所述多肽包含抗体Fc片段变体,所述变体包含能够提高Fc和FcRn亲和力的突变,所述突变优选为YTE、YTEKF、LS、NHS,所述抗体Fc片段例如Efgartigimod。所述变体可以为单体、二聚体、多聚体。可用于本发明的所述YTE、YTEKF、LS、NHS等突变,所述突变的位置分别如Dall'Acqua等所描述(WF,D.A.等(2002).Journal of immunology(Baltimore,Md.:1950)169(9):5171-5180.)、Lee等所描述(Lee,C.H.等(2019).Nat Commun 10(1):5031.)。所述突变对象选自人IgG,所述IgG选自IgG1、IgG2、IgG3、IgG4。
可用于本发明的其他Fc片段变体,所述变体包含包括但不限于Dall'Acqua等描述的突变(WF,D.A.等(2002).Journal of immunology(Baltimore,Md.:1950)169(9):5171-5180.)、Shan等描述的突变(Shan,L.等(2016).PLoS One 11(8):e0160345.)、Lee等描述的突变(Lee,C.H.等(2019).Nat Commun 10(1):5031.)、Mackness等描述的突变(Mackness,B.C.等(2019).MAbs 11(7):1276-1288.)、Christophe等描述的突变(Dumet Christophe,Pottier Jérémy,Gouilleux-Gruart Valérie等,MAbs,2019,11:1341-1350.)。
优选地,所述多肽包含抗体Fc片段变体,所述变体包含能够提高Fc和FcγR亲和力的突变,所述变体优选为S239D/I322E、S239D/I322E/A330L、K326W/E333S、R214K突变;所述变体优选为无岩藻糖修饰。所述变体可以为单体、二聚体、多聚体。可用于本发明的其他Fc片段变体,所述变体包含包括但不限于Wang等描述的突变(Wang Xinhua.,Mathieu Mary.,Brezski Randall J.(2018).Protein Cell,9(1),63-73.doi:10.1007/s13238-017-0473-8)。
优选地,所述包含能够提高Fc和FcRn亲和力的变体同时包含能够提高Fc和FcγR亲和力的突变。所述变体可以为单体、二聚体、多聚体。
优选地,如上所述的药物组合,其中,所述多肽选自抗FcRn抗体,所述抗体例如Nipocalimab、Rozanolixizumab、RVT-1401、HBM9161、ALXN1830、SYNT001、Nirsevimab。
优选地,如上所述的药物组合,其中,所述多肽选自能特异性结合FcRn的小肽片段,所述小肽片段的长度为10-70个氨基酸;所述小肽片段例如ABY-039。
优选地,所述多肽选自能特异性结合FcRn的Fc多聚体,所述Fc多聚体例如GL-2045、M230、PRIM、HexaGard
TM、CSL777、Hexavalent molecules by UCB。
优选地,所述多肽包括但不限于Sockolosky等描述的多肽片段(Sockolosky Jonathan T,Szoka Francis C.Adv.Drug Deliv.Rev.,2015,91:109-24)。
2.4病毒载体药物
优选地,如上所述的组合物,其中,所述病毒载体药物中,所述病毒载体药物所用的病毒选自ssDNA类病毒、dsDNA类病毒、ssRNA类病毒或dsRNA类病毒;和/或,所述病毒载体药物所用的病毒选自野生型病毒株或自然减毒株、基因工程选择性减毒株、基因加载型病毒株、基因转录靶向型病毒株。
优选地,所述野生型病毒株或自然减毒株选自新城疫病毒、呼肠孤病毒、流行性腮腺炎病毒、西尼罗河病毒、腺病毒、牛痘病毒等。
优选地,所述基因工程选择性减毒株通过人工方式删除关键基因而实现病毒复制的肿瘤选择性,例如胸苷激酶(Thymidinekinase,TK)敲除的基因改造人单纯疱疹病毒I(HSV-1),所述基因工程选择性减毒株例如ONYX-015、G207。ONYX-015在E1b区域删除了827bp,并且在针对E1B55K蛋白的基因进行点突变,使其表达基因提前终止,无法表达E1B55K蛋白。G207删除了γ34.5基因,该基因为HSV-1的神经毒性决定因素。
优选地,所述基因加载型病毒株加载了外源基因,所述外源基因例如为粒细胞巨噬细胞集落刺激因子(GM-CSF),所述基因加载型病毒株例如为JX-594或T-VEC。
优选地,所述基因转录靶向型病毒株,即在病毒必需基因前插入组织或肿瘤特异性启动子来控制溶瘤病毒在肿瘤细胞内复制,所述基因转录靶向型病毒株例如为G92A。
优选地,如上所述的药物组合,其中,所述ssDNA类病毒选自细小病毒(parvovirus),优选所述细小病毒为H-1PV病毒。
优选地,所述dsDNA类病毒选自单纯疱疹病毒(herpes simplex virus)、腺病毒(adeno virus)、poxvirus;更优选地,所述单纯疱疹病毒优选为I型单纯疱疹病毒HSV-1,例如为R3616、T-VEC、HF10、G207、NV1020、OrienX010,所述poxvirus选自Pexa-Vec(vaccinia viruse)、JX-594(vaccinia viruse)、GL-ONC1、Myxoma;所述腺病毒选自Enadenotucirev、DNX-2401、C-REV、NG-348、ProsAtak、CG0070、ADV-TK、EDS01、KH901、H101、H103、VCN-01、Telomelysin(OBP-301)。
优选地,所述ssRNA类病毒选自Picornavirus、alphavirus、Retroviruses、 Paramyxoviruses、Rhabdoviruses;优选地,所述Picornavirus选自CAVATAK、PVS-RIPO、CVA21(enterovirus)、RIGVIR,所述alphavirus选自M1、Sindbis AR339、Semliki Forest virus,所述Retroviruses选自Toca511,所述Paramyxoviruses选自MV-NIS、PV701(Newcastle disease virus),所述Rhabdoviruses选自VSV-IFNβ、MG1-MAGEA3、VSV-GP。
优选地,所述dsRNA类病毒选自Reoviruses;优选地,所述Reoviruses选自Pelareorep、呼肠孤病毒(Reolysin)、牛痘病毒(vaccinia virus)、腮腺炎病毒、人类免疫缺陷病毒(human immunodeficiency virus,HIV);优选的,所述RNA类病毒选自呼肠孤病毒(reovirus)、柯萨奇病毒(coxsackievirus)、脊髓灰质炎病毒(polio virus)、猪塞内加谷病毒(seneca valley virus)、麻疹病毒(measles virus)、新城疫病毒(newcastle disease virus)、水泡性口炎病毒(vesicular stomatitis virus)、流感病毒。
优选地,如上所述的药物组合,其中,所述溶瘤病毒表达外源基因,所述外源基因优选双特异性T细胞结合子(Bispecific T cell engagers,BiTE)、scFv片段、细胞因子、趋化因子。所述BiTE能结合CD3等激活T细胞的分子,同时能结合癌细胞表面的抗原靶点;所述scFv靶向免疫检查点;所述免疫检查点包括CTLA-4、PD-1、TIM-3、LAG3、Siglec15、4-1BB、GITR、OX40、CD40L、CD28、TIGIT、VISTA。所述细胞因子、趋化因子例如GM-CSF、白细胞介素-2(IL-2)、白细胞介素-12(IL-12)、白细胞介素-15(IL-15)、干扰素(IFN)、肿瘤坏死因子(TNF)、可溶性CD80、CCL3。
在一些实施案例中,所述病毒药物载体优选为AAV病毒,例如AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV3B、AAV-2i8、Rh10、Rh74。
在一些实施案例中,所述病毒药物载体优选为腺病毒、慢病毒、逆转录病毒。
所述的病毒载体药物和/或免疫球蛋白降解酶变体可以用脂质体、纳米颗粒、脂质纳米颗粒、聚合物、微粒、微胶囊、胶束或外泌体包裹或者融合。
2.5基因治疗药物
优选地,如上所述的组合物,其中,所述基因治疗病毒表达外源基因,所述外源基因编码基因缺陷疾病所需的蛋白,所述蛋白选自酸性α-葡糖苷酶、铜转运ATPase2、α半乳糖苷酶、精氨酸琥珀酸酯合酶、β-葡萄糖脑苷脂酶、 β-己糖胺酶A、Cl蛋白酶抑制剂或Cl酯酶抑制剂、葡萄糖6磷酸酶、胰岛素、胰高血糖素、生长激素、甲状旁腺激素、生长激素释放因子、卵泡刺激素、黄体生成激素、人绒毛膜促性腺激素、血管内皮生长因子、血管生成素、血管生成抑制素、粒细胞集落刺激因子、促红细胞生成素、结缔组织生长因子、碱性成纤维细胞生长因子、酸性成纤维细胞生长因子、表皮生长因子、转化生长因子a、血小板衍生生长因子、胰岛素生长因子I和II、TGF、骨形态发生蛋白、神经生长因子、脑源性神经营养因子、神经营养蛋白NT-3和NT4/5、睫状神经营养因子、神经胶质细胞系衍生神经营养因子、神经营养素、凝集素、netrin-1和netrin-2、肝细胞生长因子、ephrins、酪氨酸羟化酶、血小板生成素、白介素(IL-1至IL-36等)、单核细胞趋化蛋白、白血病抑制因子、粒细胞巨噬细胞的蛋白质集落刺激因子、Fas配体、肿瘤坏死因子a和b、干扰素a/b/g、干细胞因子、flk-2/flt3配体、IgM,IgA,IgD和IgE、嵌合免疫球蛋白、人源化抗体、单个链抗体、T细胞受体、嵌合T细胞受体、单链T细胞受体、I类和II类MHC分子、囊性纤维化跨膜调节蛋白、凝血(凝血)因子(因子XIII,因子IX,因子VIII,因子X,因子VII,因子VIIa,蛋白C等)、视网膜色素上皮特异性65kDa蛋白、LDL受体、脂蛋白脂肪酶、鸟氨酸转氨甲酰酶、β-球蛋白、α-球蛋白、血影蛋白、α-抗胰蛋白酶腺苷脱氨酶、金属转运蛋白(ATP7A或ATP7)、磺酰胺酶、参与溶酶体贮积病的酶(ARSA)、次黄嘌呤鸟嘌呤磷酸核糖基转移酶、b-25葡糖脑苷脂酶、鞘磷脂酶、溶酶体己糖胺酶、支链酮酸脱氢酶。
优选地,如上所述的组合物,其中,所述基因治疗病毒携带外源基因,所述外源基因编码选自siRNA,反义分子,miRNA,RNAi,核酶和shRNA的抑制性核酸。所述抑制性核酸结合至多核苷酸重复疾病相关的基因,该基因的转录物或该基因的转录物的多核苷酸重复。所述疾病基因编码相关蛋白,所述蛋白选自选自亨廷顿蛋白(HTT)、脊髓球肌萎缩症X染色体上的雄激素受体、人Ataxin-1/-2/-3/-7、Cav2.1P/Q电压依赖性钙通道(CACNA1A)、TATA结合蛋白、Ataxin8反向链(ATXN80S)、丝氨酸/苏氨酸蛋白磷酸酶2A55kDa脊髓小脑性共济失调的亚型B亚型β亚型(1、2、3、6、7、8、1217型)、FMR1(脆性X综合征的脆弱性1)、脆性X相关性震颤/共济失调综合征的FMR1(脆性X智力障碍1)、脆性XE智力低下的FMR1(脆性X智力障碍2)或AF4/FMR2家庭成员2;肌强直性营养不良中的肌钙蛋白激酶 (MT-PK)、Frataxin。所述疾病基因选自,超氧化物歧化酶1(SOD1)基因的突变体、与帕金森氏病和/或阿尔茨海默氏病发病机理有关的基因、载脂蛋白B(APOB)、PCSK9、HIV感染相关基因(HIVTat、TAR、HIVTAR、CCR5)、流感病毒感染中的甲型流感病毒基因组/基因序列、SARS感染中的严重急性呼吸综合征(SARS)冠状病毒基因组/基因序列、呼吸道合胞病毒感染中的呼吸道合胞病毒基因组/基因序列、埃博拉病毒感染中的埃博拉病毒基因组/基因序列、乙型和丙型肝炎病毒在乙型和丙型肝炎病毒中的基因组/基因序列、HSV感染的单纯疱疹病毒(HSV)基因组/基因序列、柯萨奇病毒B3感染的柯萨奇病毒B3基因组/基因序列、沉默原发性肌张力障碍中基因的致病性等位基因(等位基因特异性沉默)如torsinA、在移植中特异性泛I类和HLA等位基因、常染色体显性遗传性视网膜色素变性中的突变和视紫红质基因。
III.产品和试剂盒
本发明还提供了一种产品,所述产品含有本发明的突变体、蛋白和/或组合物和另外的治疗剂;所述另外的治疗剂选自病毒载体药物、抗体、能降低血液IgG水平的多肽药物。
本发明还提供了一种试剂盒或套装药盒,所述试剂盒包含:1)治疗有效量的包含本发明的突变体、蛋白和/或组合物的药物;和2)治疗有效量的另外的治疗剂;所述治疗剂选自病毒载体药物、抗体、能降低血液IgG水平的多肽药物;所述病毒载体药物优选溶瘤病毒、基因治疗病毒。所述试剂盒还可以包括3)靶向药物或化疗药物或免疫检查点阻断剂。所述靶向药物选自表观遗传学药物、靶向PI3K/Akt/mTOR信号通路的抑制剂和酪氨酸激酶抑制剂,所述化疗药物选自免疫抑制剂、蛋白酶体抑制剂、细胞毒药物和细胞周期非特异性药物;所述表观遗传学药物例如组蛋白去乙酰化酶抑制剂,所述靶向PI3K/Akt/mTOR信号通路的抑制剂例如Tricibine,所述酪氨酸激酶抑制剂例如舒尼替尼,所述免疫抑制剂例如环磷酰胺,所述蛋白酶体抑制剂例如硼替佐米,所述免疫抑制剂例如沙利度胺、泊马度胺,所述细胞毒药物例如吉西他滨、替莫唑胺,所述细胞周期非特异性药物例如米托蒽醌。
所述试剂盒或套装药盒包括药盒A和药盒B,所述药盒A包括治疗有效量的本发明的突变体、蛋白和/或组合物,所述药盒B包括治疗有效量的另外的治疗剂;所述治疗剂选自病毒载体药物、抗体、能降低血液IgG水平 的多肽药物;所述病毒载体药物优选溶瘤病毒、基因治疗病毒。所述套装药盒还可以包括药盒C。所述药盒C包括靶向药物或化疗药物或免疫检查点阻断剂。所述靶向药物选自表观遗传学药物、靶向PI3K/Akt/mTOR信号通路的抑制剂和酪氨酸激酶抑制剂,所述化疗药物选自免疫抑制剂、蛋白酶体抑制剂、细胞毒药物和细胞周期非特异性药物;所述表观遗传学药物例如组蛋白去乙酰化酶抑制剂,所述靶向PI3K/Akt/mTOR信号通路的抑制剂例如Tricibine,所述酪氨酸激酶抑制剂例如舒尼替尼,所述免疫抑制剂例如环磷酰胺,所述蛋白酶体抑制剂例如硼替佐米,所述免疫抑制剂例如沙利度胺、泊马度胺,所述细胞毒药物例如吉西他滨、替莫唑胺,所述细胞周期非特异性药物例如米托蒽醌。
该试剂盒可以包含涉及治疗有效量的本发明的突变体、蛋白和/或组合物和治疗有效量的另外的治疗剂施用(例如,剂量信息、给药时间间隔信息)的说明书。所述另外的治疗剂选自病毒载体药物、抗体、能降低血液IgG水平的多肽药物;所述病毒载体药物优选溶瘤病毒、基因治疗病毒。
可利用成熟完善的表达系统来制造病毒载体药物。一些方法示例包括利用哺乳动物细胞表达系统来产生病毒颗粒,例如使用HEK293细胞生产腺病毒类病毒载体药物(Freedman Joshua D,Duffy Margaret R,Lei-Rossmann Janet等,An Oncolytic Virus Expressing a T-cell Engager Simultaneously Targets Cancer and Immunosuppressive Stromal Cells.[J].Cancer Res.,2018,78:6852-6865)。
药物载剂可以是液体,并且药物组合物可以为溶液形式。液体载剂用于制备溶液、悬浮液、乳液、糖浆、酏剂和加压组合物。活性成分可以溶解或悬浮在药学上可接受的液体载剂中,例如水、有机溶剂、二者的混合物或药学上可接受的油或脂肪。
用于肠胃外施用的药物组合物是无菌的、基本上等渗的、无热原的,并根据FDA或类似机构的GMP来制备。病毒载体药物可以作为该物质的溶液或悬浮液的可注射剂型施用,其中,该物质处在生理上可接受的稀释剂和药物载剂(可以是无菌液体,例如水、油、盐水、甘油或乙醇)中。另外,组合物中可存在辅助物质,例如润湿剂或乳化剂、表面活性剂和pH缓冲物质等。药物组合物的其他组分有石油、动物、植物或合成来源的组分,例如花生油、大豆油和矿物油。通常,例如丙二醇或聚乙二醇等二醇是优选的液体载剂,对于可注射溶液尤其如此。病毒载体药物可以以积存注射剂或植入制 剂的形式施用,这些形式能够被配制成允许活性成分持续释放。通常,将组合物制备成可注射物,即液体溶液或悬浮液;也可以制备成适合于在注射前溶解或悬浮在液体载质中的固体形式。
IV.突变体、蛋白、药物组合物和试剂盒的用途
本发明还涉及本发明的突变体、蛋白、组合物和/或试剂盒在制备药物中的用途。在一些实施例中,所述药物用于治疗受试者中的自身抗体介导的病症。在一些实施例中,所述药物用于降低受试者中的IgG水平。在一些实施例中,所述药物用于预防和/或治疗受试者中的实体器官移植后自身抗体介导的器官排斥。在一些实施例中,所述药物用于基因治疗。在一些实施例中,所述药物用于在病毒载体为基础的基因治疗前清除体内预存的抗病毒载体的中和抗体。在一些实施例中,所述药物用于治疗受试者中的肿瘤。在一些实施例中,所述药物用于清除受试者中的自身抗体以使得含Fc剂更好发挥疗效。在一些实施例中,所述药物用于在已施用含Fc剂的受试者中降低所述含Fc剂的血清水平。
在一优选实施例中,本发明的突变体、蛋白、组合物和/或试剂盒可用于IgG的分析。其中,将使用本发明的突变体、蛋白、组合物和/或试剂盒切割IgG后得到Fc和F(ab’)2片段用于例如质谱分子量分析、糖型修饰分析、ADC分子分析等。
在另一优选实施例中,本发明的突变体、蛋白、组合物和/或试剂盒还可用于制备Fab抗体片段。其中通过对使用本发明的突变体、蛋白、组合物和/或试剂盒切割IgG后所产生的F(ab’)2片段进行还原来制备Fab片段。
4.1自身抗体介导的病症
本发明涉及本发明的突变体、蛋白、组合物和/或试剂盒在制备用于治疗受试者中的自身抗体介导的病症的药物中的用途。在一些实施例中,所述自身抗体介导的病症为自身免疫性疾病和/或由致病性抗体介导的疾病或病症。
优选地,所述疾病为由致病性抗体介导的疾病或病症;包括但不限于所述由致病性IgG介导的自身免疫性疾病或病症,例如阿狄森氏病、斑秃、强直性脊椎炎、抗磷脂综合征、再生障碍性贫血、抗GBM肾小球肾炎、抗NMDAR脑炎、抗磷脂血症综合征、自身免疫性胃炎、自身免疫性失聪、自身免疫性溶血性贫血、自身免疫性肝炎、自身免疫性甲状旁腺机能减退、自 身免疫性垂体炎、自身免疫性内耳疾病、自身免疫性淋巴细胞增生综合征、自身免疫性心肌炎、自身免疫性卵巢炎、自身免疫性大疱性皮肤病、自身免疫性睾丸炎、自身免疫性多种内分泌病、贝切特氏病、大疱性类天疱疮、心肌病、炎症性脱髓鞘性多神经病、急性运动性轴索神经病、丘-施氏综合征、腹部疾病、自身免疫性荨麻疹、克罗恩病、CREST综合征、乳糜泻、德戈斯病、抗中性粒细胞胞质抗体相关血管炎症、自身免疫性中性白细胞减少症、后天性大疱性表皮松解、原发性混合冷凝球蛋白血栓、巨细胞动脉炎、肾小球肾炎、古德帕斯彻综合征、格雷夫斯病、格林巴利综合征、桥本甲状腺炎、特发性血小板减少性紫癜、炎性肠病、川崎氏病、美尼尔综合征、混合性结缔组织病、莫伦溃疡、类风湿性关节炎、多发性硬化症、重症肌无力、僵人综合征、完全性先天性心脏阻滞、获得性大疱性表皮松懈病、落叶性天疱疮、寻常天疱疮、恶性贫血、结节性多动脉炎、多腺性自身免疫综合征类型、原发性胆汁性肝硬化、多腺性自身免疫综合征类型、多腺性自身免疫综合征类型、多发性肌炎/皮肌炎、牛皮癣、牛皮癣性关节炎、雷诺综合征、莱特尔综合征、风湿性心脏病、血友病-获得性FVIII缺乏、Lambert-Eaton肌无力综合症、多发性骨髓瘤、肉状瘤病、胶原沉着病、干燥综合征、亚急性甲状腺炎、交感性眼炎、全身性红斑狼疮、高安氏动脉炎、
综合症、I型糖尿病、白癜风、伏格特-小柳-原田三氏综合征或韦格纳肉芽肿病、急性哮喘或慢性哮喘、器官移植排斥、原发性进行性多发性硬化症、系统性硬化症、血清病和免疫复合物超敏反应。
器官移植中宿主IgG会引起急性移植排斥反应。移植排斥反应(transplant rejection)分为两种情况,一种是宿主抗移植物反应(host versus graft reaction,HVGR),另一种是移植物抗宿主反应(graft versus host reaction,GVHR)。在实体器官移植中,主要为宿主抗移植物反应,移植物抗宿主反应罕见。在骨髓移植中,则以移植物抗宿主反应常见。
移植物抗宿主反应GVHR是指受者进行同种异体组织或器官移植后,外来的组织或器官等移植物作为一种异己成分被受者免疫系统识别,后者发起针对移植物的攻击、破坏和清除的免疫学反应。对于人类淋巴细胞抗原(human lymphocyte antigen,HLA)高度敏感的病人,其移植排斥反应更易发生。排斥反应的发生机制主要包括细胞免疫和体液免疫两个方面,其中体液免疫(humoral immunity)是以效应B细胞产生抗体IgG来达到保护目的 的免疫机制。
本发明涉及本发明的突变体、蛋白、组合物和/或试剂盒在制备用于预防和/或治疗受试者中的实体器官移植后自身抗体介导的器官排斥的药物中的用途。在一些实施方案中,所述器官排斥包括但不限于器官移植中同种异体移植物排斥例如:肾脏移植排斥、异体胰岛移植排斥、胰腺移植排斥、心脏移植排斥、肝脏移植排斥、肺移植排斥或小肠移植排斥。
由致病性抗体介导的疾病或病症还包括高球蛋白血症。其中所述的高球蛋白由白细胞产生,所述白细胞选自B细胞、异常B细胞;所述球蛋白包括γ球蛋白;所述的高球蛋白血症包括原发性单克隆丙种球蛋白血症、结缔组织病、肝脏病、传染病、类肉瘤病、重症肌无力、霍奇金病、白塞(Behcet)病、肾炎、过敏性紫癜、免疫性(或自发性)血小板减少症、恶性单克隆丙种球蛋白血症(如多发性骨髓瘤、重链病、恶性淋巴瘤、慢性淋巴细胞白血病、巨球蛋白血症等)、继发性单克隆丙种球蛋白血症(如非淋巴网状系统肿瘤、单核细胞白血病、冷球蛋白血症等)、良性M蛋白血症、意义未明的单克隆丙种球蛋白病(MGUS)、华氏巨球蛋白血症、AL型淀粉样变性、孤立性浆细胞瘤(骨或骨外)、POMES综合征、反应性浆细胞增多症、转移性癌的溶骨性病变、浆母细胞性淋巴瘤、单克隆免疫球蛋白相关肾损害(MGRS)等。所述病症优选多发性骨髓瘤。
本发明还涉及本发明的突变体、蛋白、组合物和/或试剂盒在制备用于治疗或预防疾病的药物中的应用。优选地,所述疾病包括但不限于肿瘤、癌症、传染性疾病、基因缺陷型疾病、由致病性IgG抗体介导的疾病或病症。所述传染性疾病包括病毒感染、细菌感染或真菌感染。
4.2肿瘤或癌症
所述肿瘤或癌症选自由以下组成的组:急性淋巴母细胞白血病、急性髓样白血病、肾上腺皮质癌、AIDS相关的癌症、AIDS相关淋巴瘤、肛门癌、阑尾癌、星形细胞瘤、儿童小脑或大脑癌、基细胞癌、肝外胆管癌、膀胱癌、骨癌、骨肉瘤/恶性纤维组织细胞瘤、脑干胶质瘤、脑癌、脑瘤-小脑星形细胞瘤、脑瘤-大脑星形细胞瘤/恶性胶质瘤、脑瘤-室管膜瘤、脑瘤-髓母细胞瘤、脑瘤-幕上原始神经外胚层瘤、脑瘤-视觉通路和下丘脑胶质瘤、乳腺癌、支气管腺瘤/类癌、Burkitt淋巴瘤、类癌肿瘤、不明原发癌、中枢神经系统淋巴瘤、小脑星形细胞瘤、大脑星形细胞瘤/恶性神经胶质瘤、宫颈癌、慢性淋巴 细胞性白血病、慢性髓性白血病慢性骨髓增殖性疾病、结肠癌、皮肤T细胞淋巴瘤、结缔组织增生性小圆细胞肿瘤、子宫内膜癌、室管膜瘤、食管癌、尤因肿瘤家族中的尤因氏肉瘤、颅外生殖细胞肿瘤、儿童性腺外生殖细胞瘤、肝外胆道癌、眼癌-眼内黑色素瘤、眼癌-视网膜母细胞瘤、胆囊癌、胃癌、胃肠道类癌肿瘤、胃肠道间质瘤(GIST)、颅外、性腺外、或卵巢生殖细胞瘤、妊娠滋养细胞瘤、脑干胶质瘤、童年大脑星形细胞瘤神经胶质瘤、儿童视觉通路和下丘脑神经胶质瘤、胃类癌、毛细胞白血病、头颈癌、心脏癌、肝细胞(肝)癌、霍奇金淋巴瘤、下咽癌、下丘脑和视觉通路胶质瘤、眼内黑色素瘤、胰岛细胞癌(内分泌胰腺)、卡波西肉瘤、肾癌(肾细胞癌)、喉头癌、白血病、急性成淋巴细胞白血病(也称为急性淋巴细胞性白血病)、急性髓样白血病(也称为急性髓细胞性白血病)、慢性淋巴细胞白血病(也称为慢性淋巴细胞性白血病)、慢性髓细胞性白血病(也称为慢性髓样白血病)、毛细胞白血病、唇和口腔癌、脂肪肉瘤、肝癌(原发性)、非小细胞肺癌、小细胞肺癌、淋巴瘤、皮肤T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤(旧分类:除了霍奇金氏淋巴瘤之外的其他全部淋巴瘤)、原发性中枢神经系统淋巴瘤、巨球蛋白血症、骨恶性纤维组织细胞瘤/骨肉瘤、髓母细胞瘤、黑色素瘤、眼内(眼)黑色素瘤、Merkel细胞癌、间皮瘤、成人恶性间皮瘤、原发性隐性转移性鳞状颈部癌、口腔癌、多发性内分泌腺瘤综合征、蕈样肉芽肿、骨髓增生异常综合征、骨髓增生异常/骨髓增生性疾病、慢性骨髓性白血病、成人急性髓样白血病、儿童急性髓样白血病、骨髓增生病、鼻腔和鼻旁窦癌、鼻咽癌、神经母细胞瘤、非霍奇金淋巴瘤、口腔癌、口咽癌、骨肉瘤/骨恶性纤维组织细胞瘤、卵巢癌、卵巢上皮癌(表面上皮-间质细胞瘤)、卵巢生殖细胞肿瘤、卵巢低度恶性潜在肿瘤、胰腺癌、胰岛细胞胰腺癌、鼻旁窦和鼻腔癌、甲状旁腺癌、阴茎癌、嗜铬细胞瘤、松果腺星形细胞瘤、松果腺生殖细胞瘤、成松果腺细胞瘤和幕上原始神经外胚层肿瘤、脑垂体瘤、浆细胞瘤/多发性骨髓瘤、胸膜肺母细胞瘤、原发性中枢神经系统淋巴瘤、前列腺癌、直肠癌、肾盂和输尿管肾细胞癌(肾癌)、移行细胞癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、尤因家族肿瘤肉瘤、卡波济肉瘤、软组织肉瘤、子宫肉瘤、塞扎里(Sézary)综合征、皮肤癌(非黑色素瘤)、皮肤癌(黑色素瘤)、Merkel细胞皮肤癌、小细胞肺癌、小肠癌、软组织肉瘤、鳞状细胞癌、原发性隐性鳞状颈部癌、转移性胃癌、幕上原始神经外胚层瘤、皮肤T 细胞淋巴瘤(见蕈样肉芽肿和塞扎里综合征)、睾丸癌、咽喉癌、胸腺瘤、胸腺瘤和胸腺癌、甲状腺癌、甲状腺癌、肾盂和输尿管移行细胞癌、输尿管和肾盂滋养细胞瘤、移行细胞癌尿道癌、子宫内膜子宫癌、子宫肉瘤、阴道癌、视觉通路和下丘脑胶质瘤、外阴癌、巨球蛋白血症和肾母细胞瘤(肾癌)。
4.3癌症或传染性疾病
所述癌症或传染性疾病可以为兽类疾病、也可以为人类疾病,举例如下:
4.4基因缺陷相关疾病
所述基因缺陷相关疾病,包括但不限于蛋白过表达、蛋白表达缺失、病毒感染导致的异源蛋白表达;优选地,所述基因治疗药物用于治疗基因过表达或者基因低表达或者基因缺陷或者传染性疾病;所述疾病选自肺部疾病(例如,囊性纤维化),出血性疾病(例如,具有或不具有抑制剂的血友病A或血友病B),地中海贫血,血液疾病(例如,贫血),阿尔茨海默氏病,帕金森氏 病,亨廷顿氏病,肌萎缩性侧索硬化症(ALS),癫痫病,溶酶体贮积病(例如天冬氨酰葡萄糖尿症,巴滕病,晚期婴儿神经元类脂褐质病2型(CLN2),胱氨酸病,法布里病,高歇氏I,II和III型,糖原贮积病II(庞贝病),I型GM2-神经节病(Tay Sachs病),GM2-神经节病II(Sandhoff病),I型黏膜脂溢性疾病(I和II型唾液中毒,II型(I细胞疾病),III型(假性Hurler疾病)和IV,粘多糖贮积病(Hurler疾病和变异,Hunter,Sanfilippo A,B型),C,D,Morquio A和B型,Maroteaux-Lamy和Sly疾病),Niemann-Pick疾病A/B,C1和C2型以及Schindler疾病I和II型),遗传性血管性水肿(HAE),铜或铁累积障碍(例如威尔逊氏病或Menkes病),溶酶体酸性脂肪酶缺乏症,神经系统或神经退行性疾病,癌症,1型或2型糖尿病,腺苷脱氨酶缺乏症,代谢缺陷(例如糖原贮积病),实体器官(例如脑,肝,肾,心脏)或传染性病毒(例如B型和C型肝炎,HIV等),细菌或真菌病;凝血障碍。
优选地,其中所述受试者患有血友病A,具有抑制抗体的血友病A,血友病B,具有抑制抗体的血友病B,任何凝血因子:VII,VIII,IX,X,XI,V,XII,II,von Willebrand因子或FV/FVIII合并缺乏症,地中海贫血,维生素K环氧还原酶Cl缺乏症或γ-羧化酶缺乏症。
优选地,其中所述基因缺陷导致的疾病是贫血,与创伤,损伤,血栓形成,血小板减少,中风,凝血病,弥散性血管内凝血(DIC)相关的出血;与肝素,低分子量肝素,五糖,华法林,小分子抗血栓形成剂(即FXa抑制剂)或血小板疾病(如Bernard Soulier综合征,Glanzmann血虚症或储存库缺乏)相关的过度抗凝。
4.5药物的施用和治疗方法
本发明还涉及施用本发明的突变体、蛋白、药物组合物和/或试剂盒的方法以及施用本发明的突变体、蛋白、药物组合物和/或试剂盒来治疗疾病或病症的方法。
优选地,本发明的突变体、蛋白和/或组合物可在机体内已产生抗药抗体或易产生抗药抗体的另外的治疗剂给药前施用。
优选地,本发明的突变体、蛋白和/或组合物可在机体内已产生抗药抗体或易产生抗药抗体的另外的治疗剂给药前、同时和/或给药后施用。
在本发明的应用中,本发明突变体、蛋白和/或组合物与另外的治疗剂作 为用于同时、分开或依次使用的联合制剂存在。
在一些实施方式中,所述方法包括以下步骤:1)向受试者施用本发明的突变体、蛋白和/或组合物;随后,2)向所述受试者施用所述另外的治疗剂。优选地,本发明的突变体、蛋白和/或组合物与所述另外的治疗剂的施用存在时间间隔。
在一些实施方式中,所述方法包括以下步骤:1)向所述受试者施用所述另外的治疗剂;随后,2)向受试者施用本发明的突变体、蛋白和/或组合物。优选地,本发明的突变体、蛋白和/或组合物与所述另外的治疗剂的施用存在时间间隔。
优选的是,本发明的突变体、蛋白和/或组合物的施用量和时间间隔足以将受试者体内的免疫球蛋白水平降至起始水平的60%。更优选的是,本发明的突变体、蛋白和/或组合物的施用量和时间间隔足以将受试者体内的免疫球蛋白水平结合降低至低于该患者体内起始水平的50%、40%、30%、20%或10%。本发明的突变体、蛋白和/或组合物可以在一个单一时间点施用或在设定的时间内施用。
优选的是,其中本发明的突变体、蛋白和/或组合物通过静脉输液、腹腔注射、肌肉注射、关节注射、皮内注射或者皮下注射施用,优选的注射方式为静脉输液方式。并且/或者所施用的本发明的突变体、蛋白和/或组合物的量为0.01mg/kg体重至2mg/kg体重、0.04至2mg/kg体重、0.12mg/kg体重至2mg/kg体重、0.24mg/kg体重至2mg/kg体重或1mg/kg体重至2mg/kg体重。
优选的是,其中本发明的突变体、蛋白和/或组合物和所述另外的治疗剂的给药时间间隔至少30分钟、至少1小时、至少2小时、至少3小时、至少4小时、至少4小时、至少5小时或至少6小时;并且最多35天、最多28天、最多21天、最多18天、最多14天、最多13天、最多12天、最多11天、最多10天、最多9天、最多8天、最多7天、最多6天、最多5天、最多4天、最多3天、最多2天、最多24小时、最多18小时、最多12小时、最多10小时、最多8小时、最多7小时或最多6小时。
优选的是,其中本发明的突变体、蛋白和/或组合物和所述另外的治疗剂的时间间隔为30分钟至1小时、30分钟至2小时、30分钟至3小时、30分钟至4小时、30分钟至5小时、30分钟至6小时、1至2小时、1至3小 时、1至4小时、1至5小时、1至6小时、2至3小时、2至4小时、2至5小时、2至6小时、3至4小时、3至5小时、3至6小时、4至5小时、4至6小时或5至6小时。
在又一实施方式中,所述方法包括以下步骤:1)用本发明的突变体、蛋白和/或组合物对来自所述受试者的血液进行离体处理;2)将血液返回所述受试者;3)向所述受试者施用所述另外的治疗剂。
在又一实施方式中,所述方法包括以下步骤:1)向所述受试者施用所述另外的治疗剂;2)用本发明的突变体、蛋白和/或组合物对来自所述受试者的血液进行离体处理;3)将血液返回所述受试者。
在优选的实施方式中,本发明的突变体、蛋白和/或组合物与另外的治疗剂组合用于预防和/或治疗癌症。
在优选的实施方式中,本发明的突变体、蛋白和/或组合物与另外的治疗剂组合用于预防和/或治疗病毒感染。
在优选的实施方式中,本发明的突变体、蛋白和/或组合物与另外的治疗剂组合用于预防和/或治疗细菌感染。
在优选的实施方式中,本发明的突变体、蛋白和/或组合物与另外的治疗剂组合用于预防和/或治疗真菌感染。
在优选的实施方式中,本发明的突变体、蛋白和/或组合物与另外的治疗剂组合用于预防和/或治疗基因缺陷相关疾病。
在优选的实施方式中,本发明的突变体、蛋白和/或组合物与另外的治疗剂组合用于治疗由致病性IgG抗体介导的疾病或病症。
本发明还提供了将所述药物组合施用于受试者来治疗或预防基因缺陷相关疾病或癌症或感染或由致病性IgG抗体介导的疾病或病症的方法。其中所述方法导致所述病毒载体结合抗体减少20-50%,50-75%,75-90%,90-95%或95%或95%以上的抗体;其中所述方法导致所述致病性IgG抗体减少20-50%,50-75%,75-90%,90-95%或95%或95%以上。优选的是,所述药物用于治疗基因缺陷相关疾病的方法。优选的是,所述药物用于治疗癌症、预防癌症、预防感染的方法。所述感染优选为病毒感染、细菌感染或真菌感染。优选的是,所述药物用于癌症的治疗方法。优选的是,所述药物用于治疗由致病性IgG抗体介导的疾病或病症的方法。
优选地,其中所述另外的治疗剂为病毒载体药物;优选地,所述病毒载 体药物为溶瘤病毒、病毒疫苗、基因治疗病毒。
优选地,其中所述另外的治疗剂为抗体。
优选地,其中所述另外的治疗剂为能降低血液IgG水平的多肽药物,例如Efgartigimod。更优选地,所述能降低血液IgG水平的多肽药物用于上述由致病性IgG抗体介导的疾病治疗。
优选的,其中所述药物组合的成分单独给药,或所述药物组合的成分同时给药。
如上所述的这些用途和方法中,还可以进一步与另外的治疗剂,例如抗炎剂组合。
在一些实施例中,所述另外的治疗剂是白细胞消耗剂。
在一些实施例中,所述另外的治疗剂是B细胞消耗剂。
在一些实施例中,所述的B细胞消耗剂是抗体,优选用于肿瘤治疗的抗体,更优选所述抗体与CD10、CD19、CD20、CD21、CD22、CD23、CD24、CD37、CD53、CD70、CD72、CD74、CD75、CD77、CD79a、CD79b、CD80、CD81、CD82、CD83、CD84、CD3、CD11a、CD14、CD25、CD28、CD30、CD33、CD36、CD38、CD40、CD44、CD52、CD55、CD59、CD56、CD103、CD134、CD137、CD138、CD152、CD3、IL-1β、IL-2R、IL-6、IL-6R、IL-12、IL-23、C5、BAFF、BLyS、BCMA、CXCR-4、ICAM-1、SLAMF7/CS1、TNFα、IgE、CD85或CD86特异性结合。
在一些实施例中,所述另外的治疗剂是利妥昔单抗、达克珠单抗、巴利昔单抗、莫罗单抗-CD3、英夫利昔单抗、阿达木单抗、奥马珠单抗、依法利珠单抗、那他珠单抗、托珠单抗、依库珠单抗、戈利木单抗、卡那单抗、优特克单抗、贝利木单抗、达雷妥尤单抗、Isatuximab或其组合。
在一些实施例中,所述含Fc剂是治疗剂或诊断剂,优选所述含Fc剂是抗体、Fc融合蛋白抗体药物缀合物。
V.名词解释
除非另外定义,否则本文所用的所有技术及科学术语都具有与本发明所属领域的普通技术人员通常所了解相同的含义。虽然在本发明的实践或测试中可使用与本文所述者类似或等效的任何方法、装置和材料,但现在描述优选方法、装置和材料。
术语“核苷酸”或者“多核苷酸”意指单股或双股形式的脱氧核糖核苷酸、脱氧核糖核苷、核糖核苷或核糖核苷酸及其聚合物。除非特定限制,否则所述术语涵盖含有天然核苷酸的已知类似物的核酸,所述类似物具有类似于参考核酸的结合特性并以类似于天然产生的核苷酸的方式进行代谢。除非另外特定限制,否则所述术语也意指寡核苷酸类似物,其包括PNA(肽核酸)、在反义技术中所用的DNA类似物(硫代磷酸酯、磷酰胺酸酯等等)。除非另外指定,否则特定核酸序列也隐含地涵盖其保守修饰的变异体(包括(但不限于)简并密码子取代)和互补序列以及明确指定的序列。特定而言,可通过产生其中一个或一个以上所选(或所有)密码子的第3位经混合碱基和/或脱氧肌苷残基取代的序列来实现简并密码子取代(Batzer等,Nucleic Acid Res.19:5081(1991);Ohtsuka等,J.Biol.Chem.260:2605-2608(1985);和Cassol等,(1992);Rossolini等,Mol Cell.Probes8:91-98(1994))。
术语“多肽”和“蛋白”在本文中互换使用以意指氨基酸残基的聚合物。即,针对多肽的描述同样适用于描述肽和描述蛋白,且反之亦然。所述术语适用于天然产生氨基酸聚合物以及其中一个或一个以上氨基酸残基为非天然编码氨基酸的氨基酸聚合物。如本文中所使用,所述术语涵盖任何长度的氨基酸链,其包括全长蛋白(即抗原),其中氨基酸残基经由共价肽键连接。
术语“宿主细胞”意指包含本发明核苷酸的细胞,而不管使用何种方法进行插入以产生重组宿主细胞,例如直接摄取、转导、配对或所属领域中已知的其它方法。外源性多核苷酸可保持为例如质粒的非整合载体或者可整合入宿主基因组中。宿主细胞可为原核细胞或真核细胞。
术语“转化”意指将异源性DNA序列引入到宿主细胞或有机体的方法。术语“表达”意指内源性基因或转基因在细胞中的转录和/或翻译。
本发明的积极进步效果在于:本发明提供一种免疫球蛋白降解酶突变体的应用,本发明的突变体在应用于所述领域时,具有活性高、预存抗体低的特征,安全性较高的优势。
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
实施例1.突变体文库的设计和表达
设计构建野生型IdeE蛋白序列突变文库,经过筛选从中获得40个突变体菌株。
通过密码子优化后合成编码野生型IdeE蛋白序列(SEQ ID NO:2)的多核苷酸序列,并加入N端信号肽序列和C末端6×组氨酸标签,序列合成后插入到pET32a表达载体中,测序正确后获得用于表达野生型IdeE的重组质粒。基于野生型IdeE的表达质粒,设计突变文库所需兼并引物,对原始野生型序列进行扩增,扩增后序列插入到载体上获得突变文库重组质粒。将野生型和突变文库重组质粒电转化到大肠杆菌BL21 Star(DE3)中,并接种在含100ug/ml氨苄青霉素的LB琼脂糖平板上。37℃培养过夜至菌落长出。挑取单个菌落,接于200ul含100ug/ml氨苄青霉素的LB培养基中,37℃、250rpm培养过夜。过夜培养物接于1ml含100ug/ml氨苄青霉素的LB培养基中,37℃培养4h后加入0.1mM IPTG,30℃继续培养过夜。过夜培养物通过离心收集上清。使用SDS-PAGE来评价突变体表达上清中突变体蛋白的浓度。
实施例2.突变体对人IgG1切割活性的评估
为了评价各突变体对人IgG1的切割活性,建立了基于ELSIA的活性测定方法。测定原理是用人IgG1特异性抗原包被酶标板,然后将含有相当浓度突变体蛋白的上清样品与人IgG1在孔中一起温育。使用针对抗体Fc部分具有特异性的人IgG1检测抗体来测量与孔结合的完整或未被完全切割的人IgG1的量。在孔中给定的上清中突变体蛋白浓度相同的情况下,突变体蛋白切割人IgG1活性越高,则越少的完整人IgG1抗体与孔结合,从而得到越低的信号。以不同浓度IgG1与对应检测信号之间的关系可制作IgG1标准曲线,根据标准曲线计算完整或未被完全切割的IgG1的量,进而计算被完全切割的IgG1的量。以被完全切割的IgG1占初始IgG1的比例来评价突变体活性的高低。
为了将实施例1中收获的上清中突变体蛋白浓度处于相当的水平,以相同的上样量进行SDS-PAGE检测,使用Quantity One对电泳图谱中目标蛋白条带的光密度值进行分析,在上样量相同的情况下,图谱中目标蛋白条带的光密度值越高,浓度越高。以IdeE上清作为对照,将其他突变体上清进行浓缩或稀释,使得突变体蛋白条带的光密度值都和IdeE对照的光密度值基本一致。
将上清中蛋白浓度调整至相当的水平后按照如下方法进行ELISA检测:将酶标板用2ug/ml人IgG1(曲妥珠单抗)特异性抗原(货号QRE-104,瑞安生物)在2~8℃包被过夜,然后用PBST(PBS+0.05%吐温20)洗涤,洗涤后的酶标板用2%BSA(PBS配制)在37℃封闭2h,封闭后PBST洗涤。
标准曲线制作:用200ng/ml曲妥珠单抗用反应缓冲液(10mM PB,10mM NaCl,pH6.5)以1:2比例进行梯度稀释直至3.125ng/ml,将100ul不同浓度的曲妥珠单抗加入酶标板的孔中,用于底物(曲妥珠单抗)标准曲线制作。
切割反应:将蛋白浓度调整后的上清用反应缓冲液(10mM PB,10mM NaCl,pH6.5)稀释5倍,将50ul 100ng/ml曲妥珠单抗和50ul稀释后的上清加入酶标板的孔中。
将酶标板放在37℃振荡温育1h,用PBST洗涤后再将40ng/ml Goat anti-Human IgG Fc Cross-Adsorbed Secondary Antibody-HRP(货号31413,Thermo)加入孔板中,在37℃振荡温育1h,用PBST洗涤后加入TMB作为HRP的显色底物温育15min,用2N H
2SO
4终止。用酶标仪检测在450nm处的吸光度。根据底物标准曲线计算不同测试孔中的完整或未被完全切割的曲妥珠单抗浓度,进而计算被完全切割的曲妥珠单抗占初始曲妥珠单抗的比例,以此来评价不同突变体的活性。
各突变体活性相对于野生型IdeE活性的倍数关系如表1所示。实施例1中筛选获得的40个突变体都具有高于或等于野生型IdeE的活性,其中15个突变体的活性为野生型IdeE的2倍或2倍以上。
表1.通过ELISA测得的突变体相对于野生型IdeE活性的倍数关系
实施例3.突变体热稳定性的评估
从表1中显示的15个活性是野生型IdeE的2倍或2倍以上的突变体中选取12个突变体来检测其热稳定性。检测方法活性检测方法如下:
将野生型或各突变体上清分两份,分别放置4℃和50℃条件下保温1h,保温后按照实施例2中的ELISA方法检测野生型或各突变体活性,用50℃保温的活性/4℃保温后的活性计算野生型或各突变体在50℃条件下保温1h的剩余活性百分比(%),并以此来比较野生型和各突变体的热稳定性。
突变体活性相对于野生型IdeE的热稳定性的倍数关系如表2所示。表2显示12个突变体都具有高于野生型的热稳定性,其中有7个突变体热稳定性是野生型的3倍以上。
表2.突变体相对于野生型IdeE热稳定性的倍数关系
实施例4.单点突变体切割人IgG1活性的比较
检测如表1和表2中显示的T8D、T8W、T24A、A59L、A59V、E97D和R280H这7个“活性是野生型IdeE的2倍以上,热稳定性是野生型IdeE的3倍以上”的单点突变体切割人IgG1的活性。
1、突变体的表达和纯化
从实施例1中上述5个单点突变体的转化的平板上各挑1单菌落,接于3ml含100ug/ml氨苄青霉素的LB培养基中,37℃、250rpm培养过夜。过夜培养物接于50ml含100ug/ml氨苄青霉素的LB培养基中,37℃培养至OD600达到0.4~0.6,加入0.1mM IPTG,30℃继续培养过夜。过夜培养物通过离心收集上清。上清再用IDA-Ni琼脂糖磁珠纯化,纯化洗脱的蛋白用超滤离心管再换液至PBS缓冲体系中。使用SDS-PAGE来评价纯化后的突变体蛋白纯度。检测OD280,根据消光系数计算纯化后的突变体蛋白浓度。
2、突变体切割人IgG1活性的比较
通过SDS-PAGE上显现有每种突变体的不同浓度对人IgG1所产生的切割产物来进一步评价不同突变体相对于野生型IdeE的切割人IgG1活性的高低。 将纯化后的突变体或野生型IdeE分别稀释至0.002mg/mL和0.001mg/mL。分别取50ul不同浓度的突变体或野生型IdeE加入50ul含有2mg/ml曲妥珠单抗的反应体系中开始切割反应,反应体系置于37℃反应30min。将样品与同等体积的2×SDS上样缓冲液混合后75℃水浴5min,SDS-PAGE检测切割产物。
图1展示了7个单点突变体及野生型IdeE切割人IgG1产生的切割产物电泳图(酶:底物=1:1000)。图2展示了7个单点突变体及野生型IdeE切割人IgG1产生的切割产物电泳图(酶:底物=1:2000)。7个单点突变体在0.001mg/ml浓度下切割IgG1的效果都不差于0.002mg/ml野生型IdeE,说明7个单点突变体的切割人IgG1的活性不低于野生型IdeE的2倍。
实施例5.N端截短截短突变体切割人IgG1活性和热稳定性的比较
在野生型IdeE基础上分别删除N端前15个(D1-V15)、前16个(D1-P16)、前17个(D1-H17)、前18个(D1-Q18)和前19个氨基酸(D1-I19),构建5个N端截短突变体(见表3)。
表3.截短突变体序列设计
突变体 | 相对于野生型或突变体序列的修饰 | SEQ ID NO: |
WT_del15 | 删除SEQ ID NO:2前15个氨基酸 | 18 |
WT_del16 | 删除SEQ ID NO:2前16个氨基酸 | 19 |
WT_del17 | 删除SEQ ID NO:2前17个氨基酸 | 20 |
WT_del18 | 删除SEQ ID NO:2前18个氨基酸 | 21 |
WT_del19 | 删除SEQ ID NO:2前19个氨基酸 | 22 |
1、突变体的表达和纯化
按照实施例1的方法合成表3中的突变体多核苷酸序列,构建突变体表达重组质粒,转化大肠杆菌BL21 Star(DE3)。按照实施例4中的方法制备突变体纯化蛋白。
2、突变体切割人IgG1活性的比较
将纯化后的突变体或野生型IdeE分别稀释至0.002mg/mL。分别取50ul稀释后的突变体或野生型IdeE加入50ul含有2mg/ml曲妥珠单抗的反应体系中开始切割反应,反应体系置于37℃反应30min。将样品与同等体积的2×SDS上样缓冲液混合后75℃水浴5min,SDS-PAGE检测切割产物。
图3展示了5个截短突变体切割人IgG1产生的切割产物电泳图(酶:底物=1:1000)。5个截短突变体切割活性都与野生型IdeE没有明显差别。
3、突变体热稳定性的比较
将纯化后的突变体或野生型IdeE分别稀释至0.1mg/ml,50℃条件下保温1h,保温后再稀释至0.002mg/mL。分别取50ul稀释后的突变体或野生型IdeE加入50ul含有2mg/ml曲妥珠单抗的反应体系中开始切割反应,反应体系置于37℃反应30min。将样品与同等体积的2×SDS上样缓冲液混合后75℃水浴5min,SDS-PAGE检测切割产物。
图4展示了50℃条件下保温1h后5个截短突变体及野生型IdeE切割人IgG1产生的切割产物电泳图(酶:底物=1:1000)。50℃热处理后5个截短突变体的残余活性明显高于或等于野生型,说明5个截短突变体热稳定性相对于野生型都有明显提高。
实施例6.C端截短截短突变体切割人IgG1活性的比较
在野生型IdeE基础上分别删除C端最后5个(W311-S315)和最后10个氨基酸(S306-S315),构建2个C端截短突变体(见表4)。
表4.截短突变体序列设计
突变体 | 相对于野生型或突变体序列的修饰 | SEQ ID NO: |
WT_delC5 | 删除SEQ ID NO:2后5个氨基酸 | 23 |
WT_delC10 | 删除SEQ ID NO:2后10个氨基酸 | 24 |
1、突变体的表达和纯化
按照实施例1的方法合成表4中的突变体多核苷酸序列,构建突变体表达重组质粒,转化大肠杆菌BL21 Star(DE3)。按照实施例4中的方法制备突变体纯化蛋白。
2、突变体切割人IgG1活性的比较
将纯化后的突变体或野生型IdeE分别稀释至0.002mg/mL。分别取50ul稀释后的突变体或野生型IdeE加入50ul含有2mg/ml曲妥珠单抗的反应体系中开始切割反应,反应体系置于37℃反应30min。将样品与同等体积的2×SDS上样缓冲液混合后75℃水浴5min,SDS-PAGE检测切割产物。
图5展示了2个C端截短突变体切割人IgG1产生的切割产物电泳图(酶:底物=1:1000)。2个截短突变体切割活性都比野生型IdeE高出2倍以上。
实施例7.组合突变体切割人IgG1活性和热稳定性的比较
在T24A、A59L、A59V、E97D和R280H 5个单点突变体的基础上分别 删除前18个(D1-Q18)氨基酸,构建5个组合突变体(见表5)。
表5.组合突变体序列设计
突变体 | 相对于野生型或突变体序列的修饰 | SEQ ID NO: |
T24A_del18 | 删除SEQ ID NO:9前18个氨基酸 | 25 |
A59L_del18 | 删除SEQ ID NO:13前18个氨基酸 | 26 |
A59V_del18 | 删除SEQ ID NO:14前18个氨基酸 | 27 |
E97D_del18 | 删除SEQ ID NO:15前18个氨基酸 | 28 |
R280H_del18 | 删除SEQ ID NO:16前18个氨基酸 | 29 |
1、突变体的表达和纯化
按照实施例1的方法合成表5中的突变体多核苷酸序列,构建突变体表达重组质粒,转化大肠杆菌BL21 Star(DE3)。按照实施例4中的方法制备突变体纯化蛋白。
2、突变体切割人IgG1活性的比较
将纯化后的突变体分别稀释至0.001mg/mL。分别取50ul稀释后的突变体或野生型IdeE加入50ul含有2mg/ml曲妥珠单抗的反应体系中开始切割反应,反应体系置于37℃反应30min。将样品与同等体积的2×SDS上样缓冲液混合后75℃水浴5min,SDS-PAGE检测切割产物。
图6展示了5个组合突变体切割人IgG1产生的切割产物电泳图(酶:底物=1:2000)。比较图6和图2的切割效果,5个截短突变体和单点组合突变体切割活性没有明显差别,说明组合突变体切割人IgG1的活性同样不低于野生型IdeE的2倍。
3、突变体热稳定性的比较
将纯化后的突变体分别稀释至0.1mg/ml,50℃条件下保温1h,保温后再稀释至0.001mg/mL。分别取50ul稀释后的突变体或野生型IdeE加入50ul含有2mg/ml曲妥珠单抗的反应体系中开始切割反应,反应体系置于37℃反应30min。将样品与同等体积的2×SDS上样缓冲液混合后75℃水浴5min,SDS-PAGE检测切割产物。
图7展示了50℃条件下保温1h后5个组合突变体切割人IgG1产生的切割产物电泳图(酶:底物=1:2000)。比较图6和图7的切割效果,5个组合突变体50℃热处理后活性只是略有下降,说明5个组合突变体相对于野生型热稳定性也都有明显提高。
实施例8.E97D_del18突变体与IdeS和IdeZ活性比较
将实施例7中纯化的E97D_del18突变体依次稀释至20μg/mL,10μg/mL,5μg/mL,2.5μg/mL和1.25μg/ml。将IdeS(
货号:A0-FRI-020,Genovis)按照其标识分别稀释至2U/μl,1U/μl,0.5U/μl,0.25U/μl和0.125U/μl。将IdeZ(
货号:A0-FRZ-020,Genovis)分别稀释至0.4U/μl,0.2U/μl,0.1U/μl,0.05U/μl和0.025U/μl。分别取50μl不同浓度的突变体、IdeS或IdeZ加入50μl含有2mg/ml曲妥珠单抗的反应体系中开始切割反应,反应体系置于37℃反应30min。将样品与同等体积的2×SDS上样缓冲液混合后75℃水浴5min,SDS-PAGE检测切割产物。
图8展示了不同浓度E97D_del18突变体和IdeS切割人IgG1产生的切割产物电泳图。从电泳图上的酶蛋白条带可以判断1号泳道IdeS酶浓度介于7号和8号泳道E97D_del18突变体酶浓度之间,由此递推3号泳道IdeS酶浓度介于9号和10号泳道E97D_del18突变体酶浓度,而3号泳道的IgG1的酶切效果介于10号和11号泳道,由此可以推断E97D_del18突变体切割人IgG1的活性接近IdeS的2倍。
图9展示了不同浓度E97D_del18突变体和IdeZ切割人IgG1产生的切割产物电泳图。从电泳图上的酶蛋白条带可以判断1号泳道IdeZ酶浓度高于7号泳道E97D_del18突变体酶浓度,由此递推3号泳道IdeZ酶浓度高于9号泳道E97D_del18突变体酶浓度,即高于11号泳道E97D_del18突变体酶浓度的4倍,而3号泳道的IgG1的酶切效果接近11号泳道,由此可以推断E97D_del18突变体切割人IgG1的活性高于IdeZ的4倍。
实施例9.E97D_del18突变体切割人IgG1活性的体外检测
通过检测加入E97D_del18突变体与人IVIg处理过的小鼠血清或血浆中完整或单切割IVIg的量来评价E97D_del18突变体对人IgG1的体外切割活性。按照表6配制不同组别的小鼠血清或血浆酶切体系。
表6.小鼠血清或血浆酶切体系
碘乙酸处理组中碘乙酸的作用是抑制IgG降解酶的活性。
将体系置于37℃反应30min。取20μl样品与同等体积的2×SDS非还原上样缓冲液混合后75℃水浴5min,SDS-PAGE检测切割产物。
图10展示了E97D_del18突变体在小鼠血清和血浆中切割人IVIg产生的切割产物电泳图。结果显示E97D_del18在小鼠血清和血浆中都可以有效切割人IVIg。
通过检测加入E97D_del18突变体处理过的小鼠或人血清来评价E97D_del18突变体是否具有对人IgG1的体外切割活性。按照表7配制不同组别的小鼠或人血清酶切体系。
表7.小鼠或人血清酶切体系
将体系置于37℃反应24h。取20μl样品与同等体积的2×SDS还原性上样缓冲液混合,再用1×SDS还原性上样缓冲液稀释20倍,75℃水浴5min,SDS-PAGE检测切割产物。
图11展示了E97D_del18突变体在小鼠和人血清中产生的切割产物电泳图。结果显示E97D_del18在人血清中切割产生明显可见的25kD的Fc片段,而在小鼠血清中则没有该片段,说明E97D_del18能有效特异性切割人血清中IgG1,而对小鼠血清中的IgG1切割活性很低或无切割活性。
实施例10.E97D_del18突变体切割不同种属的免疫球蛋白
通过检测加入E97D_del18突变体与不同种属动物血清或血浆中完整或单切割IgG的量来评价E97D_del18突变体对不同种属动物血清免疫球蛋白的体外切割活性。按照表8和表9配制不同种属的血清或抗体酶切体系。
表8比格犬血清及不同物种抗体酶切体系
将体系置于37℃反应1小时,酶切产物采用SDS-PAGE检测。
表9不同物种血清酶切体系
图12A-12D展示了E97D_del18突变体在不同物种血清和抗体的效果。结果显示E97D_del18可有效切割犬IgG、兔IgG以及小鼠IgG2a,无法切割小鼠IgG1;E97D_del18可有效切割兔、犬和猴血清IgG,其中兔血清IgG切割效果最好,猪血清IgG切割效果较差,大鼠和小鼠血清IgG则几乎未被切动。
实施例11.人体内针对E97D_del18突变体的预存抗体低
该测定是基于E97D_del18突变体与IdeS之间对于与抗E97D_del18/IdeS 抗体结合的竞争。测试酶和人血清的预温育将使得抗E97D_del18/IdeS抗体与E97D_del18突变体与IdeS能够结合。
将E97D_del18突变体与IdeS在孔板上包被过夜,然后用PBST洗涤并在2%BSA封闭液中封闭1小时,用逐步稀释的待测突变体与IdeS和人血清制备混合板,将混合版在室温下振荡温育1小时,PBST洗涤之后加入生物素标记的E97D_del18突变体与IdeS,再加入SA-HRP,用TMB显色并读数。平行比对获得约80个人血样本中E97D_del18和IdeS预存抗体的情况。
结果如表10所示,IdeS在正常人血清中预存抗体的比例高达约90%,而E97D_del18突变体仅为约20%。E97D_del18突变体在体内的预存抗体明显少于IdeS,证明E97D_del18突变体的免疫原性更低,更有利于体内用药。
表10.E97D_del18突变体和IdeS在人血样本中预存抗体比对情况
E97D_del18突变体 | IdeS | |
人血样本总数(例) | 76 | 76 |
预存抗体阳性样本比例(%) | 18.4 | 89.5 |
实施例12.E97D_del18突变体切割人IgG1活性的体内检测
在无菌条件下用人IVIg(静注人免疫球蛋白)腹腔注射2只小鼠(两只小鼠为平行实验,小鼠编号1号和2号),注射剂量为1g/kg。注射人IVIg 24h后,再将IgG降解酶突变体(E97D_del18)以5mg/kg的剂量静脉注射小鼠,2只小鼠都分别在注射E97D_del18后0h、15min、2h、6h和24h采血并收集血清样品。取20μl血清样品与同等体积的2×SDS非还原上样缓冲液混合后,再用1×SDS非还原性上样缓冲液稀释20倍,75℃水浴5min,SDS-PAGE检测。
图13展示了E97D_del18在小鼠体内不同时间内切割人IVIg产生的切割产物电泳图。结果显示,E97D_del18在小鼠体内切割IVIg效果显著,15min基本已经达到完全酶切。
实施例13.组合突变体切割人IgG1活性的比较
在上述突变体的基础上,进一步构建了6种组合突变体,所述突变的序列如表11所示。
表11.组合突变体
突变体 | 相对于野生型或突变体序列的修饰 | SEQ ID NO: |
E97D_del18_delC5 | 删除SEQ ID NO:28后5个氨基酸 | 30 |
E97D_del18_delC10 | 删除SEQ ID NO:28后10个氨基酸 | 31 |
A59V_del18_delC5 | 删除SEQ ID NO:27后5个氨基酸 | 32 |
A59L_del18_delC5 | 删除SEQ ID NO:26后5个氨基酸 | 33 |
R280H_del18_delC5 | 删除SEQ ID NO:29后5个氨基酸 | 34 |
E97D_A59V_R280H | E97D、A59V、R280H三突变组合 | 35 |
1、突变体的表达和纯化
按照实施例1的方法合成表11中的突变体多核苷酸序列,构建突变体表达重组质粒,转化大肠杆菌BL21Star(DE3)。按照实施例4中的方法制备突变体纯化蛋白。
2、突变体切割人IgG1活性的比较
将纯化后的突变体分别稀释至0.001mg/mL。分别取50ul稀释后的突变体或野生型IdeE加入50ul含有2mg/ml曲妥珠单抗的反应体系中开始切割反应,反应体系置于37℃反应30min。将样品与同等体积的2×SDS上样缓冲液混合后75℃水浴5min,SDS-PAGE检测切割产物。
图14A和14B展示了6个组合突变体切割人IgG1产生的切割产物电泳图(酶:底物=1:2000)。
实施例14.新突变体的设计和表达
通过对突变数据的进一步分析筛选,选择IdeE突变体SEQ ID NO:36进行评估,代号为IdeEv2。通过密码子优化后合成编码该突变体的多核苷酸序列,并加入N端信号肽序列,序列合成后插入到pET32a表达载体中,测序正确后获得用于表达的重组质粒。将突变体重组质粒电转化到大肠杆菌BL21Star(DE3)中,并接种在含100ug/ml氨苄青霉素的LB琼脂糖平板上。37℃培养过夜至菌落长出。挑取单个菌落,接于200ul含100ug/ml氨苄青霉素的LB培养基中,37℃、250rpm培养过夜。过夜培养物接于1ml含100ug/ml氨苄青霉素的LB培养基中,37℃培养4h后加入0.1mM IPTG,30℃继续培养过夜。过夜培养物通过离心收集上清。使用SDS-PAGE来评价突变体表达上清中突变体蛋白的表达。上清依次使用离子交换层析、疏水层析进行纯化,得到纯品蛋白。采用相同方式制备得到IdeS、IdeZ蛋白。采用SEC-HPLC方法检测所得蛋白纯度,均超过95%。
实施例15.IDEEV2突变体切割人IgG1活性和热稳定性的比较
1、突变体切割人IgG1活性的比较
将纯化后的突变体和野生型IdeE、IdeS、IdeZ分别稀释至0.0025mg/mL。分别取50μl不同浓度的突变体、IdeE、IdeS或IdeZ加入50ul含有2mg/ml曲妥珠单抗的反应体系中开始切割反应,反应体系置于37℃反应30min。将样品与同等体积的2×SDS上样缓冲液混合后75℃水浴5min,SDS-PAGE检测切割产物。结果显示,组合突变体切割人IgG1的活性与野生型IdeE有相似的活性(图15A)。
2、突变体热稳定性的比较
将纯化后的突变体分别稀释至0.1mg/ml,50℃条件下保温1h,保温后再稀释至0.0025mg/mL。分别取50ul稀释后的突变体或野生型IdeE加入50ul含有2mg/ml曲妥珠单抗的反应体系中开始切割反应,反应体系置于37℃反应30min。将样品与同等体积的2×SDS上样缓冲液混合后75℃水浴5min,SDS-PAGE检测切割产物。结果显示,突变体IDEEV2 50℃热处理后活性下降最少,说明突变体IDEEV2相对于野生型和其他突变型热稳定性也都有显著提高。
实施例16.IDEEV2突变体对人不同免疫球蛋白切割特异性评估
通过SDS-PAGE上显现IDEEV2突变体对人不同IgG所产生的切割产物来进一步评价突变体对不同底物的切割特异性。将纯化后的IDEEV2突变体分别稀释至0.01mg/mL。分别取50ul不同浓度的突变体或野生型IdeE加入50ul含有2mg/ml不同免疫球蛋白(人IgG1~4、IgM、IgA、IgE和IgD)的反应体系中开始切割反应,反应体系置于37℃反应30min。将样品与同等体积的2×SDS上样缓冲液混合后75℃水浴5min,SDS-PAGE检测切割产物。
结果显示,IDEEV2可有效酶切人IgG1、IgG2、IgG3、IgG4(图16A),无法酶切人免疫球蛋白IgA、IgE、IgD和IgM(图16B)。说明该变体的底物特异性高。
实施例17.IDEEV2突变体切割不同种属的免疫球蛋白
通过检测加入IDEEV2突变体与不同种属动物血清或血浆中完整或单切割IgG的量来评价IDEEV2突变体对不同种属免疫球蛋白的体外切割活性。 按IDEEV2:不同动物种属或人纯化IgG=1:200蛋白量比例酶切兔、犬、大鼠、小鼠、猴和人纯化IgG,37℃酶切1h,非还原型SDS-PAGE电泳检测酶切产物。
结果显示,在种属特异性方面IDEEV2可有效切割兔、犬、猴和人的IgG,但对大鼠和小鼠血清中的IgG无显著切割(图17)。
实施例18.IDEEV2突变体切割新西兰兔体内IgG实验
采用新西兰兔研究IDEEV2在动物体内切割IgG的活性。IDEEV2静脉输注给予新西兰兔,每周给药1次,给药2次,2mg/kg剂量。血样检测采用ELISA或SDS-PAGE法对动物血清中IgG含量进行检测,评价IDEEV2静脉输注对动物体内IgG的酶切作用。
结果显示IDEEV2可快速酶切兔体内IgG:首末次药后第一个血样采集点(给药结束前1min),2mg/kg剂量下兔体内IgG含量基本低于检测下限。首末次给药后约1-2天,兔体内IgG水平逐步回升,酶切产物含量逐步恢复至给药前水平。给药2次后,兔体内IgG含量约10天后可恢复至正常水平范围。(图18A)
IDEEV2静脉输注给予新西兰兔,每周给药1次,给药4次,0.2、2、20mg/kg剂量组血样检测结果显示IDEEV2可快速酶切兔体内IgG:最低剂量(0.2mg/kg)已具有完全的药理活性。(图18B)
从以上数据可见,IDEEV2静脉输注给予新西兰兔后,0.2-20mg/kg剂量范围内均可快速酶切兔体内IgG。大部分兔体内IgG在IDEEV2给药后第一个血样采集点(给药结束前1min)内被酶切。给药后约1-2天,酶切产物含量逐步恢复至给药前水平。给药后约10天,兔体内IgG含量可恢复至正常水平范围。
实施例19.IDEEV2突变体切割比格犬体内IgG实验
IDEEV2静脉输注给予Beagle犬,每周给药1次,给药2次,0.2、2、20mg/kg剂量组血样检测结果显示IDEEV2可快速酶切犬体内IgG;首末次给药约3天后,犬体内IgG水平逐步回升,酶切产物含量恢复至给药前水平。给药2次后,恢复期犬(2只/性别/组)体内IgG回升情况存在一定的个体差异,0.2、2mg/kg剂量下约10天后可恢复到正常水平范围,20mg/kg剂量下 4周基本能恢复至正常水平范围。IgG含量的下降和恢复速度与给药剂量总体呈现量效关系。
从以上数据可见(图19A、19B),IDEEV2静脉输注给予Beagle犬后,0.2-20mg/kg剂量范围内均可快速酶切犬体内IgG,大部分犬体内IgG在IDEEV2给药后第一个血样采集点(给药结束前1min)内被酶切。给药约3天后,酶切产物含量逐步恢复至给药前水平。IgG回升情况存在一定的个体差异,给药后约10-28天,犬体内IgG含量可恢复至正常水平范围。
综合如上数据,无论是在新西兰兔还是比格犬体内,IDEEV2均可快速有效切割IgG,显示出IDEEV2在抗体介导的自身免疫性疾病中的优势,尤其是急性重症型危及生命的抗体介导的自身免疫性疾病。
实施例20.IDEEV2可以有效逆转抗血小板抗体导致的低血小板血症
通过腹腔注射10mg/只造模剂(抗小鼠血小板的兔抗血清纯化制备所得的兔IgG),建立BALB/c小鼠血小板减少模型,评价IDEEV2静脉注射对BALB/c小鼠的血小板减少模型的药效作用。
造模前模型对照组和IDEEV2低、高剂量组血小板计数结果相似。造模后0.5h各组血小板计数均明显下降。IDEEV2给药前(即造模后约2h)各组血小板计数持续下降。模型对照组动物给予造模剂后血小板计数持续处于低水平(图20A),且该组动物3天内全部死亡(图20B)。IDEEV2低、高剂量组动物给药后血小板计数开始恢复,D20时与造模前水平相似,说明IDEEV2对BALB/c小鼠血小板减少症有明显的改善作用。进而说明在由抗自身抗体引起的自免疾病中,本发明变体具有较好的症状改善效果。
实施例21.免疫球蛋白降解酶突变体有效排除高免疫球蛋白对单抗抗
肿瘤效果的负面影响
采用Daudi小鼠模型评价IDEEV2对抗CD38单抗。实验设计为4组:1)溶剂对照组;2)抗CD38单抗daratumumab;3)抗CD38单抗daratumumab+IVIg;4)抗CD38单抗daratumumab+IDEEV2+IVIg。具体的,取对数生长期细胞,小鼠皮下接种,每只CB-17 SCID小鼠无菌条件下右侧腋窝皮下接种5×10
6cells的Daudi细胞,接种量均为0.1mL/只。细胞接种当天单次腹腔注射给予1g/kg IVIg。24h后给予单次静脉注射5mg/kg免疫球蛋白降 解酶E97D_del18。IVIg给药后10天腹腔注射给予2mg/kg抗CD38单抗,每周给药1次,共给药4次。CD38开始给药后,每周测量2次肿瘤体积,共检测4周。
实验结果显示(图21),IgG(IVIg)的存在会抑制抗CD38单抗治疗肿瘤的疗效。IDEEV2可降低天然存在的IgG对抗体疗效的抑制,显著增强治疗性抗体的治疗效果。
实施例22.IgG降解酶突变体对AAV体内感染的影响
C57BL/6J小鼠单次腹腔给予IVIg(剂量1g/kg),IVIg给予后30min后单次静脉给予IDEEV2(剂量5mg/kg)。IVIg给予后24h给予AAV9-Fluc(剂量2×10
11vg/只)。D8、D15、D22、D29、D36和D43时进行荧光成像。D44取心脏和肝脏组织样本检测Fluc基因拷贝数。
1)荧光对照组(AAV9-Fluc);
2)模型组(IVIg+AAV9-Fluc);
3)供试品组(IVIg+IDEEV2+AAV9-Fluc)。
结果显示在IVIg存在时,AAV对小鼠无感染效果,而E97D_del18可完全排除IVIg对AAV感染的影响(图22A、22B)。心脏及肝脏组织中,病毒均可有效转导(图23)。该实验结果表明,本发明的突变体在体内可有效降解人免疫球蛋白G,并排除其中病毒中和抗体对以病毒为治疗载体药物的干扰。
申请人声明,本发明通过上述实施例来说明本发明的详细方法,但本发明并不局限于上述详细方法,即不意味着本发明必须依赖上述详细方法才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。
Claims (44)
- 一种免疫球蛋白降解酶IdeE的突变体在制备用于治疗受试者中的自身抗体介导的病症的药物中的用途,其中所述的免疫球蛋白降解酶IdeE包含SEQ ID NO:2所示的氨基酸序列或由所述氨基酸序列组成,所述突变选自下组:(1)对所述氨基酸序列的位置8、10、24、59、97和280中的一位或者多位进行取代;和/或,(2)对所述免疫球蛋白降解酶IdeE进行截短,删除其N端的前1个、前2个、前3个、前4个、前5个、前6个、前7个、前8个、前9个,前10个、前11个、前12个、前13个、前14个、前15个、前16个、前17个、前18个或者前19个氨基酸序列;和/或,(3)对所述免疫球蛋白降解酶IdeE进行截短,删除其C端的最后1个、最后2个、最后3个、最后4个、最后5个、最后6个、最后7个、最后8个、最后9个或者最后10个氨基酸序列;其中所述的突变体具有高于或等于所述免疫球蛋白降解酶IdeE的活性,和/或具有高于或等于所述免疫球蛋白降解酶IdeE的热稳定性。
- 如权利要求1所述的用途,其中所述突变选自下组:(1)对SEQ ID NO:2所示的氨基酸序列的位置8、10、24、59、97或者280进行替换;和/或(2)删除所述免疫球蛋白降解酶IdeE N端的前15个、前16个、前17个、前18个或者前19个氨基酸;优选删除前18个氨基酸;和/或(3)删除所述免疫球蛋白降解酶IdeE C端的最后5个或者最后10个氨基酸;优选删除最后5个氨基酸。
- 如权利要求1或2所述的用途,其中所述突变选自下组:(1)所述位置8的苏氨酸被替换成半胱氨酸、苯丙氨酸、色氨酸、酪氨酸、天冬氨酸、谷氨酸、丙氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、蛋氨酸、天冬酰胺、脯氨酸、谷氨酰胺、丝氨酸、缬氨酸、精氨酸和赖氨酸中的任意一种;(2)所述位置10的丙氨酸被替换成半胱氨酸、天冬氨酸、谷氨酸、苯丙氨酸、甘氨酸、组氨酸、异亮氨酸、赖氨酸、亮氨酸、蛋氨酸、天冬酰胺、 脯氨酸、谷氨酰胺、精氨酸、丝氨酸、苏氨酸、缬氨酸、色氨酸和酪氨酸中的任意一种;(3)所述位置24的苏氨酸被替换成丙氨酸、半胱氨酸、天冬氨酸、天冬酰胺、谷氨酸、苯丙氨酸、甘氨酸、组氨酸、异亮氨酸、赖氨酸、亮氨酸、蛋氨酸、脯氨酸、谷氨酰胺、精氨酸、丝氨酸、缬氨酸、色氨酸和酪氨酸中的任意一种;(4)所述位置59的丙氨酸被替换成半胱氨酸、天冬氨酸、谷氨酸、苯丙氨酸、甘氨酸、组氨酸、异亮氨酸、赖氨酸、亮氨酸、蛋氨酸、天冬酰胺、脯氨酸、谷氨酰胺、精氨酸、丝氨酸、苏氨酸、缬氨酸、色氨酸和酪氨酸中的任意一种;(5)所述位置97的谷氨酸被替换成丙氨酸、半胱氨酸、天冬氨酸、苯丙氨酸、甘氨酸、组氨酸、异亮氨酸、赖氨酸、亮氨酸、蛋氨酸、天冬酰胺、脯氨酸、谷氨酰胺、精氨酸、丝氨酸、苏氨酸、缬氨酸、色氨酸和酪氨酸中的任意一种;和(6)所述位置280的精氨酸被替换成丙氨酸、天冬氨酸、谷氨酸、半胱氨酸、丝氨酸、苯丙氨酸、组氨酸、异亮氨酸、赖氨酸、亮氨酸、蛋氨酸、天冬酰胺、脯氨酸、谷氨酰胺、色氨酸、苏氨酸、缬氨酸和酪氨酸中的任意一种。
- 如权利要求3所述的用途,其中所述的突变体如SEQ ID NO:3-36中任一个所示。
- 一种包含如权利要求1-4任一项中的突变体的蛋白在制备用于治疗受试者中的自身抗体介导的病症的药物中的用途。
- 如权利要求5所述的用途,其中所述蛋白在所述突变体的N末端包含信号肽;优选地,所述蛋白在所述突变体的N末端连接有分泌信号序列并在所述分泌序列的N末端连接有甲硫氨酸和/或在在所述突变体C末端连接有组氨酸标签;更优选地,所述蛋白从N末端至C末端由如下组成:甲硫氨酸、分泌信号序列和所述突变体。
- 一种组合物在制备用于治疗受试者中的自身抗体介导的病症的药物中的用途,其中所述组合物包含:权利要求1-4任一项中的突变体或包含所述突变体的蛋白;和任选的药学上可接受的载体或赋形剂。
- 如权利要求7所述的用途,其中所述组合物进一步包含另外的治疗剂,所述另外的治疗剂选自下组:(a)抗体或者含有Fc的蛋白,优选地所述抗体的靶点选自下组:细胞表面蛋白、细胞因子、激素、酶、胞内信使、胞间信使和免疫检查点;(b)病毒载体药物,优选地所述病毒载体药物选自下组:溶瘤病毒、基因治疗病毒和病毒载体疫苗;和(c)能降低血液IgG水平的药物,优选地所述降低血液IgG水平的药物选自下组:FcRn抗体、与FcRn高亲和力的Fc片段变体。
- 一种试剂盒在制备用于治疗受试者中的自身抗体介导的病症的药物中的用途,其中所述试剂盒包含:(1)权利要求1-4任一项中的突变体或包含所述突变体的蛋白;和(2)选自下组的一种或多种:(a)药学上可接受的载体或赋形剂;(b)抗体或者包含Fc的蛋白;(c)病毒载体药物,优选地所述病毒载体药物选自溶瘤病毒、基因治疗病毒和病毒载体疫苗;和(d)能降低血液IgG水平的药物,优选地所述降低血液IgG水平的药物选自FcRn抗体、与FcRn高亲和力的Fc片段变体。
- 一种试剂盒在制备用于治疗受试者中的自身抗体介导的病症的药物中的用途,其中所述试剂盒包含:药盒A和药盒B,其中所述药盒A含有权利要求1-4任一项中的突变体或包含所述突变体的蛋白,所述的药盒B含有选自下组的一种或多种:(1)药学上可接受的载体或赋形剂;(2)抗体或者包含Fc的蛋白;(3)病毒载体药物,优选地所述病毒载体药物选自溶瘤病毒、基因治疗病毒和病毒载体疫苗;和(4)能降低血液IgG水平的药物,优选地所述降低血液IgG水平的药物选自FcRn抗体、与FcRn高亲和力的Fc片段变体。
- 如权利要求1-10中任一项所述的用途,其中所述抗体介导的病症是自身免疫性疾病或高球蛋白血症。
- 如权利要求11所述的用途,其中自身免疫性疾病选自:阿狄森氏病、斑秃、强直性脊椎炎、抗磷脂综合征、再生障碍性贫血、抗GBM肾小球肾炎、抗NMDAR脑炎、抗磷脂血症综合征、自身免疫性胃炎、自身免疫性失聪、自身免疫性溶血性贫血、自身免疫性肝炎、自身免疫性甲状旁腺机能减 退、自身免疫性垂体炎、自身免疫性内耳疾病、自身免疫性淋巴细胞增生综合征、自身免疫性心肌炎、自身免疫性卵巢炎、自身免疫性大疱性皮肤病、自身免疫性睾丸炎、自身免疫性多种内分泌病、贝切特氏病、大疱性类天疱疮、心肌病、炎症性脱髓鞘性多神经病、急性运动性轴索神经病、丘-施氏综合征、腹部疾病、自身免疫性荨麻疹、克罗恩病、CREST综合征、乳糜泻、德戈斯病、抗中性粒细胞胞质抗体相关血管炎症、自身免疫性中性白细胞减少症、后天性大疱性表皮松解、原发性混合冷凝球蛋白血栓、巨细胞动脉炎、肾小球肾炎、古德帕斯彻综合征、格雷夫斯病、格林巴利综合征、桥本甲状腺炎、特发性血小板减少性紫癜、炎性肠病、川崎氏病、美尼尔综合征、混合性结缔组织病、莫伦溃疡、类风湿性关节炎、多发性硬化症、重症肌无力、僵人综合征、完全性先天性心脏阻滞、获得性大疱性表皮松懈病、落叶性天疱疮、寻常天疱疮、恶性贫血、结节性多动脉炎、多腺性自身免疫综合征类型、原发性胆汁性肝硬化、多腺性自身免疫综合征类型、多腺性自身免疫综合征类型、多发性肌炎/皮肌炎、牛皮癣、牛皮癣性关节炎、雷诺综合征、莱特尔综合征、风湿性心脏病、血友病-获得性FVIII缺乏、Lambert-Eaton肌无力综合症、多发性骨髓瘤、肉状瘤病、胶原沉着病、干燥综合征、亚急性甲状腺炎、交感性眼炎、全身性红斑狼疮、高安氏动脉炎、 综合症、I型糖尿病、白癜风、伏格特-小柳-原田三氏综合征或韦格纳肉芽肿病、急性哮喘或慢性哮喘、器官移植排斥、原发性进行性多发性硬化症、系统性硬化症、血清病和免疫复合物超敏反应;其中,所述免疫复合物例如抗药抗体和药物形成的免疫复合物。优选的,所述自身免疫性疾病选自抗肾小球基底膜抗体病(抗GBM抗体病)、致病性IgG抗体介导的血栓性低血小板症、格林巴利综合征(GBS)、自身免疫性脑炎(AE)、视神经脊髓炎谱系疾病(NMOSD)、非典型溶血性尿毒症综合征(aHUS)、器官移植术后抗体介导的排斥反应(AMR)、重症肌无力(MG);其中所述致病性IgG抗体介导的血栓性低血小板症优选为血栓性血小板减少性紫癜(TTP)、肝素诱导的血小板减少症(HIT)、疫苗诱导的免疫性血栓性血小板减少症(VITT)。
- 如权利要求1-12中任一项所述的用途,其中所述抗体介导的病症是可使用静脉注射免疫球蛋白(IVIG)、皮下注射免疫球蛋白(SCIG)、血浆去除术和/或免疫吸附治疗的。
- 如权利要求11所述的用途,其中所述的高球蛋白由白细胞产生,所述白细胞选自B细胞、异常B细胞;所述球蛋白包括γ球蛋白;所述的高球蛋白血症包括原发性单克隆丙种球蛋白血症、结缔组织病、肝脏病、传染病、类肉瘤病、重症肌无力、霍奇金病、白塞(Behcet)病、肾炎、过敏性紫癜、免疫性(或自发性)血小板减少症、恶性单克隆丙种球蛋白血症(如多发性骨髓瘤、重链病、恶性淋巴瘤、慢性淋巴细胞白血病、巨球蛋白血症等)、继发性单克隆丙种球蛋白血症(如非淋巴网状系统肿瘤、单核细胞白血病、冷球蛋白血症等)、良性M蛋白血症、意义未明的单克隆丙种球蛋白病(MGUS)、华氏巨球蛋白血症、AL型淀粉样变性、孤立性浆细胞瘤(骨或骨外)、POMES综合征、反应性浆细胞增多症、转移性癌的溶骨性病变、浆母细胞性淋巴瘤、单克隆免疫球蛋白相关肾损害(MGRS)等。所述病症优选多发性骨髓瘤。
- 一种免疫球蛋白降解酶IdeE突变体、包含所述突变体的蛋白、或者包含所述突变体或所述蛋白的组合物或试剂盒在制备用于降低受试者中的IgG水平的药物中的用途,其中所述突变体是权利要求1-4任一项中的突变体,所述蛋白体是权利要求6中的蛋白,所述组合物是权利要求7或8中的组合物,或者所述试剂盒是权利要求9或10中的试剂盒。
- 一种免疫球蛋白降解酶IdeE突变体、包含所述突变体的蛋白、或者包含所述突变体或所述蛋白的组合物或试剂盒在制备用于预防和/或治疗受试者中的实体器官移植后自身抗体介导的器官排斥的药物中的用途,其中所述突变体是权利要求1-4任一项中的突变体,所述蛋白体是权利要求6中的蛋白,所述组合物是权利要求7或8中的组合物,或者所述试剂盒是权利要求9或10中的试剂盒。
- 如权利要求16所述的用途,其中同种异体移植物选自下组:肾脏、胰岛、胰腺、心脏、肝脏、肺或小肠。
- 一种免疫球蛋白降解酶IdeE突变体、包含所述突变体的蛋白、或者包含所述突变体或所述蛋白的组合物或试剂盒在制备用于基因治疗的药物中的用途,其中所述突变体是权利要求1-4任一项中的突变体,所述蛋白体是权利要求6中的蛋白,所述组合物是权利要求7或8中的组合物,或者所述试剂盒是权利要求9或10中的试剂盒。
- 一种免疫球蛋白降解酶IdeE突变体、包含所述突变体的蛋白、或者包含所述突变体或所述蛋白的组合物或试剂盒在制备用于在病毒载体为基 础的基因治疗前清除体内预存的抗病毒载体的中和抗体的药物中的用途,其中所述突变体是权利要求1-4任一项中的突变体,所述蛋白体是权利要求6中的蛋白,所述组合物是权利要求7或8中的组合物,或者所述试剂盒是权利要求9或10中的试剂盒。
- 一种免疫球蛋白降解酶IdeE突变体、包含所述突变体的蛋白、或者包含所述突变体或所述蛋白的组合物或试剂盒在制备用于治疗受试者中的肿瘤的药物中的用途,其中所述突变体是权利要求1-4任一项中的突变体,所述蛋白体是权利要求6中的蛋白,所述组合物是权利要求7或8中的组合物,或者所述试剂盒是权利要求9或10中的试剂盒。
- 一种免疫球蛋白降解酶IdeE突变体、包含所述突变体的蛋白、或者包含所述突变体或所述蛋白的组合物或试剂盒在制备用于清除受试者中的自身抗体以使得含Fc剂更好发挥疗效的药物中的用途,其中所述突变体是权利要求1-4任一项中的突变体,所述蛋白体是权利要求6中的蛋白,所述组合物是权利要求7或8中的组合物,或者所述试剂盒是权利要求9或10中的试剂盒。
- 一种免疫球蛋白降解酶IdeE突变体、包含所述突变体的蛋白、或者包含所述突变体或所述蛋白的组合物或试剂盒在制备用于在已施用含Fc剂的受试者中降低所述含Fc剂的血清水平的药物中的用途,其中所述突变体是权利要求1-4任一项中的突变体,所述蛋白体是权利要求6中的蛋白,所述组合物是权利要求7或8中的组合物,或者所述试剂盒是权利要求9或10中的试剂盒。
- 如权利要求8和15-22中任一项所述的用途,其中将所述IdeE突变体与另外的治疗剂同时或依次适用于所述受试者。
- 如权利要求23所述的用途,其中所述另外的治疗剂是抗炎剂。
- 如权利要求23所述的用途,其中所述另外的治疗剂是FcRn拮抗剂,所述FcRn拮抗剂优选为靶向FcRn的抗体或者Fc片段,最优选为Efgartigimod、Nipocalimab、Rozanolixizumab、RVT-1401、HBM9161、ALXN1830、SYNT001、Nirsevimab。
- 如权利要求23所述的用途,其中所述另外的治疗剂是病毒载体药物,优选用于基因治疗的病毒药物、溶瘤病毒药物,更优选的为以腺相关病毒、慢病毒、腺病毒为载体的基因治疗病毒载体药物。
- 如权利要求23所述的用途,其中所述另外的治疗剂是白细胞消耗剂。
- 如权利要求23所述的用途,其中所述另外的治疗剂是B细胞消耗剂。
- 如权利要求28所述的用途,其中所述B细胞消耗剂是抗体,优选用于肿瘤治疗的抗体,更优选所述抗体与CD10、CD19、CD20、CD21、CD22、CD23、CD24、CD37、CD53、CD70、CD72、CD74、CD75、CD77、CD79a、CD79b、CD80、CD81、CD82、CD83、CD84、CD3、CD11a、CD14、CD25、CD28、CD30、CD33、CD36、CD38、CD40、CD44、CD52、CD55、CD59、CD56、CD103、CD134、CD137、CD138、CD152、CD3、IL-1β、IL-2R、IL-6、IL-12、IL-23、C5、BAFF、BLyS、BCMA、CXCR-4、ICAM-1、SLAMF7/CS1、TNFα、IgE、CD85或CD86特异性结合。
- 如权利要求23所述的用途,其中所述另外的治疗剂是利妥昔单抗、达克珠单抗、巴利昔单抗、莫罗单抗-CD3、英夫利昔单抗、阿达木单抗、奥马珠单抗、依法利珠单抗、那他珠单抗、托珠单抗、依库珠单抗、戈利木单抗、卡那单抗、优特克单抗、贝利木单抗、达雷妥尤单抗、Isatuximab或其组合。
- 权利要求21或22所述的用途,其中所述含Fc剂是治疗剂或诊断剂,优选所述含Fc剂是抗体、Fc融合蛋白抗体药物缀合物。
- 免疫球蛋白降解酶IdeE的突变体,其特征在于,所述的突变体如SEQ ID NO:36所示。
- 一种包含如权利要求32所述的突变体的蛋白。
- 如权利要求33所述的蛋白,其特征在于,所述蛋白在所述突变体的N末端包含信号肽;优选地,所述蛋白在所述突变体的N末端连接有分泌信号序列并在所述分泌序列的N末端连接有甲硫氨酸和/或在在所述突变体C末端连接有组氨酸标签;更优选地,所述蛋白从N末端至C末端由如下组成:甲硫氨酸、分泌信号序列和所述突变体。
- 一种编码如权利要求32所述的突变体或者如权利要求33或34所述的蛋白的核苷酸。
- 一种包含如权利要求35所述的核苷酸的表达载体。
- 一种包含如权利要求36所述的表达载体或者表达如权利要求32所述的突变体或者如权利要求33或34所述的蛋白的宿主细胞;所述宿主细胞优选为大肠杆菌细胞或者酵母细胞。
- 一种组合物,其包含:如权利要求32所述的突变体或者如权利要求33或34所述的蛋白;和任选的药学上可接受的载体或赋形剂。
- 如权利要求38所述的组合物,其进一步包含:抗体或者含有Fc的蛋白。
- 如权利要求39所述的组合物,其中所述抗体的靶点选自下组:细胞表面蛋白、细胞因子、激素、酶、胞内信使、胞间信使和免疫检查点。
- 如权利要求38-40中任一项所述的组合物,其进一步包含:病毒载体药物,优选地,所述病毒载体药物选自下组:溶瘤病毒、基因治疗病毒和病毒载体疫苗。
- 如权利要求38-41中任一项所述的组合物,其进一步包含:能降低血液IgG水平的药物,优选的,所述降低血液IgG水平的药物选自下组:FcRn抗体、与FcRn高亲和力的Fc片段变体。
- 一种试剂盒,其包含:(1)如权利要求32所述的突变体或者如权利要求33或34所述的蛋白;和(2)选自下组的一种或多种:(a)药学上可接受的载体或赋形剂;(b)抗体或者包含Fc的蛋白;和/或(3)病毒载体药物,所述病毒载体药物选自溶瘤病毒、基因治疗病毒和病毒载体疫苗;和/或(4)能降低血液IgG水平的药物,所述降低血液IgG水平的药物选自FcRn抗体、与FcRn高亲和力的Fc片段变体。
- 一种试剂盒,其包含:药盒A和药盒B,其特征在于,所述的药盒A含有如权利要求32所述的突变体或者如权利要求33或34所述的蛋白,所述的药盒B含有选自下组的一种或多种:(1)药学上可接受的载体或赋形剂;(2)抗体或者包含Fc的蛋白;和/或(3)病毒载体药物;和/或(4)能降低血液IgG水平的药物;其中,所述病毒载体药物选自溶瘤病毒、基因治疗病毒和病毒载体疫苗;所述降低血液IgG水平的药物选自FcRn抗体、与FcRn高亲和力的Fc片段变体。
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