CN117980337A - 抗cd6单克隆抗体在预防由高炎症反应引起的细胞和器官损伤中的用途 - Google Patents
抗cd6单克隆抗体在预防由高炎症反应引起的细胞和器官损伤中的用途 Download PDFInfo
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Abstract
本发明涉及生物技术和医学领域。具体而言，其描述了特异性结合CD6的结构域1的抗CD6单克隆抗体在预防高炎症反应中的用途，所述高炎症反应由血液通过体外回路产生的医疗程序触发。本发明的抗CD6抗体通过较低浓度的IL‑6、CRP和LDH显示出高炎症程度的降低；从而防止细胞和器官损伤。
Description
技术领域
本发明涉及生物技术和医学的分支；特别是涉及抗CD6单克隆抗体(mAb)在预防由特定医疗程序触发或影响其最终结果的高炎症反应导致的细胞和器官损伤中的用途。
背景
体外器官支持的使用是上个世纪医学最重要的进步之一。最常用的是体外循环(ECC)和肾脏替代疗法；这两种方法都涉及通过人工回路进行体外血液循环。
ECC或心肺旁路或心肺机/泵(如其所称)，以及体外膜氧合(ECMO)适用于不同的情况，诸如严重心肺功能障碍患者的心血管手术和支持。肾脏替代疗法(透析、血液滤过、血液透析滤过等)广泛用于急性和慢性肾衰竭(Durmaz I等人(1999),Thorac CardiovascSurg.118:306-315)。
已在这些手术期间和之后描述了不同的并发症，包括心脏手术本身引起了强烈的炎症反应，这具有重要的临床意义。自开始使用CPB进行心脏手术以来，出现了诸如发热、心包炎和胸膜炎等并发症(Ribot S等人(1971)J Thorac Cardiovasc Surg.62:59-62)。
此外，慢性炎症会导致严重的不良后果。事实上，持续的低度炎症被认为是在慢性肾病和慢性透析中导致死亡风险、心血管事件(包括早期动脉粥样硬化)、肾脏疾病进展、骨质疏松症和其它不良后果的主要促成因素。(Nowak K和Chonchol M(2018)Semin Dial.31(4):388-397；(Cobo G等人(2018)Nephrol Dial Transplant 33:iii35-iii40)。在肾脏替代手术中，可能会出现中期和长期并发症。
经过几十年的研究，在1981年描述了心脏手术后炎症反应综合征(PCIRS)。在使用CPB的心脏手术患者中，发生PCIRS的频率和严重程度更高。诸如麻醉技术、输液技术、血液暴露或接触异物表面(CPB回路)、手术技术和术后护理等一系列因素通过介质激活炎症反应。在一群患者中，这种反应可能会适得其反。炎症反应综合征引起的器官功能障碍，包括心肌、肺、肾和肝功能障碍等，可在2-11％的手术患者中可能会进展为多器官功能障碍综合征，死亡率介于41-78％(Uyar IS等人(2013)，Cardiovasc J Afr.24:322-326)。尽管程度较轻，但心脏手术后的严重神经损伤也占6.1％(3.1％为局灶性损伤，3％为弥漫性损伤)，包括中枢神经系统功能障碍(Suárez Gonzalo L等人(2002Med Intensiva 26(6):292-303)。
血液与CPB回路的非内皮表面的接触导致了炎症反应综合征的发作，涉及细胞因子、凝血因子、纤溶、补体和细胞免疫系统。不同的作者已经证明，在使用CPB的心脏手术后，白细胞介素诸如IL-1、IL-6、IL-8和TNF-α的水平升高，这与心肌功能障碍、血流动力学不稳定、发热和肺损伤相关(Uyar IS等人(2013),Cardiovasc J Afr.24:322-326；Durmaz I等人(1999),Thorac Cardiovasc Surg.118:306-315)。此外，在慢性肾病患者中使用血液透析可能伴有炎症生物标志物诸如与低度炎症过程相容的IL-6和C反应蛋白(CRP)的水平升高(Nowak K和Chonchol M(2018)Semin Dial.31(4):388-397)。总之，根据体外器官支持的使用频率，体外器官支持的使用可能伴有急性或持续性炎症或高炎症反应，这可导致器官功能障碍并产生不良后果。
面对任何攻击，人体都会启动一种炎症早期反应，其由体液和细胞因素介导，以受限和局部反应为特征，这往往会限制组织损伤；其隔离、破坏和消除传染性微生物，并激活受损器官恢复其正常功能所需的修复过程。与ECC回路类似，在受伤患者的免疫反应中，单核细胞和内皮细胞最初会向受伤区域释放大量促炎细胞因子。TNFα和IL-1是创伤后分泌的第一批细胞因子，它们刺激几种免疫活性细胞并诱导促炎细胞因子(IL-6、IL-8和干扰素γ)的释放。在诊断为全身性炎症反应综合征(SIRS)的骨和软组织损伤的复杂受伤患者中，IL-6升高高达200-300pg/mL(Tanaka T等人(2016)immunothy 8(8):959-970)。
麻醉-外科手术技术的进步和更具生物相容性的回路的使用虽然显示出一些益处，但并没有消除PCIRS。胸段硬膜外麻醉联合全身麻醉用于主动脉-冠状动脉桥，降低了对围手术期应激的反应，这可能会减少术后肺和心肌的损伤。然而，胸段硬膜外麻醉不会显著降低CPB期间的细胞因子反应(Molina Méndez FJ.(2004)Arch Cardiol Mex.74(S-2):505-508)。
存在许多药物策略来影响炎症反应的不同点，诸如使用类固醇、丝氨酸蛋白酶和磷酸二酯酶抑制剂、抗氧化剂(别嘌醇、N-乙酰半胱氨酸、α硫辛酸)和mAb抗C5a。在使用CPB之前、期间或之后都使用过这些药物。还使用了诸如血液过滤/血液灌流和抗细胞因子过滤器等技术措施。尽管这些程序和药物取得了良好的反应，但它们并未显示出预期的有效性，并且仍继续报告与CPB使用相关的发病率和死亡率居高不下(Ribot S等人(1971)J ThoracCardiovasc Surg.62:59-62Uyar IS等人(2013),Cardiovasc J Afr.24:322-326)。
在手术过程中，使用在主CPB溶液中施用的α硫辛酸可以降低IL-6和CRP浓度，但尚未证明对减少并发症或死亡率有临床影响(Uyar IS等人(2013)，Cardiovasc J Afr.24:322-326)。在心脏手术的围手术期或手术中使用类固醇也不能减少最重要的并发症或30天死亡率。此外，其还包括重要的不良事件，诸如感染和心肌损伤的风险(Pasquali SK等人(2012)Pediatrics.129(2):e385-e391Whitlock RP等人(2015)Lancet 386(10000):1243-1253Graham EM等人(2019)JAm Coll Cardiol.74(5):659-668Lomivorotov V等人(2020)JAMA.323(24):2485-2492)。
手术中和手术后静脉内施用的尿胰蛋白酶抑制剂降低TNF-α、IL-1β、IL-6、IL-8和转氨酶的浓度，从而缩短重症监护室(UCI)的通气持续时间和住院时间，但尚不清楚这些参数的降低是否会降低接受治疗的患者的发病率-死亡率(Xu H等人(2017)Euro RevMedical and Pharmacol Sc.；21:2220-2225；G.He等人(2018)Herz https://doi.org/10.1007/s00059-018-4732-0)。培克珠单抗(Pexelizumab)(mAb抗-C5)在降低发病率和死亡率方面也没有显示出临床上显著的效果，并且并非没有不良反应，其中最突出的是感染，包括败血症(Shernan SK等人(2004)Ann Thorac surg.77:942-50)。
与未接受mAb以及心肌损伤和肾功能和肌酐的标志物的对照组相比，在接受心肺旁路手术的猴子中使用mAb抗因子D显示出对补体激活、嗜中性粒细胞和单核细胞上CD11b表达的抑制以及血浆IL-6浓度增加的降低。然而，在综述的文献中没有发现人体研究，在所述文献中抗因子D的使用证明了对细胞因子减少的作用，如防止和调节由通过体外回路的血流产生的高炎症反应及其随之发生的细胞损伤。
专利PCT/IB2021/052793描述了特异性结合CD6结构域I的非耗竭性抗CD6mAb在治疗由感染因子诸如病毒和细菌引起的细胞因子风暴中的用途。接受这些mAb治疗的肺炎患者显示出IL-6、IL-17、TNFα和CRP水平降低，导致肺功能参数改善，防止进展为危急或严重阶段，并改善了UCI管理。
到目前为止，还没有关于使用抗CD6的mAb预防由血液流经体外回路或创伤引起的医疗程序触发的非感染性高炎症反应导致的细胞和器官损伤的信息。
出乎意料的是，本发明的发明人通过在需要CPB或遭受创伤的患者中使用本文所述的mAb，通过较低浓度的IL-6、CRP以及器官功能和损伤标志物诸如LDH和TGP，实现了高炎症程度的降低，从而预防了细胞和器官损伤，从临床角度影响了总体发病率、多器官衰竭和术后死亡率的降低。
发明简述
在一个实施方案中，本发明涉及特异性识别CD6的mAb在预防由高度侵入性医疗程序触发或影响此类程序最终结果的高炎症反应导致的细胞和器官损伤中的用途。特别是，这些mAb是非耗竭性的，并与CD6的结构域1特异性结合。这些mAb包含SEQ ID 1和2序列或与这些序列具有98％的同一性，并且在该情况下包含SEQ ID 1和SEQ ID 3序列。或者，这些mAb可包含SEQ ID NO.4和5序列或与其具有98％的同一性，然后包含SEQ ID NO.4和SEQ IDNO.5和SEQ ID NO.6。特别是，这些抗-CD6mAb是人源化IgG1同种型，优选为mAb伊托利珠单抗(Itolizumab)。
特别地，本发明涉及本文所述mAb用于预防由以下医学程序或疾患触发的细胞和器官损伤的用途：心脏手术、肺移植手术、巨大脑动脉瘤手术、血管手术、体外膜氧合、机械循环支持、血液滤过、肾透析和血液透析过滤、损伤控制手术、创伤、多发伤、烧伤、坏死性腹膜炎、急性炎症反应综合征，但不限于这些。
在另一方面，本发明提供了抗CD6mAb与选自包括下组各项的药物组合：麻醉剂、镇静剂、松弛剂、抗病毒剂、抗生素、促红细胞生成素、阻断IL-6与IL-6受体之间相互作用的药物和阻断IL1和IL1受体之间的相互作用的药物。这种施用可以连续或同时进行。
在另外的实施方案中，本发明涉及治疗经历CPB的受试者的方法，其包括以0.3mg/kg体重至6mg/kg体重的剂量范围静脉内或皮下施用包含SEQ ID NO.1和2或SEQ ID NO.4和5中所示氨基酸序列的mAb，或者具有与它们具有98％的同一性的氨基酸序列并且包含SEQID NO.1和SEQ ID NO.3序列或序列SEQ ID NO.4和SEQ ID NO.6的氨基酸序列的mAb。向受试者施用这些mAb至少一次，两次连续施用之间的时间介于3天与7天之间。
发明详述
药物组合物
将本发明中使用的mAb作为药物组合物的一部分施用，所述药物组合物含有作为活性物质的mAb和作为适当赋形剂的生理缓冲溶液，类似于用于配制用于静脉内或皮下使用的mAb的其它赋形剂。特别是，伊托利珠单抗序列在专利US 6,572,857B1和8,524,233中有所描述，并在详细地示于表1中。
表1.伊托利珠单抗的蛋白质序列。
治疗应用和治疗方法
本发明涉及抗CD6mAb在预防由特定医疗程序触发或影响其最终结果的高炎症反应中的用途，所述特定医疗程序包括心脏手术、肺移植手术、巨大脑动脉瘤手术和血管手术、体外膜氧合(ECMO)、机械循环支持(MCS)、肾替代疗法诸如血液滤过、治疗中或反复透析、血液透析滤过、损伤控制手术、创伤、多发伤、烧伤、坏死性腹膜炎、急性炎症反应综合征。
特别是，其涉及在上述条件下使用根据本发明的抗CD6mAb，其氨基酸序列如SEQID 1(重链可变区)和SEQ ID 2(轻链可变区)所示，或者具有与其具有98％同一性且包含SEQ ID 1(重链可变区)和SEQ ID 3(轻链可变区)的序列。此外，根据本发明，抗CD6mAb具有重链和轻链区域，所述区域包含SEQ ID NO.4(重链)和SEQ ID NO.5(轻链)中所示的氨基酸序列或与其具有98％的同一性的序列。含有SEQ ID NO:4和6或由其组成的抗CD6mAb包括在本发明中。
本发明中使用的术语非耗竭性抗CD6Ac意指识别CD6的mAb，并且其一旦与CD6结合，就不会诱导Ac依赖性细胞毒性(ADCC)、补体依赖性细胞毒性(CDC)或以其它方式促进表达CD6的细胞的裂解或死亡。因此，与基于类固醇、mAb或其它免疫抑制剂的其它疗法不同，所提出的治疗的特别有利方面是不会在患者中诱导免疫缺陷。在接受治疗的患者中保留一定免疫能力可以减少出现其它机会性感染的可能性，这些感染在重症监护室很常见。
接受抗CD6mAb疗法的患者可住进重症监护室，但也可在常规病房或门诊接受治疗。成人、儿童和孕妇患者都有资格接受抗CD6mAb疗法。
应以0.3mg/kg体重至6mg/kg体重的剂量范围(分别对应于25mg和420mg的总量)向受试者(此类受试者为脊椎动物，诸如人)静脉内或皮下施用抗体。所述抗体应至少向患者施用一次，两次连续施用之间的时间应介于3天与7天之间。用于不同抗CD6ACM的剂量和方案可以如下进行调整：通过评估IL-6浓度或体外或体内抑制CD6+T和/或B淋巴细胞活化的能力，或者不诱导它们的消除/耗竭(如在伊托利珠单抗mAb的特定情况下)。
抗-CD6mAb与麻醉剂、镇静剂或松弛剂以及抗病毒或抗生素疗法的依序或相伴组合也是本发明的主题，所述抗病毒或抗生素疗法适用于由CPB或创伤导致的高炎症引起的感染。
对于使用ECMO、机械循环支持和血液过滤的患者，应使用镇静催眠剂，并在必要时使用非去极化松弛剂进行的肌肉放松。
根据患者的身体状况，可将抗CD6mAb与任何允许用于人的麻醉剂、镇静剂、松弛剂或抗生素组合。可能组合的抗病毒药物包括但不限于利巴韦林、1型和2型干扰素，以及蛋白酶抑制剂(包括但不限于博赛匹韦、特拉匹韦、西咪匹韦)、逆转录酶抑制剂(包括但不限于拉齐奥维汀(lazidovidin)、阿巴卡韦、拉米夫定、恩曲他滨、替诺福韦、奈韦拉平、依法韦仑、etravir)、聚合酶抑制剂(包括但不限于索非布韦、雷迪帕韦、维帕他韦、沙奎那韦、利托那韦、茚地那韦、奈非那韦、洛匹那韦、Atazanovir、福沙那韦、替拉那韦、达芦那韦)和NS5A蛋白(包括但不限于依巴司韦/格拉瑞韦)或其组合。要使用的抗生素或抗病毒方案将是每种药物的常规使用方案，而抗-CD6mAb方案将如上所述。
本发明还涉及抗CD6mAb与阻断IL-6与IL-6R之间或IL-1与IL-1R之间相互作用的治疗剂的依序或相伴组合。特别是，附加疗法的治疗应该足够短，以有助于减轻高炎症，但不会诱导促进患者体内细菌和病毒传播的免疫抑制。
另一方面，抗CD6mAb与促红细胞生成素的依序或相伴组合是本发明的主题。特别是主要在接受透析的患者中保护肾损伤方面。
附图简述
图1.接受剂量为1.6mg/kg体重的伊托利珠单抗治疗的患者的炎症特征(LDH、IL-6和CRP浓度)。
图2.经历CPB手术但未接受和接受剂量为1.6mg/kg体重的伊托利珠单抗治疗的患者中的IL-6浓度的比较。
图3.与剂量为1.6mg/kg体重的伊托利珠单抗治疗相比，不同评估条件下的CRP浓度。正常值<6pg/L
图4.与剂量为1.6mg/kg体重的伊托利珠单抗治疗的相比，未接受伊托利珠单抗治疗的经历CPB手术的患者中的LDH浓度。参考范围：240-480IU/L
图5.接受剂量为1.6mg/kg体重的伊托利珠单抗治疗的患者的肝脏特征(ALT、FAL和总胆红素浓度)。正常值：ALT<40IU/L，ALF 39-117IU/L，总胆红素<20μg/L。
图6.接受剂量为1.6mg/kg体重的伊托利珠单抗治疗的患者的肾脏特征(肌酐和尿素浓度)。男性肌酐正常值：62-106μmol/L，女性肌酐正常值：44-80μmol/L，尿素：1.7-8.3μmol/L。
图7.接受剂量为0.3mg/kg体重的伊托利珠单抗治疗的患者中的IL-6和LDH浓度。
图8.与剂量为0.3mg/kg体重的伊托利珠单抗治疗相比，不同测试条件下的IL-6浓度的比较。
图9.接受剂量为1.6mg/kg体重的伊托利珠单抗治疗的经历骨科手术的创伤后患者中的IL-6和乳酸浓度。乳酸值：0.5-1.6mmol/L。
实施例
实施例1.接受伊托利珠单抗(1.6mg/kg体重)治疗的二尖瓣置换手术和CPB患者中的高炎症程度降低的证明。
向经历二尖瓣置换手术的患者施用1.6mg/kg体重的伊托利珠单抗mAb(100mg)(在250mL盐水中)和作为麻醉前药物的2mg咪达唑仑。在基本监测后，在桡动脉中放置套管进行有创血压监测。在监测心率、有创血压、心电图和氧饱和度后，使用利多卡因70mg、芬太尼350μg、咪达唑仑8mg，然后使用阿曲库铵35mg进行麻醉诱导。使用与容量控制通气的麻醉机偶联的8.0气管导管进行喉镜检查和简易插管。通过经皮穿刺颈内静脉放置中央静脉导管。维持是在异氟烷平衡麻醉下进行的，并按需连续输注芬太尼(5μg/kg/h)、咪达唑仑(0.15mg/kg/h)和阿曲库铵(0.2mg/kg)。在1小时内连续施用4mg镁溶液。
胸骨开口无并发症。对升主动脉和上下腔静脉进行插管。在肝素化5mg/kg后，开始CPB，平均流量保持在1.8L/m2与2.4L/m2体表面积之间，平均动脉压介于60mmHg与70mmHg之间。夹闭主动脉，并使用高血钾心脏停搏液进行心肌保护。进行了人工瓣膜替换术，无并发症。主动脉钳夹时间为64分钟。患者窦性心律活跃。内环境正常，生命体征在生理参数范围内，在没有血液动力学支持的情况下退出旁路。CPB时间为156分钟。肝素被逆转。
手术顺利完成。患者被转入重症监护室，插管后血流动力学稳定。心率每分钟76次，血压110/60mmHg，动脉血氧分压99％。患者术后病情稳定发展，没有器官损伤的体征或症状。没有后续感染，他在术后7天出院。
为了评估IL-6、LDH和CRP、ALT、FAL、总胆红素、肌酐和尿素浓度，在手术或伊托利珠单抗治疗(0小时)以及12小时、24小时、48小时和168小时采集样品。
在炎症特征方面，于CPB手术后(图1)12小时观察到IL-6浓度为18.6pg/mL，高于参考值(≤7pg/mL)；但远低于(小9倍)未接受伊托利珠单抗治疗的经历CPB手术的患者组的平均水平(图2)，因此伊托利珠单抗治疗(1.6mg/kg体重)成功控制了CPB产生的IL-6浓度升高，甚至低于单独手术的情况。此外，CRP浓度于24小时达到最高水平(45.1pg/L，图1)；但是当将结果与需要CPB的患者组的结果进行比较时(图3)，发现以1.6mg/kg体重的剂量使用伊托利珠单抗治疗时，CRP浓度增加较少(小1.8倍)。
此外，伊托利珠单抗(1.6mg/kg体重)治疗可防止LDH浓度升高至高于参考范围上限，反映了无细胞或器官损伤，这与经历CPB手术的患者中发生的情况相反(图4)。关于肝脏特征(图5)，测量的参数(ALT、FAL、总胆红素)的浓度始终保持在正常参考范围内，表明没有肝脏损伤。肌酐和尿素浓度保持在正常范围内，表明没有检测到肾损害(图6)。
实施例2.用伊托利珠单抗(0.3mg/kg体重)治疗的二尖瓣置换手术患者中的高炎症程度降低的证明。
向经历二尖瓣置换手术的患者施用0.3mg/kg体重的伊托利珠单抗mAb(25mg)(在50mL盐水中)和作为麻醉前药物的2mg咪达唑仑。在基本监测后，在桡动脉中放置套管进行有创血压监测。在手术室，在监测心率、有创血压、心电图和氧饱和度后，使用利多卡因80mg、芬太尼400μg、咪达唑仑8mg，然后使用阿曲库铵40mg进行麻醉诱导。用与容量控制通气的麻醉机偶联的气管导管8.5进行喉镜检查和简易插管。通过经皮穿刺颈内静脉放置中央静脉导管。维持是在异氟烷平衡麻醉下进行的，并按需连续输注芬太尼(5μg/kg/h)、咪达唑仑(0.15mg/kg/h)和阿曲库铵(0.2mg/kg)。在一小时内连续施用4mg镁溶液。
胸骨开口无并发症。对升主动脉和上下腔静脉进行插管。在肝素化5mg/kg后，开始CPB，平均流量保持在1.8L/m2与2.4L/m2体表面积之间，平均动脉压介于60mmHg与70mmHg之间。夹闭主动脉，并使用高血钾心脏停搏液进行心肌保护。进行了人工瓣膜替换术，无并发症。主动脉钳夹时间为71分钟。患者窦性心律活跃。内环境正常，生命体征在生理参数范围内，在没有血液动力学支持的情况下退出旁路。CPB时间为95分钟。肝素被逆转。
手术顺利完成。患者被转入重症监护病房，插管后血流动力学稳定。心率每分钟80次，血压120/70mmHg，动脉血氧分压100％。
为了测定IL-6和LDH浓度，在手术前或使用伊托利珠单抗治疗(0小时)、12小时和24小时采集样品。
如图7所示，于CPB手术后12小时IL-6浓度升高，而LDH浓度在正常参考范围内。将伊托利珠单抗(0.3mg/kg体重)对IL-6浓度的影响结果与测试的对照组进行比较(图8)，也证实了仅由外科手术引起的或加剧血液通过CPB的流动的这种细胞因子的增加显著减弱。未发现永久性并发症或后续感染。
术后十天，患者出院。如通过IL-6和CRP浓度的监测所证明的，伊托利珠单抗治疗减轻了炎症反应；证明了细胞和器官损伤得到预防。
实施例3.在遭受道路交通事故的患者中，在手术之前高炎症的程度降低的证明。
一名遭遇交通事故的患者在大约1小时后入院，意识清醒，伴有严重的精神运动性激动，语言清晰连贯，伴有创伤周期健忘症，有额颅创伤的痕迹，上肢和左肩区域有多处摩擦烧伤。呼吸系统：胸廓扩张良好(preserved thoracic expansibility,)，无创伤痕迹，肺泡呼吸音良好(preserved vesicular murmur)，无喘息，呼吸频率：23次/分钟。心血管系统：患者面色苍白、多汗，全身皮肤发凉。心率102次/分钟，心率良好的心动过速节律性噪音。腹部柔软，可压，无疼痛，无腹膜反应。左下肢体积增大，大腿和小腿中间三分之一处出现畸形和成角，并伴有明显的外旋和屈曲，肢体明显缩短。触诊显示胫骨和股骨中间三分之一的活动异常。出现线状脉搏(Thread-like pulses)，四肢发冷和出汗。保持敏感性，保持主动和被动运动。在评估他的生理状况时，根据美国胸科医师学会与重症医学学会之间的共识会议，他被认为处于复杂受伤患者的边界阶段，该会议将SIR的诊断定义为特征在于存在两种或更多种以下体征：体温<36℃或>38℃；心率>90次/分钟；呼吸频率>20次呼吸/分钟或pCo2<32mmHg且白细胞>12.000/mm3或<4,000/mm3或>10％未成熟型。决定以1.6mg/kg体重的比率(于250mL生理盐水溶液中稀释)施用mAb伊托利珠单抗(100mg)，在手术期间使用输液泵持续输注两小时。采用单髌下入路对股骨骨折进行逆行非钻尖钢髓内钉入和胫骨骨折的非钻尖钢髓内钉入，手术时间为1小时27分钟。
于事故后1小时、3小时、6小时、12小时和24小时采集血清样品用于测定IL-6浓度。
伊托利珠单抗输注2小时后IL-6浓度下降50％，加上患者的生理稳定(乳酸盐浓度下降)，允许在创伤后的最初数小时内进行最终手术。在最初的24小时内，随着体液参数的改善，尤其是乳酸参数的改善，观察到IL-6浓度下降了多达80％(图9)。这与患者的明显临床改善一起，意味着患者没有发生SIRS，从而防止了向器官功能障碍或死亡的发展。这一发现还允许在创伤后48小时与72小时之间进行最终固定，这减少了通常在5天至10天范围内的等待时间，并相应减少了住院时间。
Claims (14)
1.特异性识别CD6的单克隆抗体(mAb)用于预防由高度侵入性医疗程序触发或影响此类程序的最终结果的高炎症反应而导致的细胞和器官损伤的用途。
2.根据权利要求1的用途，其中所述mAb是非耗竭性mAb。
3.根据权利要求1的用途，其中所述mAb特异性结合CD6的结构域1并且包含序列SEQ IDNO 1和2或与SEQ ID NO 1和2具有98％的同一性的序列。
4.根据权利要求3的用途，其中与序列SEQ ID NO 1和2具有98％的同一性的抗-CD6mAb包含SEQ ID NO.1和3。
5.根据权利要求1的用途，其中所述mAb特异性结合CD6的结构域1并且包含序列SEQ IDNO 4和5或与所述SEQ ID NO.4和5具有98％的同一性的序列。
6.根据权利要求5的用途，其中与序列SEQ ID NO 4和5具有98％的同一性的抗-CD6mAb包含SEQ ID NO.4和6。
7.根据权利要求1-6中任一项的用途，其中触发或影响特定医疗程序的最终结果的状况选自包括以下各项的组：
-心脏手术、肺移植手术、巨大脑动脉瘤手术、血管手术、体外膜氧合、机械循环辅助、血液过滤、肾透析和血液透析滤过、损伤控制手术、创伤、多发伤、烧伤、坏死性腹膜炎、急性炎症反应综合征。
8.根据权利要求1-7中任一项的用途，其与选自包括以下各项的组的药物组合：麻醉剂、镇静剂、松弛剂、抗病毒剂、抗生素、促红细胞生成素、阻断IL-6与IL-6受体之间相互作用的药物以及阻断IL-1与IL-1受体之间相互作用的药物。
9.根据权利要求8的用途，其中将与所述抗CD6 mAb组合的所述药物的施用连续或同时地进行。
10.根据权利要求1-9中任一项的用途，其中所述抗CD6 mAb为人源化IgG1同种型。
11.根据权利要求10的用途，其中所述抗CD6 mAb是伊托利珠单抗。
12.一种治疗经历体外循环(ECC)的受试者的方法，其包括通过静脉内或皮下途径以0.3mg/Kg体重至6mg/Kg体重的剂量范围施用mAb，所述mAb包含SEQ ID NO.1和2中所示的氨基酸序列或与之具有98％的同一性并且包含SEQ ID NO.1和SEQ ID NO.3的氨基酸序列。
13.一种治疗经历体外循环(ECC)的受试者的方法，其包括通过静脉内或皮下途径以0.3mg/Kg体重至6mg/Kg体重的剂量范围施用mAb，所述mAb包含SEQ ID NO.4和5中所示的氨基酸序列或与之具有98％的同一性并且包含SEQ ID NO.4和SEQ ID NO.6的氨基酸序列。
14.根据权利要求12-13中任一项的方法，其中向所述受试者施用所述抗CD6 mAb至少一次，并且两次连续施用之间间隔的时间为3至7天。
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202280060524.2A Pending CN117980337A (zh) | 2021-09-08 | 2022-09-01 | 抗cd6单克隆抗体在预防由高炎症反应引起的细胞和器官损伤中的用途 |
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| Country | Link |
|---|---|
| KR (1) | KR20240055093A (zh) |
| CN (1) | CN117980337A (zh) |
| AU (1) | AU2022344418A1 (zh) |
| CA (1) | CA3231281A1 (zh) |
| IL (1) | IL311287A (zh) |
| WO (1) | WO2023036349A1 (zh) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CU22584A1 (es) | 1995-11-17 | 1999-11-03 | Centro Inmunologia Molecular | Composiciones farmacéuticas que contienen un anticuerpo monoclonal que reconoce el antígeno de diferenciación leucocitario humano cd6 y sus usos para el diagnóstico y tratamiento de la psoriasis |
| MY159517A (en) | 2008-03-14 | 2017-01-13 | Biocon Ltd | A monoclonal antibody and a method thereof |
| FR3100697B1 (fr) | 2019-09-16 | 2022-11-25 | Oreal | Nuancier et procédé de fabrication d’un tel nuancier |
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2022
- 2022-09-01 CN CN202280060524.2A patent/CN117980337A/zh active Pending
- 2022-09-01 IL IL311287A patent/IL311287A/en unknown
- 2022-09-01 KR KR1020247011767A patent/KR20240055093A/ko unknown
- 2022-09-01 CA CA3231281A patent/CA3231281A1/en active Pending
- 2022-09-01 WO PCT/CU2022/050010 patent/WO2023036349A1/es active Application Filing
- 2022-09-01 AU AU2022344418A patent/AU2022344418A1/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| AU2022344418A1 (en) | 2024-04-04 |
| CA3231281A1 (en) | 2023-03-16 |
| WO2023036349A1 (es) | 2023-03-16 |
| KR20240055093A (ko) | 2024-04-26 |
| IL311287A (en) | 2024-05-01 |
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