基于淋巴类器官的抗体药物代谢替代技术研究现状

抗体药物具有相对分子质量大、亲脂性差、膜通透性有限以及高度特异性等性质。其吸收、分布和消除过程区别于传统的小分子药物，与淋巴器官密切相关，容易产生免疫原性。淋巴类器官芯片是以淋巴系统为基础、以微流控芯片技术为核心的微型细胞培养装置，是一种更具生理真实性的体外模型。与传统的二维细胞培养相比，类器官更接近体内细胞运动和多细胞间信号交流的状态；与动物实验相比，类器官更符合伦理学要求，且能够更好地预测药物与人体的相互作用，有望对传统药代动力学评价系统加以补充和完善，从而获得更加客观真实的生理药物代谢评价结果。本文综述了基于淋巴类器官的抗体药物代谢替代技术研究现状，主要包括淋巴类器官的研究现状及其对于抗体药物代谢研究的意义，包括淋巴类器官的抗体药代动力学替代研究和免疫原性替代研究，以期为相关药物研究提供新思路。     

单克隆抗体药物及抗体偶联药物的药代动力学研究进展

近几年来,随着国际上一些重磅生物药专利的到期或即将到期,以及以PD-1、PD-L1等免疫检查点为靶标的单克隆抗体药物的上市和其在肿瘤治疗方面显示的疗效,在国内引发了抗体药物的仿制以及研发热潮。与传统小分子药物的药代动力学特征不同,抗体类药物的药物代谢动力学特征有着其特有的规律。本文从药代动力学特征的四个方面：吸收（Absorption）、分布（Distribution）、代谢（Metabolism）、排泄（Excretion）,对单克隆抗体药物以及抗体偶联药物（Antibody-Drug Conjugates, ADC）的药代动力学特征进行综述。     

单克隆抗体药物研发进展

目的：对单克隆抗体药物研发进展进行综述,为行业提供参考。方法：通过查阅文献和相关数据库,对经典的单克隆抗体药物,以及由此衍生的抗体偶联药物、双特异性抗体药物的研究进行汇总、梳理。结果与结论：自1986年第一个单克隆抗体药物上市以来,全球已有超过100种单抗药物获批上市。国内已获批的进口单抗药物达42个,国产单抗药物达31个。经过30多年的研究和发展,单抗药物以其高度特异性和疗效确切的特点,在肿瘤、自身免疫、代谢、病毒感染等疾病领域显示出独特的优势和广阔的应用前景。     

微生物药物和抗体药物——发现和研制新药的重要领域

自然界存在的微生物种类繁多 ,微生物的代谢产物极其复杂多样 ,是发现与研制新药的丰富来源。单克隆抗体 (单抗 )对相应的抗原具有高度特异性 ,因此 ,单抗在疾病的诊断与治疗中有巨大的潜力与应用价值。以细胞工程技术和基因工程技术为基础研制的抗体工程药物通称单克隆抗体治疗剂(monoclonalantibodytherapeutics)或称抗体药物(antibody -baseddrugs)。抗体药物可能用于治疗肿瘤、病毒性感染、心血管病及其他疾患。 2 0世纪 90年代后期以来 ,美国FDA相继批准多种抗体药物应用于临床治疗 ,抗体药物的研究与开发显示了新的发展势头 ,成为生物技术药物 (biotechnologymedicines)的新热点。 2 0 0 0年批准的Mylotarg是由抗CD33分子的单抗和抗肿瘤抗生素calicheamicin连接的偶联物。Mylotarg的研发表明 ,微生物药物与抗体药物的研究出现了新的结合点。微生物药物具有高度多样性 (diversity)。表现为 :(1)生物作用的多样性。已报告的活性物质种类繁多 ,包括抗肿瘤、抗病毒、抗细菌、抗真菌、以及作用于心血管和免疫系统等各种各...     

生物大分子药物代谢消除途径及体外代谢研究方法进展

由于理化及生物学性质的差异,生物大分子药物与传统小分子药物相比,药代动力学机制更加复杂,在体内表现出不同的吸收、分布、代谢、排泄过程。大分子药物一般不经CYP 450酶代谢,其体内消除途径主要有肾小球滤过、酶水解、受体介导的胞吞消除和抗药物抗体介导的消除。近年来,除了常用的免疫分析法、放射性同位素示踪法、LC-MS/MS等分析方法外,还有计算机模型被开发用于模拟预测大分子药物药代动力学性质的研究并发挥越加重要的作用。本文主要综述了大分子药物主要代谢消除途径及体外研究模型TMDD、PBPK的应用和发展。     

抗体药物在肿瘤治疗中的应用与进展

单克隆抗体药物以其特异性高、亲和力强、血清半衰期长等优点在肿瘤治疗领域得到广泛应用。基于母体单克隆抗体而设计的双特异性抗体、抗体片段、抗体药物偶联物等将抗体类药物的开发推至新的高潮。通过对抗体药物在肿瘤治疗领域的应用和最新进展、抗体药物的结构和作用机制进行介绍,并对肿瘤治疗抗体药物上市与临床开发现状进行总结,以期为抗体药物在肿瘤治疗领域的未来发展提供参考。     

抗体偶联药物研究进展

抗体-药物偶联物(Antibody-drug conjugates,ADCs)由“弹头”药物(细胞毒药物)、抗体以及偶联抗体和药物的偶联链3部分组成,其作为一种新型药物,结合了抗体的靶向特异性和小分子药物的细胞毒作用,已成为当今肿瘤研究领域的热点。根据其细胞毒药物来源可分为陆地与海洋两大类,本文总结了近年来这两大类抗体偶联药物的研究进展,并从靶点的特异性、抗体的亲和力、高效的细胞毒分子及合适的偶联链等方面对ADCs的发展关键进行了简要评述。     

纳米抗体偶联药物的研究进展

抗体偶联药物(antibody-drug conjugate, ADC)因其具有靶点清晰、特异性强等优点已成为临床上治疗多种疾病尤其是癌症的有效手段。但传统ADC中的单克隆抗体组织渗透能力差,存在免疫原性和免疫毒性等风险,且改造成本高。由驼科动物血液中提取的纳米抗体(nanobody, Nb)是目前已知具有完整抗原结合能力的最小抗体片段,具有组织渗透能力强、免疫原性低、特异性强、稳定性高等优势,可以代替传统单克隆抗体参与构建纳米抗体偶联药物(nanobody-drug conjugate, NDC)。本文从纳米抗体结构优势、NDC的构建、纳米抗体偶联物的应用三个方面进行综述与讨论,以期为NDC的研究与发展提供思路。     

抗体偶联药物的临床应用及其耐药性优化对策的研究进展

抗体–药物偶联(ADC)是现代“精准医疗”需求下药学发展的必然趋势。从2000年第一款ADC药物的上市成功到2020年ADC药物的研发层出不穷。肿瘤靶向治疗的发展带动了ADC药物研发领域的快速兴起。ADC药物是使用具有特异性的单克隆抗体与具有生物活性的细胞毒素结合,将药物特异性递送至肿瘤表面位点,避免对正常细胞的杀伤,减少毒副作用。ADC为细胞毒性有效载荷提供了一种较为理想的递送方法。但是也必须清楚的认识到,由于肿瘤异质性、肿瘤代谢、肿瘤血供等多种因素导致的肿瘤耐药是ADC药物发展中所面临的一大挑战。从ADC药物的发展进程、临床应用及其所面临的耐药问题进行综述,探讨抗体偶联药物的临床应用及其所面临的挑战和策略。     

抗体偶联药物及其体内外代谢的研究进展

抗体偶联药物（ADC）是由单克隆抗体和细胞毒性有效载荷通过连接子偶联而成,结合了单克隆抗体的高特异性靶向能力和细胞毒活性小分子高效杀伤作用的优点,实现了对癌细胞的精准高效清除,已成为抗癌药物研发的热点之一。自2000年美国食品药品监督管理局（FDA）批准第一个ADC药物吉妥珠单抗（Mylotarg）以来,迄今全球已有14个ADC药物获批上市。这类新型的抗癌药物正引领癌症靶向治疗的新时代。基于ADC药物的构建核心和抗肿瘤作用机制,对ADC药物的体内外代谢的研究进展进行综述,以期从代谢角度为ADC药物的设计、开发、临床前药理、毒理及后续研究提供参考。     

Antibody pharmacokinetics and pharmacodynamics

The U.S. Food and Drug administration (FDA) has approved several polyclonal antibody preparations and at least 18 monoclonal antibody preparations (antibodies, antibody fragments, antibody fusion proteins, etc.). These drugs, which may be considered as a diverse group of therapeutic proteins, are associated with several interesting pharmacokinetic characteristics. Saturable binding with target antigen may influence antibody disposition, potentially leading to nonlinear distribution and elimination. Independent of antigen interaction, concentration-dependent elimination may be expected for IgG antibodies, due to the influence of the Brambell receptor, FcRn, which protects IgG from catabolism. Antibody administration may induce the development of an endogenous antibody response, which may alter the pharmacokinetics of the therapeutic antibody. Additionally, the pharmacodynamics of antibodies are also complex; these drugs may be used for a wide array of therapeutic applications, and effects may be achieved by a variety of mechanisms. This article provides an overview of many of the complexities associated with antibody pharmacokinetics and pharmacodynamics.     

抗体药物的药学监护

近年来，抗体药物在自身免疫性疾病及肿瘤治疗领域表现非凡，成为当前药物研发的热点之一。与传统小分子药物相比，抗体药物具有结构功能复杂、药动学特殊及免疫原性等特点，使其对临床合理用药提出了新的挑战。本文以抗体药物的结构和药动学特征为基础，从抗体药物的有效性、安全性、经济性、免疫原性和药物警戒五个方面，阐述如何将药学监护手段应用于抗体药物，旨在为抗体药物的临床合理使用提供参考。     

Dosing Considerations for Antibodies Against COVID-19

At present, no cure is available for COVID-19 but vaccines, antiviral drugs, immunoglobulins, or the combination of immunoglobulins with antiviral drugs have been suggested and are in clinical trials. The purpose of this paper is to discuss the role of a pharmacokinetic and viral load analysis as a basis for adjusting immunoglobulin dosing to treat COVID-19. We reviewed the pre-clinical and clinical literature that describes the impact of a high antigen load on pharmacokinetic data following antibody treatment. Representative examples are provided to illustrate the effect of high viral and tumor loads on antibody clearance. We then highlight the implications of these factors for facilitating the development and dosing of hyperimmune anti-SARS CoV2 immunoglobulin. Both nonclinical and clinical examples indicate that high antigen loads, whether they be viral, bacterial, or tumoral in origin, result in increased clearance and decreased area under the curve and half-life of antibodies. A dosing strategy that matches the antigen load can be achieved by giving initially high doses and adjusting the frequency of dosing intervals based on pharmacokinetic parameters. We suggest that study design and dose selection for immunoglobulin products for the treatment of COVID-19 require special considerations such as viral load, antibody-virus interaction, and dosing adjustment based on the pharmacokinetics of the antibody.     

低温治疗对药物的药代动力学和药效学影响的系统性评价

目的 系统评价低温治疗对人体药代动力学和药效学的影响.方法 检索PubMed、EmBase和Cocrane Library从数据库建库至2020-03-17,有关低温治疗对于人体药代动力学及药效学的比较研究,限制语言为英语.将纳入文献中药代动力学及药效学参数用相对差异表示,进行系统性评价.结果 共纳入27项研究.在低温...     

Hepatic clearance measurements and pharmacokinetics.

This review emphasizes the need for well-defined models for hepatic pharmacokinetics and discusses the interpretation of hepatic clearance measurements. Such recent approaches are subjected to theoretical and experimental comparisons. The pharmacokinetic consequences, including a classification of drugs according to hepatic clearance, are outlined.     

生物技术药物药代动力学研究进展

生物技术药物作为现代药物研发热点而备受关注,它具有和传统小分子药物截然不同的理化性质,因此其药动学呈现出独特性和复杂性。阐述生物技术药物的概念;总结4种主要的生物技术药物分析方法;进一步综述生物技术药物在体内吸收、分布、代谢和排泄的药动学特点;最后以生物技术药物主流之一的单克隆抗体药物为代表,通过相关数据对比单克隆抗体药物与传统小分子药物在药动学方面的差异。以期为充分了解生物技术药物的药动学特征以及形成机制、研发和筛选新型生物技术药物提供强有力的支持,同时为药物安全性评价和临床用药提供重要参考。     

Clinical pharmacology of valpromide

Valpromide has been used as an antiepileptic and antipsychotic drug for the past 25 years in several European countries. Unlike its corresponding acid, valproic acid, whose pharmacokinetics have been quite extensively reviewed, and despite years of clinical use, it appears that no reviews have been written on the pharmacokinetics of valpromide. This article summarises and analyses its pharmacokinetics from various aspects, with a special emphasis on the differences between valpromide and valproic acid. In humans, valpromide is a prodrug of valproic acid. Despite their chemical similarity, the pharmacokinetics of the 2 drugs in humans are quite distinct. Compared with valproic acid. valpromide has a very short half-life (mean +/- SD: 0.84 +/- 0.33h; n = 6), a high clearance value (70 +/- 31 L/h) and a large volume of distribution (75 +/- 13L). Despite its rapid biotransformation to valproic acid, valpromide has some special characteristics, such as its inhibition of the enzyme epoxide hydrolase which is responsible for the metabolism of carbamazepine-10, 11-epoxide. This review discusses the pharmacokinetics of valpromide, the interactions between it and other drugs such as carbamazepine and amitriptyline, and its antiepileptic and antipsychotic activities.     

Development of gene drug delivery systems based on pharmacokinetic studies.

A series of pharmacokinetic studies following systemic or local administration for the development of delivery systems for gene drugs, such as plasmid DNA and oligonucleotides, are reviewed. The pharmacokinetics of gene drugs after intravenous injection into mice was evaluated based on clearance concepts. Pharmacokinetic analysis revealed that the overall disposition characteristics of the gene drug itself were determined by the physicochemical properties of its polyanionic DNA. Based on these findings, liver cell-specific carrier systems via receptor-mediated endocytosis were successfully developed by optimizing physicochemical characteristics. On the other hand, the pharmacokinetics of gene drugs after intratumoral injection were assessed in a tissue-isolated tumor perfusion system. The relationship between the physicochemical properties of gene drug delivery systems and intratumoral pharmacokinetics was determined and the therapeutic effect was also discussed in relation to pharmacokinetics. Collectively, it was demonstrated that a rational design of gene drug delivery systems that can control their in vivo disposition is possible by means of pharmacokinetic studies at whole body, organ and cellular levels.     

Physiochemical and Biochemical Factors Influencing the Pharmacokinetics of Antibody Therapeutics

Monoclonal antibodies are increasingly being developed to treat multiple disease areas, including those related to oncology, immunology, neurology, and ophthalmology. There are multiple factors, such as charge, size, neonatal Fc receptor (FcRn) binding affinity, target affinity and biology, immunoglobulin G (IgG) subclass, degree and type of glycosylation, injection route, and injection site, that could affect the pharmacokinetics (PK) of these large macromolecular therapeutics, which in turn could have ramifications on their efficacy and safety. This minireview examines how characteristics of the antibodies could be altered to change their PK profiles. For example, it was observed that a net charge modification of at least a 1-unit shift in isoelectric point altered antibody clearance. Antibodies with enhanced affinity for FcRn at pH 6.0 display longer serum half-lives and slower clearances than wild type. Antibody fragments have different clearance rates and tissue distribution profiles than full length antibodies. Fc glycosylation is perceived to have a minimal effect on PK while that of terminal high mannose remains unclear. More investigation is warranted to determine if injection route and/or site impacts PK. Nonetheless, a better understanding of the effects of all these variations may allow for the better design of antibody therapeutics.     

A Minimal Physiologically Based Pharmacokinetic Model with a Nested Endosome Compartment for Novel Engineered Antibodies

We proposed here a minimal physiologically based pharmacokinetic (mPBPK) model for a group of novel engineered antibodies in mice and humans. These antibodies are designed with altered binding properties of their Fc domain with neonatal Fc receptor (FcRn) or the Fab domain with their cognate targets (recycling antibodies) in acidic endosomes. To enable simulations of such binding features in the change of antibody pharmacokinetics and its target suppression, we nested an endothelial endosome compartment in parallel with plasma compartment based on our previously established mPBPK model. The fluid-phase pinocytosis rate from plasma to endothelial endosomes was reflected by the clearance of antibodies in FcRn dysfunctional humans or FcRn-knockout mice. The endosomal recycling rate of FcRn-bound antibodies was calculated based on the reported endosomal transit time. The nonspecific catabolism in endosomes was fitted using pharmacokinetic data of a human wild-type IgG₁ adalimumab in humans and B21M in human FcRn (hFcRn) transgenic mice. The developed model adequately predicted the pharmacokinetics of infliximab, motavizumab, and an Fc variant of motavizumab in humans and the pharmacokinetics of bevacizumab, an Fc variant of bevacizumab, and a recycling antibody PH-IgG₁ and its non-pH dependent counterpart NPH-IgG₁ in hFcRn transgenic mice. Our proposed model provides a platform for evaluation of the pharmacokinetics and disposition behaviors of Fc-engineered antibodies and recycling antibodies.