抗体偶联药物的研发进展和挑战

抗体偶联药物（ADC）由单克隆抗体与不同数目的小分子毒素通过连接子偶联组成,是近年来肿瘤学发展较快的药物类别之一。由于兼具单抗药物的高靶向性以及细胞毒素在肿瘤组织中高活性的双重优点,ADC药物可高效杀伤肿瘤细胞,较化疗药物不良反应更低,较传统抗体类肿瘤药物具有更好的疗效,是近年来肿瘤创新药研发的热点。随着新一代工程抗体展现出良好的治疗前景以及新药研发技术的不断突破,抗体偶联药物经历了三个发展阶段,技术日臻成熟,但ADC药物还存在诸多问题和挑战。本文主要从抗体偶联药物的研发历程、抗体、连接子、偶联技术及细胞毒素的类型等方面进行综述,为ADC创新药物研发提供参考。     

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。     

抗体偶联药物临床前安全性评价考虑要点

抗体偶联药物（Antibody Drug Conjugate,ADC）,是通过连接子将高细胞毒性化合物连接到靶向肿瘤抗原的抗体上,利用抗体靶向识别将化合物递呈至肿瘤细胞表面,杀死肿瘤细胞。ADC药物同时具有抗体和化学药物属性,是将两者的优势结合,极大地提高了药物安全有效性。ADC药物结构复杂,在抗原识别表位、连接位点、连接子以及小分子药物各组分均存在特异性,所以在开展安全性评价研究时有一定的特殊性。本文将从动物种属选择、一般毒性研究、毒代动力学研究、组织交叉反应、免疫原性检测、安全药理研究、遗传毒性研究等方面,阐述ADC药物临床前安全性评价的考虑要点和研究策略。     

抗体偶联药物研究进展

靶向治疗已成为肿瘤治疗新趋势。抗肿瘤靶向药物与传统的细胞毒性化疗药物相比具有特异性高、选择性强和非细胞毒性等优点,抗体偶联药物（ ADC）属于抗肿瘤靶向药物,由抗体、“弹头”药物（细胞毒性药物）通过链分子连接而成。 ADC 将抗体的靶向性与细胞毒性药物的抗肿瘤作用相结合,可以降低细胞毒性抗肿瘤药物的不良反应,提高肿瘤治疗的选择性,还能更好地应对靶向单抗的耐药性问题。     

抗体药物偶联物相关药物性肝损伤研究进展

抗体药物偶联物（ADC）通过将细胞毒药物与单克隆抗体偶联实现有效载荷的靶向递送，为恶性肿瘤治疗提供了一种有效治疗手段。随着ADC在全球范围内越来越多地应用于肿瘤治疗，其导致的用药相关不良反应日益受到关注。其中，ADC导致的药物性肝损伤是最常见的不良反应之一，临床治疗过程中应积极关注，并根据肝损伤程度采取相应的管理措施。通过对ADC导致肝损伤不良反应的临床表现、发生率以及发生机制等进行回顾性分析，并对ADC导致肝损伤后的应对处置进行归纳综述，以期为ADC临床合理用药提供参考。     

抗体药物偶联物及其在恶性血液系统肿瘤治疗中的应用

单克隆抗体靶向治疗是目前临床肿瘤治疗的热点。针对抗体分子大而组织穿透性差以及临床使用剂量大、生产成本高的问题,抗体的小型化和高效性设计已成为抗体药物研发的新趋势。近年来,单抗与细胞毒性药物的结合物被称为抗体药物偶联物(antibody-drug conjugates,ADCs),已加入到抗癌药物的行列中,成为新型的抗体药物而受到广泛关注。泛义的ADC通常由抗体、接头(linker)和效应分子等3部分组成。根据效应分子的不同,可将ADC分为化学免疫偶联物、免疫毒素、放射性免疫偶联物等3类。ADC被内化进入细胞后,通过细胞内的化学和酶解作用释放出细胞毒性物质,细胞毒性物质则通过抑制蛋白合成、解聚微管蛋白或断裂双链DNA等作用而对靶细胞产生杀伤作用。近年来,FDA已经批准2种ADC药物上市,有多种处于II～III期临床试验阶段,取得了显著的临床效果,吸引了越来越多的制药企业争相竞逐。本文介绍ADC的过去和现状,结合临床肿瘤应用中的实际问题,探讨其将来的发展趋势。     

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。     

抗体偶联药物在肺癌中的研究进展

肺癌是世界上最常见的恶性肿瘤之一,传统化疗可有限地延长患者生存期,但结果仍不够理想。随着基因检测技术的提升,靶向和免疫治疗显著延长了肺癌患者的生存期,但仍有一部分患者无法从中获益。抗体偶联药物（ADC）是一类具有独特作用机制的抗肿瘤新药,包含具有高度特异性和亲和力的抗体、高效细胞毒药物和高稳定性连接子,兼有传统化疗药物的强大杀伤作用和抗体药物的精确靶向性。目前,不少针对肺癌ADC的基础及临床研究正在开展。本文就ADC在肺癌中的研究进展进行综述。     

抗肿瘤抗体偶联药物临床药理学研究的若干问题与考虑

抗体偶联药物(antibody-drug conjugates, ADC)由靶向特异性抗原的抗体药物与有效载荷(如小分子细胞毒药物)通过连接子偶联而成，兼具传统小分子细胞毒药物的强大杀伤效应和抗体药物的肿瘤靶向性。截至2022年2月，美国食品药品监督管理局(FDA)已批准12个ADC抗肿瘤药物。本文通过分析已批准ADC药物的临床药理学审评报告结合相关指导原则，梳理ADC药物临床药理学的研究要点，发现在ADC药物研发中，除临床药理学方面的常规研究外，由于ADC特殊的抗肿瘤作用机制，其剂量选择以及特殊人群用药有着特殊的考虑。希望本文对国内研发人员在开发ADC药物时有所启示。     

抗体-药物偶联药物的研究进展

抗体-药物偶联物（ADC）也称为免疫偶联物,属于靶向抗肿瘤药物,由药物、抗体以及偶联抗体和药物的连接物所组成。当抗体和肿瘤细胞表面的抗原特异性结合时,抗体-药物偶联物可将药物成功释放到肿瘤细胞特定部位。本文主要概述抗体-药物偶联物的作用机理、分类以及相关药物的临床进展并重点介绍最新上市的药物曲妥珠单抗-美登木素I（T-DM1,Kadcyla）。     

抗体偶联药物研究进展

抗体偶联药物(antibody drug conjugates,ADCs)是通过化学键将毒性小分子与单克隆抗体偶联的靶向抗肿瘤药物,其充分利用了抗体的特异性和毒性小分子的高抗肿瘤活性,达到了高效低毒的目的。抗体、连接物以及毒性小分子是ADCs的3个重要组成部分,文章介绍了ADCs制备中靶点选择,抗体小型化和人源化改造,高活性毒性小分子使用,可断开和不可断开连接物的特点以及越来越受关注的定点偶联策略,为ADCs临床前研发提供依据。     

Canonical and new generation anticancer drugs also target energy metabolism

Significant efforts have been made for the development of new anticancer drugs (protein kinase or proteasome inhibitors, monoclonal humanized antibodies) with presumably low or negligible side effects and high specificity. However, an in-depth analysis of the side effects of several currently used canonical (platin-based drugs, taxanes, anthracyclines, etoposides, antimetabolites) and new generation anticancer drugs as the first line of clinical treatment reveals significant perturbation of glycolysis and oxidative phosphorylation. Canonical and new generation drug side effects include decreased (1) intracellular ATP levels, (2) glycolytic/mitochondrial enzyme/transporter activities and/or (3) mitochondrial electrical membrane potentials. Furthermore, the anti-proliferative effects of these drugs are markedly attenuated in tumor rho (0) cells, in which functional mitochondria are absent; in addition, several anticancer drugs directly interact with isolated mitochondria affecting their functions. Therefore, several anticancer drugs also target the energy metabolism, and hence, the documented inhibitory effect of anticancer drugs on cancer growth should also be linked to the blocking of ATP supply pathways. These often overlooked effects of canonical and new generation anticancer drugs emphasize the role of energy metabolism in maintaining cancer cells viable and its targeting as a complementary and successful strategy for cancer treatment.     

Antibody drug conjugates - Trojan horses in the war on cancer

Antibody drug conjugates (ADCs) consist of an antibody attached to a cytotoxic drug by means of a linker. ADCs provide a way to couple the specificity of a monoclonal antibody (mAb) to the cytotoxicity of a small-molecule drug and, therefore, are promising new therapies for cancer. ADCs are prodrugs that are inactive in circulation but exert their cytotoxicity upon binding to the target cancer cell. Earlier unsuccessful attempts to generate ADCs with therapeutic value have emphasized the important role each component plays in determining the efficacy and safety of the final ADC. Scientific advances in engineering antibodies for maximum efficacy as anticancer agents, identification of highly cytotoxic molecules, and generation of linkers with increased stability in circulation have all contributed to the development of the many ADCs that are currently in clinical trials. This review discusses parameters that guide the selection of the components of an ADC to increase its therapeutic window, provides a brief look at ADCs currently in clinical trials, and discusses future challenges in this field.     

体内药物相互作用机制及其评价方法的研究进展

药物–药物相互作用是目前临床不良反应的主要来源之一,药物相互作用产生的效益和风险会严重影响药物的安全性和有效性。根据药物在体内的过程,分别从吸收、分布、代谢、排泄4个方面阐述了体内药物相互作用机制并佐以实例;潜在药物相互作用的研究以预测其可能发生的药物相互作用也已成为药物开发的必须过程,综述了近些年比较成熟的药物相互作用评价模型的及其研究进展。     

Taxane anticancer agents: a patent perspective

Introduction:Paclitaxel and docetaxel were two epoch-making anticancer drugs and have been successfully used in chemotherapy for a variety of cancer types. In the year 2010, a new taxane, cabazitaxel, was approved by FDA for use in combination with prednisone for the treatment of metastatic hormone-refractory prostate cancer. Albumin-bound paclitaxel (nab?-paclitaxel; abraxane) nanodroplet formulation was another notable invention (FDA approval 2005 for refractory, metastatic, or relapsed breast cancer). Abraxane in combination with gemcitabine for the treatment of pancreatic cancer was approved by FDA in 2013. Accordingly, there have been a huge number of patent applications dealing with taxane anticancer agents in the last 5 years. Thus, it is a good time to review the progress in this area and find the next wave for new developments.

Area covered: This review covers the patent literature from the year 2010 to early 2015 on various aspects of taxane-based chemotherapies and drug developments.

Expert opinion: Three FDA-approved taxane anticancer drugs will continue to expand their therapeutic applications, especially through drug combinations and new formulations. Inspired by the success of abraxane, new nano-formulations are emerging. Highly potent new-generation taxanes will play a key role in the development of efficacious tumor-targeted drug delivery systems.     

The development of antibody delivery systems to target cancer with highly potent maytansinoids

Improving the tumour selectivity of cytotoxic drugs through conjugation to tumour-reactive monoclonal antibodies may lead to novel, more potent agents for cancer therapy. The maytansinoid drugs are 100- to 1000-fold more cytotoxic in vitro than current clinical anticancer drugs. We recently demonstrated that conjugation of maytansinoid drugs to monoclonal antibodies renders them highly efficacious against cancers of breast and colon in both in vitro and in in vivo tumour models. Antibody-maytansinoids represent a new generation of immunoconjugates that may yet fulfil the promise of effective cancer therapy through antibody targeting of cytotoxic agents.     

纳米药物制剂体内分析方法及药动学研究进展和问题策略分析

近年来随着纳米技术的不断发展,纳米药物制剂在改善药物递送、提高生物利用度方面显示出独特优势,已成为临床新药开发研究的热点,为诸多疾病尤其是恶性肿瘤的治疗提供了新思路。然而,由于对纳米药物制剂的体内过程了解不够全面,导致纳米药物制剂的临床转化率极低,严重制约了纳米药物制剂的发展。基于纳米药物制剂良好的应用前景及目前药动学研究中存在的关键问题,调研了国内外的相关文献,首先介绍了常见的具有不同纳米载体类型的纳米药物制剂的种类,对纳米药物制剂体内药物浓度分析测定的方法进行归纳总结,最后分析纳米载体的理化性质对纳米药物制剂体内药动学行为的影响,旨在为纳米药物制剂的体内过程研究提供参考,以获取更为全面的体内药动学数据,提高药物的临床转化率。同时针对目前纳米药物制剂的载体研究、体内浓度定量分析方法以及药动学研究中存在的问题进行讨论,以期为纳米药物制剂的研究与开发利用提供方向。     

Antibody‐Drug Conjugates: A Clinical Pharmacy Perspective on an Emerging Cancer Therapy

Antibody‐drug conjugates (ADCs) combine highly specific monoclonal antibodies with potent cytotoxic drugs. Their synergy allows for targeted delivery of toxic drugs to cancer cells while sparing systemic exposure. In this review, we focus on the history and clinical applications of ADCs approved by the U.S. Food and Drug Administration (FDA) for the treatment of cancer and highlight new ADCs in the drug development pipeline. Three ADCs have received FDA approval thus far. Gemtuzumab ozogamicin, although withdrawn from the U.S. market, may still be an effective treatment modality in subsets of patients with acute myeloid leukemia. Brentuximab vedotin and ado‐trastuzumab emtansine have shown improved efficacy and safety data compared with standard chemotherapy for the treatment of advanced lymphoma and breast cancer, respectively. With a number of ADCs with promising preliminary data in the clinical trial pipeline, cancer therapy is moving forward from traditional chemotherapy to targeted treatment modalities driven by the specificity of monoclonal antibodies and advancing biotechnology.