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。     

肿瘤靶向药物抗体-药物偶联物的研究进展

抗体-药物偶联物(Antibody-drug conjugates,ADC)具有单克隆抗体的靶向特异性和细胞毒素的抗肿瘤能力,其利用化学接头将细胞毒性药物与单克隆抗体偶联,与肿瘤部位的靶抗原结合后释放毒素.尽管概念简单,但是结构设计复杂、药物副作用明显和疗效欠佳等问题为其进一步研究应用带来了挑战.随着新技术的出现,AD...     

抗肿瘤抗体药物研究进展

自1997年以来,抗体药物用于肿瘤治疗取得突破性的进展。据统计,国内外已有约17种抗体药物被批准用于临床肿瘤治疗。除了一直比较成功的裸抗体,抗体药物偶联物(ADC)成为抗肿瘤抗体药物研发的新热点。抗原靶标及作用机制特点决定了抗肿瘤抗体药物在临床的安全性和疗效。本文主要从肿瘤细胞杀伤机制、作为抗体靶标的肿瘤抗原、在临床的应用情况及ADC纳米粒研究方面对抗肿瘤抗体药物进行了综述。     

抗体药物偶联物的研究进展

传统的癌症化疗常伴随着系统毒性,靶向治疗已成为当今肿瘤研究领域的热点。抗体-药物偶联物(antibody drug conjugates,ADCs)利用单克隆抗体(m ABs)对肿瘤细胞表面过表达抗原的特异性,将"弹头"药物(细胞毒药物)选择性地输送到肿瘤细胞中以改善药物治疗窗。ADCs由"弹头"药物、抗体和药物的偶联链三个部分组成,其兼具了抗体的高特异性和细胞毒素的高活性。而随着抗体药物偶联物brentuximab vedotin(SGN-35,Adcetris)和trastuzumab emtansine(T-DM1,Kadcyla)的成功上市,ADCs引起了人们极大的关注。本文综述ADC的分子特征以及组分优化选择,并简单介绍ADC的发展历程。     

ADC药物配体结合生物分析常见技术问题探讨

目的:抗体药物偶联物(ADC)是一类新的生物治疗药物,通常由细胞毒性有效载荷通过连接子与抗体共价结合组成。ADC在体内经历不断的脱偶联和生物转化过程,导致形成复杂且结构不均一的混合物,除了脱偶联的游离抗体和游离载荷外,还存在不同程度与小分子药物偶联的ADC分子,因此,对生物分析方法的开发带来很大挑战。为了解ADC药物在非临床和临床研发阶段的药代和药效特征,以及免疫原性和安全性,对给药后体内存在的不同分子形式的实体比如药物偶联的抗体、裸抗和总抗体等需要使用不同的方法进行分析。本文总结了在ADC药物分析方法开发中遇到的较为常见的技术问题并提供相关的解决方案,以期为相关的分析方法开发提供参考,促进ADC药物安全有效地开发。     

设计新一代抗体药物偶联物

化疗依然是包括手术、放疗、以及靶向疗法在内的最重要的抗癌手段之一。尽管高效细胞毒素很多,但癌细胞和健康细胞之间微小的差别限制了这些抗癌化合物因为毒副作用在临床上的广泛应用。鉴于抗肿瘤单克隆抗体对肿瘤细胞表面抗原的特异性,抗体药物已经成为肿瘤治疗的标准疗法,但单独使用时疗效经常不尽人意。抗体药物偶联物(antibody drug conjugate,ADC)把单克隆抗体和高效细胞毒素完美地结合到一起,充分利用了前者靶向、选择性强,后者活性高,同时又消除了前者疗效偏低和后者副作用偏大等缺陷。其中抗体是ADC的制导系统,能够靶向性地把效应分子输送到肿瘤细胞,有效地提高了抗体本身对癌细胞的杀伤力。ADC包括抗体、接头(linker)和细胞毒素(也经常称为效应分子)三个组成部分。通过靶向特定抗原,ADC有效地渗透到肿瘤组织,并被肿瘤细胞吞噬进入酶溶体,释放效应分子。尽管ADC新药的开发已经获得前所未有的成功,技术上仍然有待进一步优化,其中包括被肿瘤细胞吞噬的效率、细胞毒素的活性以及效应分子的释放等。本文简单介绍ADC领域的研究进展,并试图从抗体、接头和效应分子三个方面,讨论提高ADC分子在循环系统的稳定性等一系列优化ADC分子特征的策略。对当前ADC领域技术上存在的问题,以及中国公司进入这个领域要面临的挑战进行深度分析,并提出一些积极的应对方案。     

抗体和抗体偶联药物的机遇和挑战

<正>1单克隆抗体药物自Trastuzumab(Herceptin)于1998年被批准用于抗肿瘤治疗到具有细胞毒性的T淋巴细胞相关联抗原-4(cytotoxic T lymphocyte associated antigen-4,CTLA-4)和程序性死亡受体-1(programmed death-1,PD-1)抗体被用于肿瘤的免疫治疗以来,抗体药物研发已取得迅猛发展。新的技术和平台不断出现,包括抗体展示技术、全人源化小鼠和单B细胞技术。抗体药物的结构模式也出现了多样化,开发出了双特异性抗体、抗体融合蛋白、小分子抗体片段等多种形式,尤其是以PD-1抗体为代表的免疫检查点抑制剂、抗体药物偶联物（antibody drug conjugate,ADC）、嵌合抗原受体T细胞（chimeric antigen receptor T cell,CAR-T）/自然杀伤细胞（natural killer cell,NK）治疗的应用,把肿瘤的抗体治疗推向了新的高度,为人类征服癌症和治愈一些疑难杂症提供了不同的、更有效的方法。     

单克隆抗体治疗肿瘤的研究进展

在过去十年中,单克隆抗体已经实现临床应用并且成为肿瘤治疗的主要药物。抗体能够瞄准和杀死肿瘤细胞,同时通过补体级联或者抗体依赖细胞的细胞毒性激活免疫效应分子最终杀死肿瘤细胞。本文就目前针对肿瘤治疗的单克隆抗体的靶点和临床应用情况做一个综述。     

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。     

抗体与药物的位点特异性偶联化学方法学研究进展

发展高效、安全的肿瘤治疗方法是现代医学的主要挑战之一。目前临床上抗体偶联药物(antibody drug conjugates, ADC)已成为肿瘤治疗最有力的工具之一。传统的ADC药物是利用赖氨酸残基作为偶联位点，其偶联具有高度异质性，可能会导致药物可重复性差，治疗指数低下。因此，如何通过位点特异性偶联来规避这些潜在问题是ADC药物研究的重点领域。最近几年，位点特异性的蛋白化学修饰方法领域取得的重大进展，也一定程度上促进了均质ADC药物的合成。因此，本文重点对目前用于构建ADC的位点特异性化学偶联方法进行综述，以期为抗体偶联药物偶联化学的发展提供参考。     

Antibody Drug Conjugates: Nonclinical Safety Considerations

Antibody drug conjugates (ADCs) are biopharmaceutical molecules consisting of a cytotoxic small molecule covalently linked to a targeted protein carrier via a stable cleavable or noncleavable linker. The process of conjugation yields a highly complex molecule with biochemical properties that are distinct from those of the unconjugated components. The impact of these biochemical differences on the safety and pharmacokinetic (PK) profile of the conjugate must be considered when determining the types of nonclinical safety studies required to support clinical development of ADCs. The hybrid nature of ADCs highlights the need for a science-based approach to safety assessment that incorporates relevant aspects of small and large molecule testing paradigms. This thinking is reflected in current regulatory guidelines, where sections pertaining to conjugates allow for a flexible approach to nonclinical safety testing. The aim of this article is to review regulatory expectations regarding early assessment of nonclinical safety considerations and discuss how recent advances in our understanding of ADC-mediated toxicity can be used to guide the types of nonclinical safety studies needed to support ADC clinical development. The review will also explore nonclinical testing strategies that can be used to streamline ADC development by assessing the safety and efficacy of next generation ADC constructs using a rodent screen approach.KEY WORDS: antibody drug conjugates, regulatory guidance, safety assessment, therapeutic index     

Antibody Drug Conjugates: Design and Selection of Linker,Payload and Conjugation Chemistry

Antibody drug conjugates (ADCs) have emerged as an important pharmaceutical class of drugs designed to harness the specificity of antibodies with the potency of small molecule therapeutics. The three main components of ADCs are the antibody, the linker, and the payload; the majority of early work focused intensely on improving the functionality of these pieces. Recently, considerable attention has been focused on developing methods to control the site and number of linker/drug conjugated to the antibody, with the aim of producing more homogenous ADCs. In this article, we review popular conjugation methods and highlight recent approaches including “click” conjugation and enzymatic ligation. We discuss current linker technology, contrasting the characteristics of cleavable and non-cleavable linkers, and summarize the essential properties of ADC payload, centering on chemotherapeutics. In addition, we report on the progress in characterizing to determine physicochemical properties and on advances in purifying to obtain homogenous products. Establishing a set of selection and analytical criteria will facilitate the translation of novel ADCs and ensure the production of effective biosimilars.KEY WORDS: ADC, antibody drug conjugate, biopharmaceutics, enzymatic ligation, therapeuticsAntibody drug conjugates (ADCs) couple the highly desirable pharmacokinetic (PK) profile and targetability of monoclonal antibodies (mAbs) with the potent cytotoxicity of small molecule drugs. Such a combination can potentially minimize dose-limiting toxicities while maximizing desired therapeutic effects. Yet, initial ADCs pairing standard anti-cancer agents, such as doxorubicin, were ineffective in clinical trials (1). These failures were linked to (1) the limited number of drug molecules that can be conjugated to one antibody without affecting antigen binding and (2) the limited number of antigens on target cell surfaces, preventing therapeutic levels of drug accumulation in cells. To date, the most successful approaches to overcome these challenges are improved linker technology and the selection of extremely potent drugs to the pair with the antibody (e.g., ado-trastuzumab emtansine and brentuximab vedotin) (2,3). Innovations in linker design are focused on multiple issues ranging from serum stability to mechanism of release to drug to antibody ratio (DAR). As linkers become increasingly sophisticated, more emphasis is being placed on the methods of bioconjugation between linker and antibody, with the goal of producing homogeneous ADC populations. Several methods of characterization are now employed to assess the composition of such conjugates and to increase our understanding of correlations between ADC structure and efficacy. These many facets of ADC synthesis will be addressed in this review.     

auristatin类细胞毒素及其在抗体药物偶联物中的应用

auristatin类细胞毒素作为抗体药物偶联物（antibody-drug conjugate,ADC）的主要成分,因具有高度生物活性而引起学术界和产业界的广泛关注。研究发现,对auristatin类细胞毒素结构进行修饰和优化,可以获得效果更好的生物活性药物。此文介绍了auristatin类细胞毒素及其在ADC中的应用研究,概述了部分auristatin类ADC的临床开发现状。     

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.     

Development and Translational Application of an Integrated,Mechanistic Model of Antibody-Drug Conjugate Pharmacokinetics

Antibody drug conjugates (ADC), in which small molecule cytotoxic agents are non-specifically linked to antibodies, can enable targeted delivery of chemotherapeutics to tumor cells. ADCs are often produced and administered as a mixture of conjugated antibodies with different drug to antibody ratios (DAR) resulting in complex and heterogeneous disposition kinetics. We developed a mechanism-based platform model that can describe and predict the complex pharmacokinetic (PK) behavior of ADCs with protease-cleavable valine-citrulline (VC) linker linked to Monomethylmonomethyl auristatin F/E by incorporating known mechanisms of ADC disposition. The model includes explicit representation of all DAR species; DAR-dependent sequential deconjugation of the drug, resulting in the conversion of higher DAR to lower DAR species; and DAR-dependent antibody/ADC clearance. PK profiles of multiple analytes (total antibody, drug-conjugated antibody, and/or antibody-conjugated drug) for different ADC molecules and targets in rodents and cynomolgus monkeys were used for model development. The integrated cross-species model was successful in capturing the multi-analyte PK profiles after administration of purified ADCs with defined DAR species and ADCs with mixtures of DAR. Human PK predictions for DSTP3086S (anti-STEAP1-vc-MMAE) with the platform model agreed well with PK (total antibody and antibody-conjugated drug concentrations) measurements in the dose-ranging phase I clinical study. The integrated model is applicable to various other ADCs with different formats, conjugated drugs, and linkers, and provides a valuable tool for the exploration of mechanisms governing disposition of ADCs and enables translational predictions.     

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。     

Antibody Drug Conjugates: Preclinical Considerations

The development path for antibody drug conjugates (ADCs) is more complex and challenging than for unmodified antibodies. While many of the preclinical considerations for both unmodified and antibody drug conjugates are shared, special considerations must be taken into account when developing an ADC. Unlike unmodified antibodies, an ADC must preferentially bind to tumor cells, internalize, and traffic to the appropriate intracellular compartment to release the payload. Parameters that can impact the pharmacological properties of this class of therapeutics include the selection of the payload, the type of linker, and the methodology for payload drug conjugation. Despite a plethora of in vitro assays and in vivo models to screen and evaluate ADCs, the challenge remains to develop improved preclinical tools that will be more predictive of clinical outcome. This review will focus on preclinical considerations for clinically validated small molecule ADCs. In addition, the lessons learned from Mylotarg®, the first in class FDA-approved ADC, are highlighted.     

Pharmacokinetic Considerations for Antibody-Drug Conjugates against Cancer

Antibody-drug conjugates (ADCs) are ushering in the next era of targeted therapy against cancer. An ADC for cancer therapy consists of a potent cytotoxic payload that is attached to a tumour-targeted antibody by a chemical linker, usually with an average drug-to-antibody ratio (DAR) of 3.5–4. The theory is to deliver potent cytotoxic payloads directly to tumour cells while sparing healthy cells. However, practical application has proven to be more difficult. At present there are only two ADCs approved for clinical use. Nevertheless, in the last decade there has been an explosion of options for ADC engineering to optimize target selection, Fc receptor interactions, linker, payload and more. Evaluation of these strategies requires an understanding of the mechanistic underpinnings of ADC pharmacokinetics. Development of ADCs for use in cancer further requires an understanding of tumour properties and kinetics within the tumour environment, and how the presence of cancer as a disease will impact distribution and elimination. Key pharmacokinetic considerations for the successful design and clinical application of ADCs in oncology are explored in this review, with a focus on the mechanistic determinants of distribution and elimination.     

FDA“抗体偶联药物的考虑”供企业用的指导原则草案介绍

美国食品药品监督管理局（FDA）于2022年2月发布了“抗体偶联药物的考虑”供企业用的指导原则草案,旨在帮助企业和其他参与者开发细胞毒性小分子药物（有效载荷）的抗体偶联药物（ADC）。该指导原则阐述了FDA目前对ADC临床药理学开发方案的建议,包括生物分析方法、给药方案、剂量和暴露反应分析、内在因素、QTc评估、免疫原性和药物-药物相互作用。ADC主要用于治疗肿瘤,又是当前国内药物研发的热点。中国目前还没有类似的指导原则,详细介绍FDA的该指导原则,期望有助于国内对这类新药的研发与监管。