An Insight into FDA Approved Antibody-Drug Conjugates for Cancer Therapy 癌症治疗中FDA批准的抗体药物结合物的洞察
Juliana T. W. Tong , Paul W. R. Harris , Margaret A. Brimble and Iman Kavianinia 朱莉安娜·T·W·汤，保罗·W·R·哈里斯，玛格丽特·A·布林布尔和伊曼·卡维安尼娅1 School of Chemical Sciences, The University of Auckland, Auckland 1010, New Zealand; 新西兰奥克兰大学化学科学学院，奥克兰 1010，新西兰;jton210@aucklanduni.ac.nz (J.T.W.T.); paul.harris@auckland.ac.nz (P.W.R.H.)2 Maurice Wilkins Centre for Molecular Biodiversity, The University of Auckland, 纽西兰奥克兰大学分子生物多样性莫里斯·威尔金斯中心Auckland 1010, New Zealand 纽西兰奥克兰 10103 School of Biological Sciences, The University of Auckland, Auckland 1010, New Zealand 纽西兰奥克兰大学生物科学学院，奥克兰 1010，纽西兰* Correspondence: m.brimble@auckland.ac.nz (M.A.B.); i.kavianinia@auckland.ac.nz (I.K.); * 通讯：m.brimble@auckland.ac.nz（M.A.B.）；i.kavianinia@auckland.ac.nz（I.K.）；Tel.: +64-9-923-8259 (M.A.B.); +64-21-100-3164 (I.K.) 电话：+64-9-923-8259（M.A.B.）；+64-21-100-3164（I.K.）
Citation: Tong, J.T.W.; Harris, P.W.R. Brimble, M.A.; Kavianinia, I. An Insight into FDA Approved Antibody-Drug Conjugates for Cancer Therapy. Molecules 2021, 26, 5847. https://doi.org/10.3390/ molecules26195847 引用：Tong, J.T.W.；Harris, P.W.R. Brimble, M.A.；Kavianinia, I. 对癌症治疗的 FDA 批准的抗体药物偶联物的洞察。Molecules 2021, 26, 5847. https://doi.org/10.3390/molecules26195847
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Abstract 摘要
The large number of emerging antibody-drug conjugates (ADCs) for cancer therapy has resulted in a significant market 'boom', garnering worldwide attention. Despite ADCs presenting huge challenges to researchers, particularly regarding the identification of a suitable combination of antibody, linker, and payload, as of September 2021, 11 ADCs have been granted FDA approval, with eight of these approved since 2017 alone. Optimism for this therapeutic approach is clear, despite the COVID-19 pandemic, 2020 was a landmark year for deals and partnerships in the ADC arena, suggesting that there remains significant interest from Big Pharma. Herein we review the enthusiasm for ADCs by focusing on the features of those approved by the FDA, and offer some thoughts as to where the field is headed. 癌症治疗中新兴抗体药物复合物（ADCs）的大量涌现导致了一个显著的市场“繁荣”，引起了全球关注。尽管 ADCs 给研究人员带来了巨大挑战，特别是在于寻找合适的抗体、连接物和荷载物的组合方面，截至 2021 年 9 月，已有 11 种 ADCs 获得了 FDA 批准，其中自 2017 年以来仅有 8 种获得批准。对这种治疗方法的乐观态度是明显的，尽管新冠疫情肆虐，2020 年是 ADC 领域交易和合作的里程碑之年，这表明大型制药公司仍然对 ADC 保持着浓厚兴趣。在这里，我们通过关注 FDA 批准的 ADC 的特点来回顾 ADC 的热情，并提出一些关于该领域未来发展方向的想法。
Paul Ehrlich's vision of a rationally targeted strategy to eliminate disease, whether it be microbes or malignant cells, has driven research over the past century, particularly creating a targeted cancer therapy revolution [1]. In 1913, it was theorized that a so-called 'magic bullet' drug could cause selective destruction by employing a toxin and a targeting agent. Over 80 years following Ehrlich's fundamental realization, and supported by the successful development of chemotherapy in the 1940s [2] and monoclonal antibodies (mAbs) in the 1970s [3], in 1983 the first successful antibody-drug conjugate (ADC) human clinical trial began using an anti-carcinoembryonic antibody tethered to vindesine [4]. The safety of administration and the ability of the conjugate to localize after radiolabeling was investigated in eight patients with advanced metastatic carcinoma. While the feasibility of this approach was demonstrated, several hurdles were identified, the most significant being aggregation [4]. 保罗·埃尔利希（Paul Ehrlich）对有针对性地消除疾病的愿景，无论是微生物还是恶性细胞，推动了过去一个世纪的研究，特别是创造了有针对性的癌症治疗革命[1]。1913 年，有理论认为所谓的“魔术子弹”药物可以通过使用毒素和靶向剂来引起选择性破坏。在埃尔利希基本认识的 80 多年后，并得到了 1940 年代化疗药物[2]和 1970 年代单克隆抗体（mAbs）的成功发展的支持[3]，1983 年，第一个成功的抗体药物结合物（ADC）人类临床试验开始使用抗癌胚抗体与长春碱结合[4]。在 8 名晚期转移性癌症患者中研究了该结合物的给药安全性和放射性标记后的局部化能力。虽然证明了这种方法的可行性，但也发现了几个障碍，其中最重要的是聚集[4]。
ADCs are now amongst the fastest growing drug classes in oncology, as they combine the best features of mAbs and small molecule drugs, creating a single moiety that is highly specific and cytotoxic. These therapeutic entities are considered the "homing missiles" of cancer therapy, and are composed of three key elements: a monoclonal antibody that selectively binds to an antigen on the tumor cell surface, a cytotoxic drug payload, and a cleavable or non-cleavable linker, see Figure 1 [5-7]. Each of these components can vary widely between ADCs, leading to immense diversity in the overall structure, and subsequently, the ADC's pharmacological and clinical properties. ADCs are designed to deliver the toxic payload selectively to cells expressing the target antigen. Therefore, target antigens that are preferentially expressed in tumors versus non-malignant cells can be exploited to harness a greater therapeutic window and reduce the chance of off-target ADCs现在是肿瘤学中增长最快的药物类别之一，因为它们结合了单克隆抗体和小分子药物的最佳特点，创造出一种高度特异和细胞毒性的单一分子。这些治疗实体被认为是癌症治疗的“导向导弹”，由三个关键元素组成：选择性结合于肿瘤细胞表面抗原的单克隆抗体、细胞毒药物载体以及可切割或不可切割的连接剂，见图1。ADCs的每个组成部分在不同ADCs之间可能存在广泛变化，导致整体结构和ADC的药理学和临床特性具有极大的多样性。ADCs旨在将有毒载体选择性地传递给表达目标抗原的细胞。因此，相对于非恶性细胞，肿瘤中优先表达的靶抗原可以被利用来获得更大的治疗窗口并降低非靶向作用的机会。
effects associated with systemic administration of traditional chemotherapeutics. The advent of ADCs has thus sparked a revival of chemotherapeutic payloads, which cannot be administered systemically due to their extreme potency and ensuing toxicity profiles. 与传统化疗药物的全身给药相关的效应。ADC 的出现引发了化疗药物有效载荷的复苏，这些药物由于其极高的毒性和随之而来的毒性特征而无法全身给药。
Only of the administered dose of tumortargeted mAbs reach the tumor tissue, therefore highly potent payloads are required to achieve therapeutic efficacy. 仅有 经给药的靶向肿瘤 mAbs 剂量达到肿瘤组织，因此需要高效的有效载荷才能实现治疗效果。
ADCs exhibit both on-target and off-target toxicities. While most toxicities are related to the payload being released off-target, notable examples of target-dependent toxicities exist. ADC 既表现出靶向毒性，也表现出非靶向毒性。虽然大多数毒性与有效载荷在非靶向释放有关，但也存在与靶向相关的毒性的显著例子。
Figure 1. The general structure of an antibody-drug conjugate (ADC) and key points about the different components. (Created with BioRender.com, accessed 27 September 2021). 抗体药物结合物（ADC）的一般结构及其不同组分的关键要点。 （使用 BioRender.com 创建，于 2021 年 9 月 27 日访问）。
Many ADCs have demonstrated impressive activity against treatment-refractory cancers, resulting in their approval for both hematologic malignancies and solid tumor indications. At the time of writing, 11 different ADCs have been approved by the US Food and Drug Administration (FDA) for clinical use, see Figure 2A and Table 1. Of these, seven have also obtained approval by the European Medicines Agency (EMA) (Appendix A). The recent surge in ADC approvals, of which Polivy (polatuzumab vedotin-piiq), Padcev (enfortumab vedotin-ejfv), Enhertu (fam-trastuzumab deruxtecan-nxki), Trodelvy (sacituzumab govitecan-hziy), Blenrep (belantamab mafodotin-blmf), Zynlonta (loncastuximab tesirine-lpyl), and Tivdak (tisotumab vedotin-tftv) have all gained FDA approval since 2019, belies the turbulent past these biologics have experienced, both in academic and regulatory settings. 许多 ADC 已经展示出对难治性癌症的令人印象深刻的活性，导致它们获得了用于治疗血液恶性肿瘤和实体肿瘤的批准。 在撰写本文时，美国食品和药物管理局（FDA）已批准了 11 种不同的 ADC 供临床使用，详见图 2A 和表 1。 其中，有七种也获得了欧洲药品管理局（EMA）的批准（附录 A）。 自 2019 年以来，ADC 批准数量的激增，其中包括 Polivy（波拉图祖单抗-皮克）、Padcev（恩福替单抗-伊法）、Enhertu（fam-曲妥珠单抗-恩西）、Trodelvy（萨曲单抗-戈维替卡）、Blenrep（贝兰替单抗-布尔姆夫）、Zynlonta（隆卡替单抗-利皮尔）和 Tivdak（替索单抗-特夫特夫）自 2019 年以来获得了 FDA 的批准，这表明这些生物制剂在学术和监管环境中经历了动荡的过去。
While several publications have listed Lumoxiti (moxetumomab pasudotox-tdfk) as an FDA approved ADC [8,9], we have excluded it from our discussions as we consider it an immunotoxin [10-13]. Besides Lumoxiti , the immunotoxins Ontak (denileukin diffittox) [16] and Elzonris (tagraxofusp-erzs) [17], have also been granted FDA approval. 尽管有几份出版物将Lumoxiti（moxetumomab pasudotox-tdfk）列为FDA批准的ADC[8,9]，但我们在讨论中将其排除在外，因为我们认为它是一种免疫毒素[10-13]。除了Lumoxiti之外，免疫毒素Ontak（denileukin diffittox）[16]和Elzonris（tagraxofusp-erzs）[17]也获得了FDA批准。
In this review, we aim to provide a brief and up to date overview of each of the FDA approved ADCs. We begin with the general mechanism of action (MoA) of an ADC, see Figure 3, followed by a chronological discussion of the FDA approved ADCs (based on year of first approval). References to pivotal clinical studies leading to approval are included. We conclude with our thoughts on where the ADC field is headed, particularly focusing on expected market growth and the use of artificial intelligence (AI) to drive the development of ADC technologies. Literature documenting ADCs is extensive, with over 60,000 research articles pertaining to ADCs published between 2011 and 2018 [18]. We recommend several excellent review articles in the field of ADCs for more detail and to promote the understanding and an appreciation of these next-generation therapeutics [19-24]. 在这篇评论中，我们旨在提供每种 FDA 批准的 ADC 的简要且最新的概述。我们从 ADC 的一般作用机制（MoA）开始，参见图 3，然后按照 FDA 批准的 ADC 的时间顺序进行讨论（根据首次批准的年份）。包括导致批准的关键临床研究的参考资料。我们最后总结了 ADC 领域的发展方向，特别关注预期市场增长和利用人工智能（AI）推动 ADC 技术的发展。有大量文献记录了 ADC，2011 年至 2018 年间发表了超过 60,000 篇与 ADC 相关的研究文章[18]。我们推荐几篇关于 ADC 领域的优秀评论文章，以获取更多细节，并促进对这些下一代治疗药物的理解和欣赏[19-24]。
Figure 2. (A) Structures of FDA approved antibody-drug conjugates (ADCs). The antibody is shown in blue, and chemical structures for linker and payload are in red and green, respectively. Scissors indicate the cleavage site (if applicable). Pharmaceutical makers and drug-to-antibody ratio for each ADC is indicated. (B) Comparison of approximate payload potency ranges (Created with BioRender.com, accessed September 2021). 图 2. (A) FDA 批准的抗体药物结合物（ADCs）的结构。抗体显示为蓝色，连接剂和药物负载的化学结构分别为红色和绿色。剪刀表示裂解位点（如适用）。每种 ADC 的制药商和药物对抗体比例均已指明。 (B) 大致药物负载效力范围的比较（使用 BioRender.com 制作，截至 2021 年 9 月访问）。
Table 1. FDA approved ADCs currently on the market. 表 1. 目前市场上有 FDA 批准的 ADC。
ADC
Target
Linker
Payload/
Payload
Class
Payload
Action
DAR
Disease Indication (Year of 疾病适应症（年份）
Approval)
Mylotarg
(gem-
tuzumab
ozogamicin)
CD33
IgG4
acid
cleavable
ozogamicin/
calicheam-
icin
DNA
cleavage
CD33+ R/R AML (2000) CD33+ 复发难治性急性髓系白血病 (2000)
Adcetris
(brentux-
imab
vedotin)
CD30
IgG1
enzyme
cleavable
MMAE/
auristatin
microtubule
inhibitor
4
R/R sALCL or cHL (2011)R/R 复发难治性表型异型 T 细胞淋巴瘤或经典霍奇金淋巴瘤 (2011)R/R
pcALCL or CD30+ MF (2017); 原发性皮肤 T 细胞淋巴瘤或 CD30+ 黏膜脓疱病 (2017);
cHL, sALCL or CD30+ PTCL cHL，sALCL 或 CD30+ PTCL
HER2
IgG1
non-
cleavable
DM1/ may-
tansinoid
microtubule
inhibitor
3.5
HER2+ metastatic breast cancer HER2+转移性乳腺癌
previously treated with 之前接受过治疗
trastuzumab & a taxane (2013); 曲妥珠单抗和紫杉醇（2013 年）;
HER2+ early breast cancer after HER2 阳性早期乳腺癌后
trastuzumab-based treatment 曲妥珠单抗为基础的治疗
Besponsa
(inotuzumab
ozogamicin)
CD22
IgG4
acid
cleavable
ozogamicin/
calicheam-
icin
DNA
cleavage
6
R/R B-ALL (2017) R/R B-ALL（2017 年）
Polivy (po- Polivy
latuzumab
vedotin-piiq) 维多汀-匹洛）
CD79b
IgG1
enzyme
cleavable
MMAE/
auristatin
microtubule
inhibitor
3.5
R/R DLBCL (2019)
Padcev
(enfortumab
vedotin-ejfv)
Nectin4
IgG1
enzyme
cleavable
MMAE/
auristatin
microtubule
inhibitor
3.8
Enhertu
(fam-
trastuzumab
deruxtecan-
nxki)
HER2
IgG1
enzyme
cleavable
DXd/
camptothecin
TOP1
inhibitor
8
Unresectable or metastatic 无法切除或转移性
HER2+ breast cancer after 2 or HER2 阳性乳腺癌在 2 个或者
more anti-HER2 regimens 更多的抗 HER2 疗程后
d; locally advanced or d; 本地晚期或
metastatic HER2+ gastric or 转移性 HER2+ 胃或
gastroesophageal junction 胃食管结合部
adenocarcinoma after a 腺癌治疗后
trastuzumab-based regimen 曲妥珠单抗为基础的方案
Trodelvy
(sacituzumab
govitecan-
hziy)
TROP2
IgG1
acid
cleavable
SN-38/
camp-
tothecin
TOP1
inhibitor
7.6
Locally advanced or metastatic 局部晚期或转移性
TNBC after at least two prior 至少经历两种先前治疗后的三阴性乳腺癌
therapies ; locally 治疗 ; 本地
advanced or metastatic 先进或转移性
urothelial cancer after a 尿路上皮癌后
Pt-containing chemotherapy 含铂化疗
and a PD-1 or PD-L1 inhibitor 和 PD-1 或 PD-L1 抑制剂
Blenrep
(belantamab
mafodotin-
blmf)
BCMA
IgG1
non-
cleavable
MMAF/
auristatin
microtubule
inhibitor
4
multiple myeloma after at 多发性骨髓瘤后
least 4 prior therapies including 至少 4 种先前治疗，包括
an anti-CD38 mAb, a 抗 CD38 单抗，一种
proteasome inhibitor, and an 蛋白酶体抑制剂和一种
immunomodulatory agent 免疫调节剂
Table 1. Cont. 表 1. 续表
ADC
Target
Linker
Payload/
Payload
Class
Payload
Action
DAR
Disease Indication (Year of 疾病适应症（年份
Approval)
Zynlonta
(loncastux-
imab
tesirine-lpyl) 特西林-莱普尔）
CD19
IgG1
enzyme
cleavable
SG3199/
PBD dimer
DNA
cleavage
2.3
R/R large B-cell lymphoma R/R 大 B 细胞淋巴瘤
after 2 or more lines of systemic 在系统性治疗的 2 条或更多线路之后
therapy, including DLBCL not 治疗，包括非特指的 DLBCL
otherwise specified, DLBCL DLBCL，除非另有规定
arising from low grade 起源于低级别
lymphoma, and high-grade 淋巴瘤和高级别
B-cell lymphoma (2021) d B 细胞淋巴瘤（2021）d
Tivdak
(tisotumab
vedotin-tftv)
Tissue
Factor
IgG1
enzyme
cleavable
MMAE/
auristatin
microtubule
inhibitor
4
Recurrent or metastatic cervical 经常性或转移性宫颈癌
cancer with disease progression 伴随疾病进展
on or after chemotherapy 在化疗后或之后
ADC, antibody-drug conjugate; AML, acute myeloid leukemia; B-ALL, B-cell acute lymphoblastic leukemia; BCMA, B-cell maturation antigen; cHL, classical Hodgkin lymphoma; DAR, drug-to-antibody ratio; DLBCL, diffuse large B-cell lymphoma; mAb, monoclonal antibody; MF, mycosis fungoides; MMAE, monomethyl auristatin E; MMAF, monomethyl auristatin F; pcALCL, primary cutaneous anaplastic large cell lymphoma; Pt, platinum; PTCL, peripheral T-cell lymphoma; PBD, pyrrolobenzodiazepine; R/R, relapsed and/or refractory; sALCL, systemic anaplastic large cell lymphoma; TOP1, topoisomerase I; TROP2, tumor-associated calcium signal transducer 2. a As a single agent or in combination with daunorubicin and cytarabine. Mylotarg was withdrawn from the market in 2010 and reapproved in 2017 for newly diagnosed R/R CD33-positive AML. In combination with cyclophosphamide, doxorubicin, and prednisone for newly diagnosed sALCL or CD30+ PTCL and in combination with doxorubicin, vinblastine, and dacarbazine for newly diagnosed cHL. ADC，抗体药物结合物；AML，急性髓细胞白血病；B-ALL，B 细胞急性淋巴细胞白血病；BCMA，B 细胞成熟抗原；cHL，经典霍奇金淋巴瘤；DAR，药物与抗体比率；DLBCL，弥漫性大 B 细胞淋巴瘤；mAb，单克隆抗体；MF，真菌性蕈瘤；MMAE，单甲基奥利斯他汀 E；MMAF，单甲基奥利斯他汀 F；pcALCL，原发性皮肤间变性大细胞淋巴瘤；Pt，铂；PTCL，外周 T 细胞淋巴瘤；PBD，吡咯苯并二氮䓬；R/R，复发和/或难治性；sALCL，全身性间变性大细胞淋巴瘤；TOP1，拓扑异构酶 I；TROP2，肿瘤相关钙信号转导蛋白 2。a 作为单一药物或与多柔比星和阿糖胞苷联合使用。Mylotarg 于 2010 年退出市场，并于 2017 年重新获批用于新诊断的 R/R CD33 阳性 AML。b 与环磷酰胺、多柔比星和泼尼松联合用于新诊断的 sALCL 或 CD30+ PTCL，与多柔比星、长春碱和达卡巴嗪联合用于新诊断的 cHL。
In combination with bendamustine and rituximab. Indication approved under accelerated approval. 与苯达莫司汀和利妥昔单抗联合使用。指示获得加速批准。
Figure 3. The general mechanism of action of an antibody-drug conjugate (ADC). (Adapted from “Antibody-Drug Conjugate Release", by BioRender.com (accessed 27 September 2021). Retrieved from https:/ /app.biorender-templates, accessed 27 September 2021). 抗体药物结合物（ADC）的一般作用机制图 3。（摘自“抗体药物结合物释放”，由 BioRender.com 改编（于 2021 年 9 月 27 日访问）。来源于 https://app.biorender-templates，于 2021 年 9 月 27 日访问）。
2. ADC Mechanism of Action 2. ADC 作用机制
The general mechanism of action for an ADC is depicted in Figure 3. Following the introduction of the ADC into the plasma circulation (step 1), recognition of a specific antigen on the tumor cell surface leads to strong binding and formation of an antigen-ADC complex (step 2). The entire complex is internalized, predominantly through receptormediated endocytosis with formation of a clathrin-coated early endosome (step 3) [25]. Inside the early endosome, some ADCs bind neonatal receptors ( and undergo transcytosis to the extracellular space (step 4a) [25,26]. Following endosomal maturation to a late endosome, characterized by an environment with low luminal [27], those ADCs retained in the endosome undergo drug release from cleavable linkers (step ). The late endosome fuses with a lysosome (step 5), inside which the ADC and/or its components are exposed to proteolytic enzymes (e.g., cathepsin B) and an increasingly acidic environment, promoting further payload release (step 6). The free drug then exerts its cellular destruction via a pathway specific to the mode of action of the payload. Most ADC payloads cause apoptosis by DNA damage or microtubule disruption (step 7). In addition, some payloads (those sufficiently hydrophobic to cross cell membranes and initially tethered to an antibody via a cleavable linker) exert a bystander effect. Free drug is exported from the target tumor cell, across the cell membrane to kill neighboring tumor cells, including those that may not express the relevant antigen on its cell surface or are less accessible directly from the circulatory system (step 8). ADC的一般作用机制如图3所示。将ADC引入血浆循环后（步骤1），在肿瘤细胞表面特定抗原的识别导致强烈结合并形成抗原-ADC复合物（步骤2）。整个复合物主要通过受体介导的内吞作用被内化，形成被覆有衣蛋白的早期内体（步骤3）[25]。在早期内体内，一些ADC结合新生儿受体（ ）并进行转运至细胞外空间（步骤4a）[25,26]。随着内体成熟为晚期内体，其特征是低腔内 环境[27]，那些留在内体中的ADC经可切割连接物释放药物（步骤 ）。晚期内体与溶酶体融合（步骤5），在其中ADC及/或其组分暴露于蛋白酶（如半胱氨酸蛋白酶B）和日益酸性环境，促进进一步荷载释放（步骤6）。然后，游离药物通过特定于荷载作用方式的途径发挥其细胞破坏作用。 大多数 ADC 载荷通过 DNA 损伤或微管破坏（步骤 7）导致细胞凋亡。此外，一些载荷（足够疏水以穿过细胞膜并最初通过可切割连接剂与抗体结合）产生旁观效应。游离药物从目标肿瘤细胞输出，穿过细胞膜杀死邻近的肿瘤细胞，包括那些可能不在其细胞表面表达相关抗原或直接从循环系统中不易接近的细胞（步骤 8）。
3. FDA Approved ADCs 3. FDA 批准的 ADCs
3.1. Mylotarg
Mylotarg (gemtuzumab ozogamicin) from Wyeth/Pfizer was the first ADC to reach the market. It is composed of a recombinant humanized anti-CD33 mAb (IgG4k antibody hP67.6) covalently attached to a calicheamicin derived payload ( -acetyl- -calicheamicin 1,2-dimethyl hydrazine dichloride) via a pH-sensitive hydrazone linker, see Figure 4 [28,29]. Mylotarg (gemtuzumab ozogamicin)来自 Wyeth/Pfizer，是第一个进入市场的 ADC。它由重组人源化的抗 CD33 单克隆抗体（IgG4k 抗体 hP67.6）与一种来自卡利基霉素的荷载（ -乙酰- -卡利基霉素 1,2-二甲基肼二氯化物）通过 pH 敏感的缩醛缩酮连接剂共价结合而成，详见图 4 [28,29]。
Figure 4. Structure for Mylotarg (gemtuzumab ozogamicin). The antibody is shown in blue, and chemical structures for linker and payload are in red and green, respectively. The cleavage site is indicated by scissors. 图 4. Mylotarg (gemtuzumab ozogamicin)的结构。抗体显示为蓝色，连接剂和荷载的化学结构分别为红色和绿色。剪刀表示裂解位点。
Highlighting the rocky start for ADC therapeutics, Mylotarg was granted accelerated approval for relapsed CD33+ acute myeloid leukemia (AML) in 2000, but was voluntarily withdrawn from the market in 2010 after post-approval studies failed to verify survival benefit and demonstrated a higher rate of fatal toxicity than chemotherapy alone [30,31]. Despite this, Mylotarg was reapproved by the FDA in 2017 under an alternative dosing regimen (previously administered as one dose of ) of three doses of , and a different patient population was introduced [32]. These changes reduced the maximum plasma concentration, thus improving the safety profile and response rate when administered as a single-agent or combination regimen [35,36]. 针对 ADC 治疗的艰难开局进行了突出，Mylotarg 在 2000 年获得了加速批准，用于复发的 CD33+ 急性髓样白血病（AML），但在 2010 年自愿从市场撤出，因为后续批准研究未能证实其生存益处，并显示出比单独化疗更高的致命毒性率 [30,31]。尽管如此，Mylotarg 在 2017 年由 FDA 重新批准，采用了另一种剂量方案（之前是一剂量的 ），改为三剂量的 ，并引入了不同的患者人群 [32]。这些变化降低了最大血浆浓度，从而在作为单药 或联合方案时提高了安全性和响应率 [35,36]。
The antitumor activity of Mylotarg results from the semi-synthetic payload, a calicheamicin derivative ( -acetyl- -calicheamicin 1,2-dimethyl hydrazine dichloride) produced by microbial fermentation followed by synthetic modification. The payload consists of four glycosidic units, a fully substituted iodobenzoate moiety, and an aglycon. Mylotarg 的抗肿瘤活性源自半合成药物负荷，即由微生物发酵产生的卡利基霉素衍生物（ -乙酰- -卡利基霉素 1,2-二甲基肼二氯化物），随后进行合成修饰。药物负荷由四个糖苷单元、一个全取代碘苯甲酸酯基团和一个无糖基团组成。
The highly reactive hex-3-ene-1,5-diyne subunit can be readily triggered to aromatize via a Bergman cyclization reaction, generating a benzene-1,4-diradical [37]. This aromatization process affords a resulting diradical that can abstract two hydrogen atoms from the DNA backbone, leading to unrepairable double-strand (ds) DNA breaks followed by cell-cycle arrest and apoptotic cell death, see Figure 5 [37]. 高度活性的己烯-1,5-二炔基团可以通过 Bergman 环化反应轻松地被触发芳构化，生成苯-1,4-二自由基[37]。这种芳构化过程产生了一个结果自由基，可以从 DNA 骨架中提取两个氢原子，导致无法修复的双链(ds) DNA 断裂，随后是细胞周期停滞和凋亡细胞死亡，见图 5[37]。
Figure 5. Mechanism for double-strand (ds) DNA cleavage by -acetyl- -calicheamicin. The enediyne warhead is shown in red. 图 5. -乙酰- -卡利奇阿霉素对双链(ds) DNA 裂解的机制。烯二炔战斗头部显示为红色。
A crucial feature for successful construction of an ADC is the conjugation chemistry of the linker-payload with the mAb. In Mylotarg , the bifunctional 4-(4-acetylphenoxy)butanoic acid moiety provides attachment to surface-exposed lysine residues of the mAb through an amide bond, and the linker forms an acyl hydrazone linkage with the payload. Mylotarg is considered a first-generation ADC because it utilizes -hydroxysuccinimide chemistry to conjugate calicheamicin to surface-exposed lysine residues on the antibody, yielding a heterogenous mixture with different drug-to-antibody ratios (DARs) [38]. The number of conjugated calicheamicin derivatives per ranges from zero to six, with an average drug loading of two to three molecules of calicheamicin per antibody. 成功构建ADC的关键特征是连接物负载与mAb的共轭化学。在Mylotarg中，双功能的4-(4-乙酰基苯氧基)丁酸部分通过酰胺键与mAb的表面裸露的赖氨酸残基结合，连接物与药物负载形成酰基腙键。Mylotarg被认为是第一代ADC，因为它利用羟基琥珀酰亚胺化学将卡利基霉素与抗体表面裸露的赖氨酸残基结合，产生不同药物对抗体比例（DARs）的异质混合物。每个抗体上结合的卡利基霉素衍生物数量范围从零到六，平均药物负载为每个抗体两到三个卡利基霉素分子。
The acid-cleavable hydrazone linker is designed to be stable in the neutral conditions encountered during circulation, however, hydrolysis is readily achieved under the acidic environment of lysosomes ( ) inside CD33+ target cells. The dimethyl disulfide moiety preserves the natural disulfide trigger mechanism of calicheamicin, while the added steric hindrance resulting from the methyl substituents protects the disulfide from reduction during circulation . 酸可裂解的高分子酰胺缩醛连接剂被设计成在循环过程中遇到的中性条件下稳定，然而在CD33+靶细胞内的溶酶体（ ）中，可以轻易地在酸性环境下水解。二甲基二硫醚基团保留了卡利切阿霉素的天然二硫醚触发机制，同时由于甲基取代引起的附加立体位阻保护了二硫醚不受循环期间的还原影响 。
As for all humanized antibodies, complementarity determining region (CDR) grafting was used for humanization of the anti-CD33 murine antibody, hP67.6, employed in Mylotarg . The resulting antibody is a genetically engineered IgG4 antibody containing sequences derived from the murine antibody, but with an increased similarity to antibody variants produced naturally in humans. While the IgG4 antibody isotype has the longest circulating half-life of all isotypes, it is least likely to participate in immunemediated mechanisms, such as complement fixation and antibody-dependent cellular cytotoxicity (ADCC) [42]. Although antibody effector functions, such as ADCC, complementdependent cytotoxicity, and antibody-dependent cellular phagocytosis (ADCP), have the potential to augment antitumor activities, engaging receptors can also lead to increased 至于所有人源化抗体，均采用互补决定区域（CDR）移植来人源化抗 CD33 小鼠抗体 hP67.6，该抗体用于 Mylotarg。所得抗体是一种基因工程的 IgG4 抗体，包含源自小鼠抗体的序列，但与人体自然产生的抗体变体更相似。虽然 IgG4 抗体亚型具有所有亚型中最长的循环半衰期，但它最不可能参与免疫介导机制，如补体固定和抗体依赖的细胞毒性（ADCC）。尽管抗体效应功能，如 ADCC、补体依赖性细胞毒性和抗体依赖性细胞吞噬作用（ADCP），有增强抗肿瘤活性的潜力，但结合受体也可能导致增加
off-target and dose-limiting toxicity [43-45]. Several next-generation ADCs have thus exploited antibody engineering to enhance or impair immune effector functions. 靶向和剂量限制毒性。因此，几种下一代 ADC 已利用抗体工程来增强或减弱免疫效应功能。
Demonstrating that failure is perhaps merely a step towards success, the pitfalls and limitations of this first-generation ADC provided several key lessons for future improvements in ADC research. 展示失败也许只是通往成功的一步，这一代 ADC 的缺陷和局限性为未来 ADC 研究的改进提供了几个关键教训。
3.2. Adcetris 3.2. Adcetris
Adcetris (brentuximab vedotin) from Seagen (formerly Seattle Genetics), containing a CD30-specific mAb conjugated to monomethyl auristatin E (MMAE), received FDA approval in 2011, making it the second ADC to enter the oncology market, see Figure 6 [46-49]. It is approved for Hodgkin lymphoma (HL) [50,51] and systemic anaplastic large cell lymphoma (sALCL) [52] in the USA, Europe, and Japan [47,53]. Adcetris（brentuximab vedotin）来自 Seagen（前身为 Seattle Genetics），包含一个特异性于 CD30 的单克隆抗体与单甲基奥利斯他汀 E（MMAE）结合，于 2011 年获得 FDA 批准，成为进入肿瘤学市场的第二个 ADC，详见图 6。在美国、欧洲和日本，它获得了治疗霍奇金淋巴瘤（HL）和全身性间变性大细胞淋巴瘤（sALCL）的批准。
Figure 6. Structure of Adcetris (brentuximab vedotin). The antibody is shown in blue, and chemical structures for linker and payload are in red and green, respectively. Spontaneous 1,6-elimination mechanism for the PABC-substituted MMAE, leading to release of MMAE, -iminoquinone methide, and carbon dioxide. 图6. Adcetris（贝妥单抗维度汀）的结构。抗体显示为蓝色，连接剂和药物负载的化学结构分别为红色和绿色。PABC取代的MMAE的自发1,6-消除机制，导致MMAE、-亚胺喹啉甲醚和二氧化碳的释放。
The anticancer activity of Adcetris results from the binding of MMAE to tubulin. This disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptotic cell death [54]. In addition, likely owing to the IgG1 antibody isotype, in vitro data provide evidence for ADCP antitumor activity [55]. From first-generation ADCs, it was learnt that of the injected ADC dose reaches the target tumor site, thus necessitating an increase in potency of the cytotoxic agent and/or DAR for improved therapeutic activity . Adcetris addressed these two requirements by employing the more cytotoxic payload MMAE, a tubulin-targeting agent, belonging to the auristatin family of drug payloads (cytotoxicity in the low nanomolar to sub-nanomolar range against a variety of cancer types). See Figure 2B for a comparison of approximate cytotoxicity ranges (based on concentrations giving 50% maximum inhibition, ) for payloads employed in Adcetris 的抗癌活性源自 MMAE 与微管蛋白的结合。这会破坏细胞内的微管网络，随后诱导细胞周期停滞和凋亡细胞死亡。此外，可能由于 IgG1 抗体亚型，在体外数据提供了 ADCp 抗肿瘤活性的证据。从第一代 ADCs 中得知，注射的 ADC 剂量中有一定比例达到目标肿瘤部位，因此需要增加细胞毒性药物和/或 DAR 以提高治疗活性。Adcetris 通过使用更具细胞毒性的荷载 MMAE 来满足这两个要求，MMAE 是一种针对微管的药物，属于奥利司他素药物荷载家族（对多种癌症类型的细胞毒性在低纳摩尔至亚纳摩尔范围内）。请参见图 2B，比较不同荷载的近似细胞毒性范围（基于给予 50%最大抑制的浓度）。
FDA approved ADCs. Furthermore, as compared to Mylotarg with a DAR of two to three, Adcetris has approximately four molecules of MMAE attached to each antibody molecule. FDA 批准的 ADCs。此外，与 Mylotarg 相比，Mylotarg 的 DAR 为 2 至 3，Adcetris 每个抗体分子大约附着四个 MMAE 分子。
The pitfall of premature drug release resulting from the acid-cleavable hydrazone linker in Mylotarg [20] was addressed in the second-generation ADC, Adcetris , by using the protease-cleavable "mc-vc-PABC-MMAE" linker-drug combination [48,49,58-60]. This linker construct utilizes a thiol-reactive maleimidocaproyl (mc) spacer, a valine-citrulline (vc) dipeptide, and a self-immolative para-aminobenzyloxycarbonyl (PABC) spacer [60]. The mc spacer is incorporated for conjugation to cysteine residues of the mAb, and a PABC spacer allows linker attachment to the secondary amine of MMAE. Due to the steric bulk of the payload, the PABC spacer also facilitates enzyme access allowing the vc group to be recognized by cathepsin B . Cathepsin B is a cysteine protease which presents almost exclusively in the lysosomal compartment in healthy mammals, and is overexpressed in multiple cancer types [62,63]. It is responsible for cleaving the citrullinePABC amide bond. Following proteolytic cleavage, the resultant PABC-substituted MMAE forms an unstable intermediate which spontaneously undergoes a 1,6-elimination with loss of -iminoquinone methide and carbon dioxide to release the free drug, see Figure 6. 通过在第二代ADC Adcetris中使用蛋白酶可切割的“mc-vc-PABC-MMAE”连接剂-药物组合，解决了Mylotarg中酸可切割的腙连接剂导致的药物过早释放的陷阱。这种连接剂结构利用了巯基反应性的马来酰己酰（mc）间隔物，缬氨酸-精氨酸（vc）二肽，以及自解离性对氨基苯甲氧羰基（PABC）间隔物。mc间隔物用于与mAb的半胱氨酸残基结合，PABC间隔物允许连接剂附着到MMAE的次级胺基。由于有效载荷的立体体积，PABC间隔物还促进酶的进入，使vc基团能够被cathepsin B识别。Cathepsin B是一种半胱氨酸蛋白酶，几乎只存在于健康哺乳动物的溶酶体区，且在多种癌症类型中过度表达。它负责裂解精氨酸PABC酰胺键。 在蛋白酶切割后，产生的 PABC 取代的 MMAE 形成不稳定的中间体，该中间体会自发地与 -亚胺喹啉甲烷和二氧化碳发生 1,6-消除反应，释放出游离药物，详见图 6。
Compared to Mylotarg , which uses an IgG4 antibody, the IgG subclass employed in Adcetris is IgG1. This is the most common subclass for ADCs, as while having similarly long serum half-lives to IgG4, they possess greater complement-fixation and Fc R-binding efficiencies [42]. 与使用 IgG4 抗体的 Mylotarg 相比，Adcetris 中使用的 IgG 亚类是 IgG1。这是 ADCs 中最常见的亚类，因为与 IgG4 具有类似长的血清半衰期相比，它们具有更大的补体结合和 Fc R 结合效率[42]。
Although Mylotarg utilizes lysine residues on the mAb for linker-payload conjugation, Adcetris employs cysteine-based conjugation. Due to the limited number of cysteine conjugation sites available (four interchain and twelve intrachain disulfides, see Figure 7, as opposed to 80-100 lysine amines for IgG1) and the distinct reactivity of thiols, this approach enables improved homogeneity of the ADC species and a more controlled drug loading [21]. Cysteine conjugation relies on partial or full reduction of the four interchain disulfides to produce an average number (e.g., two, four, six, or eight) of free nucleophilic thiols, while keeping the intrachain disulfide bonds intact. Interchain disulfides are generally not critical for structural stability and have higher solvent accessibility, making them an ideal target. They are typically reduced using reagents such as tris(2-carboxyethyl)phosphine (TCEP), dithiothreitol (DTT), or 2-mercaptoethylamine (2-MEA) prior to conjugation [21]. Once the free thiols are generated, they can be reacted with a linker-payload complex possessing a suitable electrophilic group, see Figure 7. Maleimide chemistry has been the mainstay for linkage to cysteines, with all auristatin-containing ADCs utilizing the maleimidocaproyl (mc) linkage to the antibody [61]. 尽管 Mylotarg 利用 mAb 上的赖氨酸残基进行连接载荷偶联，但 Adcetris 则采用基于半胱氨酸的偶联。由于半胱氨酸偶联位点数量有限（四个链间和十二个链内二硫键，见图7，相对于IgG1的80-100个赖氨酸胺基），以及巯基的不同反应性，这种方法能够提高ADC种类的均一性和更可控的药物装载[21]。半胱氨酸偶联依赖于部分或完全还原四个链间二硫键，产生平均数量的游离亲核巯基（例如两个、四个、六个或八个），同时保持链内二硫键完整。链间二硫键通常对结构稳定性不是很关键，并且溶剂可及性较高，使其成为理想的靶点。在进行偶联前，它们通常会使用三(2-羟基乙基)磷酸盐（TCEP）、二硫苏糖醇（DTT）或2-巯基乙胺（2-MEA）等试剂进行还原[21]。一旦生成了游离巯基，它们就可以与具有适当亲电性基团的连接载荷复合物发生反应，见图7。 马来酰亚胺化学一直是与半胱氨酸连接的主要方法，所有含奥利司他汀的 ADC 均利用马来酰己内酰胺（mc）连接到抗体[61]。
Figure 7. Schematic showing partial reduction of IgG1 antibody interchain disulfide bonds to generate two nucleophilic free thiol groups that can be reacted with an electrophilic linker-payload construct, such as maleimide (DAR = 2). Maleimide conjugation to cysteine is shown in this example. 图 7. 示意图显示将 IgG1 抗体亚链二硫键部分还原，生成两个亲核自由巯基，可与亲电性连接剂-荷载构建物反应，如马来酰亚胺（DAR = 2）。本示例展示了马来酰亚胺与半胱氨酸的结合。
Although an improvement over lysine conjugation, this method still produces a heterogenous mixture of ADC species, which can negatively impact on parameters including pharmacokinetics, tolerability, and efficacy [18]. Therefore, site-specific conjugation methodologies have been developed, of which THIOMAB technology is the most 尽管比赖氨酸结合有所改进，但这种方法仍会产生异质混合的 ADC 物种，这可能对药代动力学、耐受性和疗效等参数产生负面影响[18]。因此，已开发了特异位点结合方法，其中 THIOMAB 技术是最常见的。
well-known [64,65]. Genentech's THIOMAB antibody platform uses site-directed mutagenesis to incorporate cysteine residues into antibodies at positions on light and heavy chains that provide reactive thiol groups without perturbing immunoglobulin folding and assembly, or altering antigen binding [64,65]. Although homogenous ADCs have repeatedly demonstrated superior overall pharmacological profiles compared to their heterogenous counterparts, engineered antibodies for site-specific conjugation have not yet been employed in any of the FDA approved ADCs. We recommend the review by Walsh and co-workers for an in-depth understanding of chemical and enzymatic methods for site-specific antibody modification, resulting in the generation of homogenous ADCs [21]. 众所周知 [64,65]。Genentech 的 THIOMAB 抗体平台利用定点突变法在抗体的轻链和重链上引入半胱氨酸残基，提供具有反应性巯基的位置，而不扰乱免疫球蛋白的折叠和组装，也不改变抗原结合 [64,65]。尽管同质 ADCs 已经反复证明在整体药理特性上优于其异质对应物，但为了特定位点的结合而设计的抗体尚未被用于任何 FDA 批准的 ADCs。我们建议参考 Walsh 和其同事的综述，以深入了解用于特定位点抗体修饰的化学和酶法方法，从而产生同质 ADCs [21]。
3.3. adcyla 3.3. adcyla
In 2013, Kadcyla (ado-trastuzumab emtansine), developed and marketed by Genentech/Roche, revolutionized the field of ADCs by becoming the first ADC approved for the treatment of solid tumors. It is indicated as an adjuvant (after surgery) treatment for HER2+ early breast cancer in patients who previously received trastuzumab (Herceptin ) and a taxane, separately or in combination [66-69]. 2013年，由Genentech/Roche开发和推出的Kadcyla（ado-trastuzumab emtansine）通过成为首个获批用于固体肿瘤治疗的ADC，彻底改变了ADC领域。它被指定为HER2+早期乳腺癌的辅助（手术后）治疗，适用于之前接受过曲妥珠单抗（Herceptin）和紫杉醇的患者，无论是单独使用还是联合使用[66-69]。
This approval marked a milestone achievement in ADC development because effective treatment of solid tumors using such therapy previously posed a formidable challenge. Firstly, prior to Kadcyla , the treatment of solid tumors with ADCs fell short due to numerous biological barriers in the tumor microenvironment (e.g., poor vascularization, diffusion through dense stroma, overcoming tumor interstitial fluid pressure) which limited drug penetration. Secondly, unlike hematologic malignancies, the concept of lineage-specific antigen expression is not applicable to solid tumors, for which the antigens expressed are mainly "tumor associated" rather than "tumor specific" [70]. This implies both a share of on-target/off-tumor toxicity and thus reduced intra-tumoral drug delivery. Kadcyla comprises the humanized anti-HER2 IgG1 antibody, trastuzumab, linked to the antimitotic agent, DM1, see Figure 8A [69,71]. DM1 is a potent maytansine derivative, belonging to the maytansinoid family of natural products. While maytansine is difficult to conjugate due to the absence of reactive functional groups, DM1 contains a thiopropanoyl group instead of the native -acetyl group, see Figure , allowing for lysine-antibody conjugation via a non-reducible thioether linker, maleimidomethyl cyclohexane-1-carboxylate (MCC). 这一批准标志着ADC开发取得了重要的里程碑成就，因为以前使用这种疗法有效治疗实体肿瘤曾是一个艰巨的挑战。首先，在卡戴珊（Kadcyla）问世之前，ADC治疗实体肿瘤由于肿瘤微环境中存在的多种生物障碍（例如，血管化较差、穿透致密基质、克服肿瘤间质液压）而存在缺陷，从而限制了药物的渗透。其次，与血液系统恶性肿瘤不同，实体肿瘤的特定细胞表面抗原表达概念并不适用，因为实体肿瘤中表达的抗原主要是“与肿瘤相关”的，而不是“肿瘤特异性”的[70]。这意味着会发生一定比例的靶向/非靶向毒性，并因此减少了肿瘤内药物输送。卡戴珊（Kadcyla）包括人源化抗HER2 IgG1抗体曲妥珠单抗和抗有丝分裂试剂DM1的连接物，参见图8A[69,71]。DM1是一种有效的曼香树碱衍生物，属于天然产物曼香树碱类家族。 尽管马坦西因由于缺乏反应性官能团而难以结合，但 DM1 包含了一个硫丙酰基团，而不是原生的乙酰基团，见图 ，通过不可还原的硫醚连接剂，马来亚胺甲基环己烷-1-羧酸酯（MCC）可以与赖氨酸-抗体结合。
(A)
maytansine 马坦西因
DM1
Figure 8. (A) Structure of Kadcyla (ado-trastuzumab emtansine). The antibody is shown in blue, and chemical structures for linker and payload are in red and green, respectively. (B) The chemical structure for maytansine and DM1. The thiopropanoyl group of DM1, which allows for conjugation to a maleimidomethyl cyclohexane-1-carboxylate (MCC) group is shown in the red box. 图 8. （A）Kadcyla （三联抗-Her-2 负载康德拉）的结构。抗体以蓝色显示，连接剂和药物的化学结构分别以红色和绿色显示。（B）马坦西因和 DM1 的化学结构。DM1 的硫丙酰基团，允许连接到马来亚胺甲基环己烷-1-羧酸酯（MCC）基团，如红色方框所示。
Compared to the two previously mentioned FDA approved ADCs, Kadcyla consists of a non-cleavable thioether linker. Non-cleavable linkers tend to be more stable than their cleavable counterparts, but they rely on lysosomal degradation of the entire antibody-linker construct for payload release. This often results in retention of charged amino acids on the payload, which may affect its action or cell permeability. In human plasma, Kadcyla catabolites, MCC-DM1, lysine-bound emtansine (Lys-MCC-DM1), and DM1 have been detected at low levels. Cytotoxic effects of Kadcyla result from DM1-containing catabolites (primarily Lys-MCC-DM1) binding to tubulin, which disrupts microtubule networks, 与先前提到的两种获得 FDA 批准的 ADC 相比，Kadcyla
inducing cell cycle arrest and apoptotic cell death at sub-nanomolar concentrations [72]. In addition, in vitro studies have shown that Kadcyla mediates ADCC [69]. 诱导细胞周期停滞和亚纳摩尔浓度下的凋亡细胞死亡[72]。此外，体外研究表明 Kadcyla
Undoubtedly, the approval of Kadcyla in 2013 was a big win for Swiss drug maker, Roche. In 2019, annual sales surpassed US$1 billion, deeming Kadcyla the first ADC to achieve blockbuster status. 毫无疑问，2013 年批准 Kadcyla
3.4. Besponsa
Besponsa (inotuzmab ozogamicin (Pfizer/Wyeth)) obtained FDA approval in 2017 and is directed against CD22+ B-cell acute lymphoblastic leukemia (B-ALL) [73-75]. It is based on an ADC platform similar to Mylotarg (see Section 3.1) (Figure 9) [74,75]. The first difference lies in the mAb and thus the antigen target and cancer indication. The recombinant humanized monoclonal IgG4 antibody (G544) employed in Besponsa is selective for CD22 expressed on B cells in all patients with mature B-ALL, and of patients with precursor B-ALL. In addition, preclinical studies demonstrated Besponsa could tolerate a higher DAR of (cf. Mylotarg without significant aggregation [75]. Besponsa （依诺替单抗奥佐米单抗（辉瑞/惠氏））于 2017 年获得 FDA 批准，用于治疗 CD22 阳性 B 细胞急性淋巴细胞白血病（B-ALL）[73-75]。它基于类似于 Mylotarg （见第 3.1 节）（图 9）的 ADC 平台[74,75]。第一个区别在于单克隆抗体（mAb）及抗原靶点和癌症适应症。Besponsa 中采用的重组人源化的 IgG4 单克隆抗体（G544）选择性地靶向所有成熟 B-ALL 患者的 B 细胞上表达的 CD22，以及前体 B-ALL 患者的 。此外，临床前研究表明 Besponsa 可以容忍更高的 （参见 Mylotarg ），而无明显聚集[75]。
Figure 9. Structure of Besponsa (inotuzumab ozogamicin). The antibody is shown in blue, and chemical structures for linker and payload are in red and green, respectively. 图 9. Besponsa （依诺替单抗奥佐米单抗）的结构。抗体显示为蓝色，连接剂和药物负载的化学结构分别为红色和绿色。
3.5. Polivy and Padcev 3.5. Polivy 和 Padcev
Highlighting the importance of antigen selection and thus the for targeted drug delivery, both Polivy (polatuzumab vedotin-piiq) and Padcev (enfortumab vedotin-ejfv) possess the same mc-vc-PABC-MMAE linker-drug construct as Adcetris (see Section 3.2) (Figure 10) [76,77]. Both ADCs were approved by the FDA in 2019. 强调抗原选择的重要性以及针对性药物传递的需求，Polivy （polatuzumab vedotin-piiq）和 Padcev （enfortumab vedotin-ejfv）与 Adcetris （见第 3.2 节）具有相同的 mc-vc-PABC-MMAE 连接剂-药物构造（图 10）[76,77]。这两种 ADC 在 2019 年获得了 FDA 的批准。
Figure 10. Structure of Polivy (polatuzumab vedotin-piiq) and Padcev (enfortumab vedotin-ejfv). The antibody is shown in blue, and chemical structures for linker and payload are in red and green, respectively. 图 10。Polivy （polatuzumab vedotin-piiq）和 Padcev （enfortumab vedotin-ejfv）的结构。抗体显示为蓝色，连接剂和荷载的化学结构分别为红色和绿色。
Polivy is an anti-CD79b ADC developed by Genentech/Roche using a proprietary technology developed by Seagen [78]. It is indicated in combination with bendamustine and rituximab for treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), an aggressive type of non-Hodgkin lymphoma, who have received at least two prior therapies [76,79]. This indication was granted accelerated approval based on a complete response rate. Polivy has an approximate DAR of 3.5 molecules of MMAE attached to each antibody. Polivy是一种抗CD79b的ADC，由Genentech/Roche开发，使用Seagen开发的专有技术。它适用于与苯达莫司汀和利妥昔单抗联合治疗成人复发性或难治性弥漫大B细胞淋巴瘤（DLBCL），这是一种侵袭性的非何杰金淋巴瘤类型，患者至少接受过两种先前治疗[76,79]。该适应症基于完全缓解率获得了加速批准。Polivy的平均DAR约为每抗体附着3.5个MMAE分子。
Padcev , produced and marketed by Astellas Pharma Inc. and Seagen is a Nectin4directed ADC [80]. It was first granted accelerated approval in 2019 for treatment of adults with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor, and a platinum-containing therapy [81]. In 2021, this indication was granted regular approval and Padcev was granted accelerated approval for patients which are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy . Padcev is comprised of a fully humanized anti-Nectin4 IgG1 (AGS-22C3) produced by mammalian (Chinese hamster ovary) cells, and has an approximate DAR of 3.8 . Padcev ，由爱力斯制药和 Seagen 生产和销售，是一种针对 Nectin4 的 ADC [80]。它首次于 2019 年获得加速批准，用于治疗先前接受过程序性死亡受体-1（PD-1）或程序性死亡配体-1（PD-L1）抑制剂和含铂疗法的成年局部晚期或转移性膀胱癌患者[81]。2021 年，该适应症获得常规批准，并且 Padcev 获得了加速批准，用于不能接受含顺铂化疗的患者，并且先前接受过一种或多种治疗方案 。Padcev 由哺乳动物（中国仓鼠卵巢）细胞产生的全人源抗 Nectin4 IgG1 （AGS-22C3）组成，其近似 DAR 为 3.8。
3.6. Enhertu
Enhertu (fam-trastuzumab deruxtecan-nxki), developed by Daichi Sankyo/AstraZeneca, was granted accelerated FDA approval in December 2019 for treatment of adult patients with unresectable or metastatic HER2+ breast cancer who have received two or more prior anti-HER2 based regimens [84,85]. Furthermore, in 2020, the FDA granted this ADC breakthrough therapy designation for treatment of patients with metastatic, HER2-mutated non-small cell lung cancer (NSCLC) after a platinum-based therapy, and priority review for treatment of HER2+ metastatic gastric or gastroesophageal junction adenocarcinoma. Enhertu（fam-trastuzumab deruxtecan-nxki），由大塚三共/阿斯利康开发，于 2019 年 12 月获得 FDA 加速批准，用于治疗接受过两种或两种以上前线抗 HER2 治疗方案的成年患者的不可切除或转移性 HER2+乳腺癌[84,85]。此外，2020 年，FDA 授予该 ADC 突破性疗法指定，用于治疗经过铂类药物治疗后的转移性 HER2 突变非小细胞肺癌（NSCLC）患者，并优先审查用于治疗 HER2+转移性胃癌或胃食管结合部腺癌患者。
Showcasing the continued promise of Enhertu , in 2021 the ADC was approved in the US for a second oncology indication treatment of adult patients with locally advanced or metastatic HER2+ gastric or gastroesophageal junction adenocarcinoma, who have received a prior trastuzumab-based regimen . 展示了 Enhertu 持续的潜力，在 2021 年，这种 ADC 在美国获得批准，用于治疗接受过前线曲妥珠单抗治疗方案的成年患者的局部晚期或转移性 HER2+胃癌或胃食管结合部腺癌。
The ADC is comprised of an anti-HER2 antibody, a protease cleavable tetrapeptidebased linker, and DXd as the drug payload, see Figure . DXd is a novel exatecan derivative designed using Daiichi Sankyo's proprietary ADC technology. It belongs to the camptothecin class of drug payloads, which cause their cytotoxic effects by inhibiting topoisomerase I (TOP1) enzyme. TOP1 is essential in higher eukaryotes as it is responsible for relaxing DNA supercoiling generated by transcription, replication, and chromatin remodeling [88]. Therefore, inhibition of this enzyme leads to DNA damage and apoptotic cell death, resulting in destruction of HER2+ tumor cells. ADC 由抗 HER2 抗体、蛋白酶可裂四肽基链和 DXd 作为药物负载物组成，见图示 。DXd 是一种新型 exatecan 衍生物，是利用第一三共独有的 ADC 技术设计的。它属于卡铂南星类药物负载物，通过抑制拓扑异构酶 I（TOP1）酶来产生其细胞毒作用。TOP1 对较高等的真核生物至关重要，因为它负责通过转录、复制和染色质重塑产生的 DNA 超螺旋进行松弛[88]。因此，对该酶的抑制导致 DNA 损伤和凋亡细胞死亡，最终导致 HER2+肿瘤细胞的歼灭。
Figure 11. Structure of Enhertu (fam-trastuzumab deruxtecan-nxki). The antibody is shown in blue, and chemical structures for linker and payload are in red and green, respectively. 图 11. Enhertu （fam-trastuzumab deruxtecan-nxki）的结构。抗体显示为蓝色，链接和药物负载的化学结构分别为红色和绿色。
Besides the potent warhead, several biochemical improvements differentiate Enhertu from the previously approved anti-HER2 ADC, Kadcyla . Firstly, the DAR of Enhertu is more homogenous and approximately twice that of (8 vs. 3-4), thereby leading to an increased drug concentration inside target tumor cells [87]. Secondly, the drug and antibody are connected via a novel cathepsin-cleavable peptide linker. The linker is connected to a cysteine residue of the antibody via a maleimidocaproyl group, and the tetrapeptide portion consisting of the amino acid sequence, glycine-glycine-phenylalanineglycine, attaches to the proprietary payload by an amide bond. The hydrophobic nature of this payload improves cell membrane permeability, thus maximizing bystander killing effects of the ADC, and deeming it effective against HER2-negative cells. 除了强效的弹头外，几项生化改进使 Enhertu 与先前批准的抗 HER2 ADC Kadcyla 有所不同。首先，Enhertu 的 DAR 更均匀，约为（8 比 3-4）的两倍，从而导致靶向肿瘤细胞内药物浓度增加[87]。其次，药物和抗体通过一种新型的 cathepsin 可切割肽连接物连接在一起。连接物通过 maleimidocaproyl 基连接到抗体的半胱氨酸残基上，而由氨基酸序列甘氨酸-甘氨酸-苯丙氨酸-甘氨酸组成的四肽部分通过酰胺键连接到专有荷载上。这种荷载的疏水性质提高了细胞膜的渗透性，从而最大限度地增加 ADC 的旁观者杀伤效应，并使其对 HER2 阴性细胞有效。
Following the initial success of Enhertu , Daiichi Sankyo and AstraZeneca signed a billion deal to develop and commercialize other ADCs based on the same technology . According to the terms of the agreement, Daiichi Sankyo will receive billion 在 Enhertu 的初步成功之后，大塚三共和阿斯利康签署了一项数十亿美元的协议，开发和商业化基于相同技术的其他 ADC。根据协议的条款，大塚三共将获得数十亿美元。
in staged payments from AstraZeneca and the Japanese company will also be eligible for up to billion for regulatory milestones and billion for sales-related milestones . This agreement represents the second collaboration between Daiichi Sankyo and AstraZeneca, reflects AstraZeneca's continued strategy to invest in ADCs as a class, the innovative nature of the technology, and the successful existing collaboration with Daiichi Sankyo. 从 AstraZeneca 和这家日本公司的分期付款中，还有多达 亿美元的监管里程碑奖金和 亿美元的与销售相关的里程碑奖金 。该协议代表了第二次戴克·三共和阿斯利康之间的合作，反映了阿斯利康继续投资 ADC 作为一类药物的战略，技术的创新性以及与戴克·三共的成功现有合作。
3.7. Trodelvy 3.7. Trodelvy
Further highlighting the industry's appetite for ADC technology, in October 2020, Gilead Sciences paid billion to acquire Immunomedics, and its recently approved ADC, Trodelvy (sacituzumab govitecan-hziy) [91]. In April 2020, Trodelvy received accelerated FDA approval for treatment of patients with locally advanced or metastatic triple-negative breast cancer ( ) who have received at least two prior therapies for metastatic disease . Demonstrating its commercial success, Trodelvy recorded $US20 million in sales in its first two months on the market, and generated sales for the fourth quarter and full year 2020 (including the period prior to the completion of Gilead's acquisition of Immunomedics) of million and million, respectively [94]. In April 2021, the FDA granted regular approval for this indication, and in the same year, Trodelvy was granted accelerated approval for a second indication treatment of locally advanced or metastatic urothelial cancer after a platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor . 进一步突显行业对ADC技术的需求，2020年10月，吉利德科学公司支付了 亿美元收购了免疫医学公司及其最近获批的ADC产品Trodelvy （sacituzumab govitecan-hziy）[91]。2020年4月，Trodelvy 获得了FDA加速批准，用于治疗局部晚期或转移性三阴性乳腺癌（ ），这些患者已接受过至少两种转移性疾病的治疗 。Trodelvy 在上市的头两个月实现了2,000万美元的销售额，并在2020年第四季度和整个年度（包括吉利德收购免疫医学公司之前的时期）分别实现了 万美元和 万美元的销售额[94]。2021年4月，FDA为该适应症授予了常规批准，同年，Trodelvy 获得了加速批准，用于治疗局部晚期或转移性尿路上皮癌，该癌症在接受含铂类化疗和PD-1或PD-L1抑制剂治疗后 。
Trodelvy consists of a fully humanized hRS7 IgG1 antibody targeted against TROP2 (trophoblast antigen 2) conjugated to SN-38, the active metabolite of irinotecan [88] via an acid-sensitive hydrolysable linker called CL2A, see Figure . Trodelvy 由针对 TROP2（滋养层抗原 2）的全人源化 hRS7 IgG1 抗体与 SN-38（伊立替康的活性代谢物）结合而成，二者通过一种酸敏感的可水解连接剂 CL2A 相连，详见图 。
Figure 12. Structure of Trodelvy (sacituzumab govitecan-hziy). The antibody is shown in blue, and chemical structures for linker and payload are in red and green, respectively. PEG, polyethyleneglycol. 图 12. Trodelvy 的结构（sacituzumab govitecan-hziy）。抗体显示为蓝色，连接剂和药物负载的化学结构分别为红色和绿色。PEG，聚乙二醇。
This ADC is another example of an ADC with a high DAR, consisting of approximately 7.6 SN-38 molecules per antibody, which does not affect its binding and pharmacokinetics. This is allowed by the moderately toxic topoisomerase 1 inhibitor (SN-38 in the low micromolar range against several cancer types), and a non-stable linker prone to drug leakage and subsequent bystander effects. In a study by Goldenberg and co-workers, it was found that this ADC targets up to 136-fold more SN-38 to a human cancer xenograft than irinotecan [98]. Furthermore, since Trodelvy delivers SN-38 in its most active, nonglucuronidated form, this may explain the improved toxicity profile, as shown by a lower frequency of severe diarrhea than with irinotecan. Pegylation and the incorporation of a lysine residue in the linker system is thought to reduce ADC aggregation. The use of moderately toxic payloads is being further investigated as a method to increase payload concentration and overcome the challenges of stability and efficacy with higher DAR ADCs. 这种 ADC 是另一个具有高 DAR 的 ADC 的示例，每个抗体大约含有 7.6 个 SN-38 分子，这不会影响其结合和药代动力学。这是由于中度毒性的拓扑异构酶 1 抑制剂（SN-38 在低微摦范围内对多种癌症类型具有毒性），以及易于药物泄漏和随后的旁观效应的非稳定连接剂所允许的。在 Goldenberg 及其同事的一项研究中发现，这种 ADC 将 SN-38 目标定位到人类癌症异种移植物中的数量高达 136 倍，而伊立替康则不到这个数值[98]。此外，由于 Trodelvy 以其最活跃的、非葡萄糖醛酸化形式释放 SN-38，这可能解释了改善的毒性谱，如与伊立替康相比，严重腹泻的发生率较低。聚乙二醇化和在连接系统中加入赖氨酸残基被认为可以减少 ADC 的聚集。正在进一步研究中度毒性的荷载物作为一种方法，以增加荷载物浓度并克服高 DAR ADC 的稳定性和疗效挑战。
3.8. Blenrep 3.8. Blenrep
GlaxoSmithKline's ADC, Blenrep (belantamab mafodotin-blmf), is the first approved anti-BCMA (B-cell maturation antigen) therapy [99]. It was granted accelerated FDA approval in August 2020 for treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies, including an anti-CD38 , a proteasome inhibitor, and an immunomodulatory agent [100-102]. Blenrep consists of 葛兰素史克的ADC，Blenrep（belantamab mafodotin-blmf），是首个获批的抗BCMA（B细胞成熟抗原）疗法[99]。它于2020年8月获得了FDA的加速批准，用于治疗接受过至少四种先前疗法的成年复发性或难治性多发性骨髓瘤患者，包括抗CD38 、蛋白酶体抑制剂和免疫调节剂[100-102]。Blenrep 由
an afucosylated humanized conjugated to the tubulin inhibitor, monomethyl auristatin F (MMAF) via a non-cleavable maleimidocaproyl linker, see Figure 13 [100,103]. In addition to MMAF-induced apoptosis, secondary antitumor activity results from tumor cell lysis through ADCC and ADCP effector functions [100]. Besides Kadcyla , currently this is the only other FDA approved ADC to possess a non-cleavable linker. The drug-linker technology is licensed from Seagen and the Fc-engineered afucosylated mAb is produced using Potelligent Technology licensed from BioWa. The Potelligent Technology platform uses FUT8 knockout Chinese hamster ovary cells to eliminate fucose from the Fc regions in the antibody [104]. It is well established that when an antibody has reduced amounts of fucose in its sugar chains, it has increased affinity for Fc RIIIa and thus exhibits higher ADCC activity compared to highly-fucosylated conventional antibodies [103,105,106]. To date, Blenrep is the only FDA approved ADC with an afucosylated Fc-engineered antibody. 一种非fucosylated的人源化抗体与微管抑制剂单甲基奥利斯他汀F（MMAF）通过不可切割的马来酰亚胺巯基己酰连接剂结合，见图13。除了MMAF诱导的凋亡外，次级抗肿瘤活性还来自于肿瘤细胞通过ADCC和ADCP效应功能的溶解。除了Kadcyla，目前这是唯一另一种具有不可切割连接剂的FDA批准的ADC。药物-连接剂技术是从Seagen获得许可，而Fc工程化的非fucosylated mAb是使用从BioWa获得许可的Potelligent技术生产的。Potelligent技术平台使用FUT8敲除的中国仓鼠卵巢细胞来消除抗体中Fc区域的岩藻糖。已经确立，当抗体的糖链中的岩藻糖量减少时，它对Fc RIIIa的亲和力增加，因此与高度fucosylated传统抗体相比，表现出更高的ADCC活性。迄今为止，Blenrep是唯一一种具有非fucosylated Fc工程化抗体的FDA批准的ADC。
Figure 13. Structure of Blenrep (belantamab mafodotin-blmf). The antibody is shown in blue, and chemical structures for linker and payload are in red and green, respectively. Blenrep 的结构示意图。抗体显示为蓝色，连接剂和药物负载的化学结构分别为红色和绿色。
Blenrep consists of the antimitotic auristatin payload, MMAF, which differs from MMAE bearing a phenylalanine moiety at its -terminus, rather than norephedrine. though MMAF also prevents cellular division by inhibition of tubulin polymerization, this substitution leads to attenuated antitumor activity, whereby MMAF has values in the range of 100-250 which is more than 100-fold higher than those for MMAE [107]. Although the low cell permeability of MMAF, resulting from the charged phenylalanine residue, limits its toxicity if free drug is released from the ADC prematurely, MMAFmediated killing is restricted to the target cell and thus cannot cause bystander killing. Consequently, MMAF ADCs require high tumor expression of the target antigen for effectiveness but are more potent than vc-MMAE ADCs when targeting internalizing antigens in vitro. Blenrep 由抗有丝分裂作用的奥利司他汀药物负载 MMAF 组成，与携带苯丙氨酸基团的 MMAE 不同，其末端为苯丙氨酸基团而非去甲麻黄碱。尽管 MMAF 也通过抑制微管聚合来阻止细胞分裂，但这种替代导致了抗肿瘤活性的减弱，其中 MMAF 的 IC50 值在 100-250 之间，比 MMAE 高出 100 倍以上[107]。尽管 MMAF 的低细胞渗透性是由于带电的苯丙氨酸残基，这限制了其毒性，如果 ADC 过早释放了游离药物，MMAF 介导的杀伤作用仅限于靶细胞，因此不会引起旁观者杀伤。因此，MMAF ADC 需要靶抗原的高肿瘤表达以发挥作用，但在体外靶向内化抗原时比 vc-MMAE ADC 更有效。
3.9. Zynlonta
Zynlonta (loncastuximab tesirine-lpyl) developed by ADC Therapeutics is a CD19directed ADC indicated for treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL), not otherwise specified DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma [108,109]. It was granted accelerated approval for medical use by the FDA in April 2021. Zynlonta（loncastuximab tesirine-lpyl）是由ADC Therapeutics开发的CD19定向ADC，适用于经过两种或两种以上系统治疗线路治疗后仍有复发或难治性大B细胞淋巴瘤的成年患者，包括弥漫大B细胞淋巴瘤（DLBCL），非特指的由低级别淋巴瘤引起的DLBCL和高级别B细胞淋巴瘤[108,109]。它于2021年4月获得FDA加速批准用于医疗用途。
Zynlonta is composed of a humanized IgG1 mAb conjugated to SG3199, a cytotoxic pyrrolobenzodiazepine (PBD) dimer alkylating agent, through a protease-cleavable valinealanine linker, see Figure 14 [108,110]. SG3199 exhibits cytotoxicity in the picomolar range against various cancer cell types, meaning Zynlonta possesses the most cytotoxic payload employed in a marketed ADC to date. PBD dimers are extremely potent compounds which exert their cytotoxic effects by selectively alkylating the minor groove of DNA, thereby forming adducts to inhibit nucleic acid synthesis. Following insertion in the minor groove, an aminal bond is formed through the nucleophilic attack of N2 of guanine at the electrophilic C11 position on the PBD, see Figure 15. In developing Zynlonta , ADC therapeutics used the N10 position of PBD to connect the linker through a carbamate moiety. As for PABC-substituted MMAE depicted in Figure 6, PABC-substituted SG3199 undergoes a spontaneous 1,6-elimination to release the active drug, see Figure 14. Owing to Zynlonta由人源化的IgG1 mAb与SG3199结合而成，SG3199是一种细胞毒性吡咯苯并二氮杂环（PBD）二聚体烷基化剂，通过可被蛋白酶裂解的缬氨酸丙氨酸连接剂连接，见图14。SG3199对各种癌细胞类型表现出皮摩尔范围内的细胞毒性，这意味着Zynlonta具有迄今市场上使用的最具细胞毒性的有效荷载。PBD二聚体是极其有效的化合物，通过选择性烷基化DNA的小沟来发挥其细胞毒性作用，从而形成加合物以抑制核酸合成。在小沟插入后，通过胞嘧啶N2对PBD上电子亲和性的C11位置进行胞嘧啶亲核攻击形成胺键，见图15。在开发Zynlonta时，ADC治疗使用PBD的N10位置通过碳酸酯基连接连接剂。至于图6中所示的PABC取代的MMAE，PABC取代的SG3199经历自发的1,6-消除以释放活性药物，见图14。由于
the sub-picomolar potency and lipophilicity of this payload, which increases risk of toxicity in the case of premature drug release or ADC aggregation, an average of 2.3 molecules of linker-payload are attached to each , and a pegylated spacer was employed. 这种荷载物的亚皮摩尔效价和亲脂性，增加了药物过早释放或 ADC 聚集时毒性风险，平均每个 连接物上附着 2.3 个分子的连接物-荷载物，并采用了聚乙二醇间隔物。
Figure 14. Structure of Zynlonta (loncastuximab tesirine-lpyl). The antibody is shown in blue, and chemical structures for linker and payload are in red and green, respectively. PEG, polyethyleneglycol. Spontaneous 1,6-elimination mechanism for the PABC-substituted SG3199, leading to release of SG3199, p-iminoquinone methide, and carbon dioxide. 图 14. Zynlonta （隆卡司汀-利帕尔）。抗体显示为蓝色，连接物和荷载物的化学结构分别为红色和绿色。PEG，聚乙二醇。PABC 取代的 SG3199 的自发 1,6-消除机制，导致 SG3199、对亚甲基苯醌亚胺和二氧化碳的释放。
Figure 15. Schematic showing binding of the PBD dimer, SG3199, to the minor groove of DNA. The N2 of guanine binds the electrophilic C11 position on the PBD dimer. 图 15. 示意图显示 PBD 二聚体 SG3199 与 DNA 小沟的结合。鸟嘌呤的 N2 结合到 PBD 二聚体的亲电性 C11 位置。
3.10. Tivdak
In late September 2021, the FDA granted accelerated approval to Tivdak (tisotumab vedotin-tftv), deeming it the most recently approved ADC on the market. Tivdak , codeveloped by Seagen and Genmab, is the first and only approved ADC indicated for treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy [111,112]. This is the third FDA approved ADC for Seagen, further cementing their dominance as the industry leader in ADC technologies. 2021 年 9 月底，FDA 加速批准了 Tivdak （tisotumab vedotin-tftv），将其视为市场上最新批准的 ADC。Tivdak ，由 Seagen 和 Genmab 共同开发，是首个也是唯一一个获批用于治疗复发性或转移性宫颈癌成人患者的 ADC，这些患者在化疗后病情进展[111,112]。这是 Seagen 获得的第三个 FDA 批准的 ADC，进一步巩固了他们作为 ADC 技术行业领导者的地位。
Tivdak is a Tissue Factor (TF) directed ADC comprised of a human anti-TF IgG1 antibody conjugated to MMAE via the same protease-cleavable linker construct employed in Adcetris , Polivy , and Padcev , see Figure . As for these previously discussed ADCs, Tivdak carries an average of four MMAE molecules per mAb. Furthermore, in vitro studies have demonstrated that this ADC also mediates ADCP and ADCC effector functions, thus providing multimodal antitumor activity [111]. Tivdak 是一种以组织因子（TF）为靶点的 ADC，由人源抗 TF IgG1 抗体通过与 Adcetris 、Polivy 和 Padcev 中采用的相同蛋白酶可切割的连接体构建而成，见图 。与先前讨论的这些 ADC 一样，Tivdak 携带平均每个单抗四个 MMAE 分子。此外，体外研究表明，这种 ADC 还介导 ADCP 和 ADCC 效应功能，从而提供多模式抗肿瘤活性[111]。
Figure 16. Structure of Tivdak (tisotumab vedotin-tftv). The antibody is shown in blue, and chemical structures for linker and payload are in red and green, respectively. Tivdak （tisotumab vedotin-tftv）的结构图。抗体显示为蓝色，连接剂和药物负载的化学结构分别为红色和绿色。
4. Future Outlook and Conclusions 4. 未来展望和结论
After decades of research and troubleshooting, appreciable technological advances and an improved mechanistic understanding of ADC activity has culminated in the FDA approval of 11 ADCs, each providing demonstrable therapeutic benefit to cancer patients. With ADCs in pre-clinical/clinical development, this suggests the world is embracing a new era of targeted cancer therapy, despite the somewhat mixed reviews that remain within academia. Market indicators suggest the global sales of currently marketed ADCs will exceed US billion in 2026 [8]. In this analysis, Enhertu is expected to dominate the market share held by ADCs, with global sales of billion, making it the highest selling ADC by a considerable margin (Padcev is predicted to have the second highest sales of billion in 2026) [8]. This impressive sales forecast is high primarily because Enhertu can be used in several subsets of breast cancer (HER2+, HR+/HER2-, and triplenegative) (Appendix B) and it has an extended treatment duration [8]. Although drug development continues to be a very risky endeavor, those investing in ADC technology are finally beginning to reap the rewards from their sustained faith in this unique field of biologics. We highly expect to see more ADC approvals in the not-so-distant future, whether they be in the form of new ADCs, or label expansions of those already approved. 经过数十年的研究和故障排除，显著的技术进步和对ADC活性的改进机制理解已经导致FDA批准了11种ADC，每种都为癌症患者提供了可证明的治疗益处。在临床前/临床开发中有 种ADC，这表明世界正在迎接一个新的靶向癌症治疗时代，尽管学术界仍存在一些褒贬不一的评论。市场指标显示，目前上市的ADC全球销售额预计将在2026年超过 亿美元[8]。在这项分析中，Enhertu 预计将主导ADC所占市场份额，全球销售额为 亿美元，使其成为销售额最高的ADC（Padcev 预计2026年销售额为 亿美元）[8]。这一令人印象深刻的销售预测主要是因为Enhertu 可以用于乳腺癌的几个亚组（HER2+、HR+/HER2-和三阴性）（附录B），并且具有较长的治疗持续时间[8]。 尽管药物开发仍然是一项非常高风险的工作，但那些投资 ADC 技术的人终于开始从他们对这一独特生物制剂领域的持续信仰中获得回报。我们非常期待在不太遥远的将来看到更多 ADC 的批准，无论是以新的 ADC 形式还是已经获批的标签扩展。
Arguably, the lack of variety in the MoA for payloads, linker type, and an avoidance of engineered antibodies to improve DAR homogeneity seen in the FDA approved ADCs, may suggest an "if it ain't broke, don't fix it" mentality. However, we believe the true potential of this pharmacological platform is only just being realized, understood, and exploited. Given the recent enthusiasm towards the role of artificial intelligence (AI) for drug discovery and development in neighboring fields, stimulated in large part by improvements in machine learning and ultimately the competitive force in the race towards the next blockbuster drug, it is presumed that drug companies will exploit these computer-based platforms for the development of next-generation ADCs [114-118]. 可以说，在 FDA 批准的 ADC 中，药物作用机制的有效载体、连接剂类型的缺乏多样性以及为改善 DAR 均一性而避免使用工程抗体，可能表明一种“不破坏就不修复”的心态。然而，我们相信这种药理平台的真正潜力只是刚刚开始被认识、理解和利用。鉴于最近对人工智能（AI）在药物发现和开发中的作用的热情，这在相邻领域中得到了刺激，这主要是由于机器学习的改进和最终在追逐下一个畅销药物的竞争力量中的竞争力，可以推测药物公司将利用这些基于计算机的平台开发下一代 ADC [114-118]。
As ADCs have undergone clinical development, it has become clear that the rules applying to standard chemotherapy or antibody-based therapies on their own do not necessarily apply to ADCs. ADCs are modular in nature, with interchangeable components that can be altered in a strategic fashion to improve both their efficacy and toxicity profiles. AI and other computational approaches can be used to harness the wealth of data pooled together from disparate sources (e.g., from literature, chemical or pharmacological experiments, gene studies, electronic health records), which is otherwise too vast and/or complex for humans to comprehend on their own. For many years now, this has led to the development of personalized medicines and routine screening of virtual chemical libraries, searching for those that may match a newly discovered target [121]. Therefore, it is now envisaged that computer-aided design (e.g., in silico simulations and machine 随着ADCs的临床开发，人们逐渐意识到，适用于标准化疗法或基于抗体的治疗的规则并不一定适用于ADCs。ADCs具有模块化的特性，可通过战略性地改变可互换的组件来提高其疗效和毒性特征。人工智能和其他计算方法可用于利用来自不同来源（例如文献、化学或药理实验、基因研究、电子健康记录）汇集在一起的大量数据，这些数据对人类来说太庞大和/或复杂，难以单独理解。多年来，这导致了个性化药物的开发和对虚拟化学库的常规筛选，寻找可能与新发现的靶点相匹配的化合物。因此，现在人们设想计算机辅助设计（例如，通过计算模拟和机器学习）...
learning algorithms) has the potential to increase the efficiency and accuracy of completing the puzzle that is the successful three-part ADC system. These technologies may assist in identifying novel ADC constructs, perhaps with payloads and/or linker systems with unique MoAs, and could inform DAR ranges that can be tolerated (in terms of toxicity, hydrophobicity / aggregation, and size) for a particular construct. With this in mind, the importance of continuing to feed new information from the clinic to such learning systems is of vital significance. It is anticipated that AI will guide future drug and trial design, could improve the allocation of ADCs to those patients most likely to benefit from them, and may inform the selection of ideal drug targets and thus indications to treat. 学习算法）有潜力提高成功的三部分ADC系统的效率和准确性。这些技术可能有助于识别新型ADC构建物，也许具有独特的MoAs负载和/或连接器系统，并且可以确定可容忍的DAR范围（在毒性、疏水性/聚集和大小方面）以用于特定构建物。考虑到这一点，继续将来自临床的新信息输入到这些学习系统中的重要性至关重要。预计AI将指导未来的药物和试验设计，可能改善ADC分配给最有可能从中受益的患者，并可能指导选择理想的药物靶点和治疗适应症。
To keep pace with advances in the technical design of ADCs, improvements in analytical techniques for ADC characterization and purification are also expected. Currently, UV-vis spectroscopy, chromatography, and mass spectrometry are the major techniques employed [122,123]. Hydrophobic interaction chromatography, for example, allows for separation, purification, and determination of ADC attributes including DAR, drug distribution, and content of unconjugated drugs under mild nondenaturing conditions that preserve the native ADC structure and activity [124]. It is thus envisaged that novel tools and techniques will be developed, not only to improve the efficiency and accuracy of ADC structural analysis, but also to help identify new parameters that could predict safety and efficacy outcomes. 为了跟上ADC技术设计的进步，预计ADC表征和纯化的分析技术也会得到改进。目前，UV-vis光谱、色谱和质谱是主要采用的技术。例如，疏水相互作用色谱允许在温和非变性条件下分离、纯化和确定ADC属性，包括DAR、药物分布和未结合药物含量，从而保留原始ADC结构和活性。因此，预计将开发新的工具和技术，不仅提高ADC结构分析的效率和准确性，还有助于识别可能预测安全性和疗效结果的新参数。
Furthermore, the promise of ADCs as a therapeutic approach is substantial, even going beyond the realms of cancer. Research is already underway into ADCs for treatment of non-oncological indications, including autoimmune and cardiovascular diseases, diabetes, and antimicrobial infections [125]. In fact, Seagen has initiated a Phase II clinical trial (NCT03222492) to study the safety and efficacy of Adcetris in systemic sclerosis, an autoimmune disease of the connective tissue [126]. Considering this disease poses a significant and unmet need for effective treatment options, the potential for Adcetris to alleviate symptoms is highly anticipated. With Adcetris already approved by the FDA, the risk of failure is lower because the drug already has an established safety profile in preclinical models and accumulated data from more than 10 years of clinical administration. Importantly, the repurposing of this ADC is an attractive proposition for Seagen, not only for the shorter development timeline and lower development costs, but as the current patentee they may also be eligible for extended patent protection over their product [127]. While cancer has proven the testing grounds for ADC therapies, their prospective value in other fields of medicine is becoming increasingly recognized. Given the significant increase in Big Pharma interest in the ADC space, continued growth of the ADC market is inevitable, and optimism remains for the development and marketing approval of ADCs with blockbuster potential [128,129]. 此外，ADC作为一种治疗方法的前景巨大，甚至超越了癌症领域。研究已经在进行ADC用于治疗非肿瘤性疾病的领域，包括自身免疫和心血管疾病、糖尿病以及抗微生物感染[125]。实际上，Seagen已经启动了一个II期临床试验（NCT03222492），研究Adcetris在结缔组织自身免疫疾病系统性硬化症中的安全性和有效性[126]。考虑到这种疾病对有效治疗选择的需求迫切且尚未得到满足，Adcetris缓解症状的潜力备受期待。由于Adcetris已经获得FDA批准，因此失败的风险较低，因为该药物在临床前模型中已经建立了安全性档案，并且在超过10年的临床使用中积累了数据。重要的是，重新利用这种ADC对Seagen来说是一个有吸引力的提议，不仅因为开发时间线较短、开发成本较低，而且作为当前的专利持有人，他们还可能有资格获得对其产品的延长专利保护[127]。 尽管癌症已被证明是 ADC 疗法的测试基地，但它们在其他医学领域的潜在价值越来越受到认可。鉴于大型制药公司对 ADC 领域的兴趣显著增加，ADC 市场的持续增长是不可避免的，对具有巨大潜力的 ADC 的开发和上市批准仍然持乐观态度[128,129]。
Author Contributions: Conceptualization, J.T.W.T.; writing—-initial draft, J.T.W.T.; writing—review & editing, P.W.R.H., M.A.B., I.K.; supervision, P.W.R.H., M.A.B., I.K.; funding acquisition, P.W.R.H., M.A.B., I.K.; project administration, I.K. All authors have read and agreed to the published version of the manuscript. 作者贡献：概念化，J.T.W.T .; 写作-初稿，J.T.W.T .; 写作-审阅和编辑，P.W.R.H.，M.A.B.，I.K .; 监督，P.W.R.H.，M.A.B.，I.K .; 资金获取，P.W.R.H.，M.A.B.，I.K .; 项目管理，I.K. 所有作者均已阅读并同意发表的手稿版本。
Funding: This research was funded by the Health Research Council of New Zealand, grant number 18/219. 资助：本研究由新西兰卫生研究委员会资助，资助号码为 18/219。
Institutional Review Board Statement: Not applicable. 机构审查委员会声明：不适用。
Informed Consent Statement: Not applicable. 知情同意声明：不适用。
Data Availability Statement: No new data were created or analyzed in this study. Data sharing is not applicable to this article. 数据可用性声明：本研究未创建或分析新数据。本文不适用于数据共享。
Acknowledgments: We thank the Maurice Wilkins Center for Molecular Biodiscovery for support, as well as Dr Alan Cameron for the encouragement and advice when writing this manuscript. 致谢：我们感谢莫里斯·威尔金斯分子生物发现中心的支持，以及在撰写本手稿时给予鼓励和建议的 Alan Cameron 博士。
Conflicts of Interest: The authors declare no conflict of interest. 利益冲突：作者声明没有利益冲突。
Appendix A 附录 A
To date, seven of the FDA approved ADCs have also obtained EMA approval. These include, Adcetris (25 October 2012), Kadcyla (15 November 2013), Besponsa (28 June 2017), Mylotarg April 2018), Polivy (16 January 2020), Blenrep (25 August 2020), and Enhertu (18 January 2021). Trodelvy is currently under accelerated EMA review. 截至目前，FDA 批准的七种 ADCs 也获得了 EMA 批准。其中包括 Adcetris（2012 年 10 月 25 日）、Kadcyla（2013 年 11 月 15 日）、Besponsa（2017 年 6 月 28 日）、Mylotarg（2018 年 4 月）、Polivy（2020 年 1 月 16 日）、Blenrep（2020 年 8 月 25 日）和 Enhertu（2021 年 1 月 18 日）。Trodelvy 目前正在接受加速的 EMA 审查。
Appendix B 附录 B
HR+ breast cancers are those that have cells with receptors for the hormone's progesterone and estrogen. HR+ 乳腺癌是那些细胞具有激素孕激素和雌激素受体的癌症。
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