Article Figures & Data
Figures
- Fig. 1
History, progress, and research stages of drug conjugates.
- Fig. 2
ADC antibody engineering to optimize internalization rate. Classic ADC antibodies have two of the same antigen recognition sites that can recognize and bind to two molecules of the target epitope at the exact location on each molecule. The internalization rate is mainly determined by the properties of the antigen. Bispecific antibodies have two different antigen recognition sites that can recognize and bind to two different target antigens: one is a tumor target antigen with low internalization, and the other is an antigen with high internalization. The biepitope antibodies have two different antigen recognition sites that can recognize and bind to two different epitopes on the same antigen molecule. Antibody binding to different epitopes on one antigen may change the internalization rate and promote internalization and/or penetration of the ADC into tumor cells.
- Fig. 3
Schematic diagram and features of some new linker technologies tested in ADC design.
- Fig. 4
The chemical structures and characteristics of new linker technologies mentioned in this section.
- Fig. 5
The chemical structures of payloads mentioned in this section.
- Fig. 6
Schematic diagram and features of some novel drug conjugates tested in preclinical studies.
- Fig. 7
Schematic diagram of the mechanism of pHLIP-drug conjugate (pHDC). In a neutral environment (normal-cell extracellular matrix), pHDCs can circulate on the extracellular matrix or cling to the cell membrane and finally achieve a dynamic balance. However, in an acidic environment (tumor-cell extracellular matrix), pHDCs penetrate the cell membrane. The section conjugated with the payload is exposed to the intracellular cytoplasm. The linker can sense the environment difference and break to release the payload. Such linkers include disulfide linkers, which can be cleaved by intracellular reduced glutathione.
- Fig. 8
Diagram of ADCNs. These conjugates can self-assemble into nanoparticles via hydrophobicity and hydrophilicity interactions of the payload, linker, and antibody. ADCNs can carry plenty of payloads inside the nanoparticle (very high DAR) and display antibodies on their surface for targeted delivery.
Tables
Brand Name ADC Name Indication Target Linker Payload Company Launch Year 1 Mylotarg Gemtuzumab ozogamicin (GO) 1. Newly-diagnosed CD33+ acute myeloid leukemia
2. Relapsed or refractory CD33+ acute myeloid leukemiaCD33 Cleavable
Hydrozone linkerCalicheamicin Pfizer 2000
Relaunched in 20172 Adcetris Brentuximab vedotin (SGN-35) Hodgkin lymphoma, large cell lymphoma, T-cell lymphomas CD30 Cleavable
Valine-citrulline linkerMMAE Seattle Genetics/ Takeda 2011 3 Kadcyla Trastuzumab emtansine (T-DM1) HER2+ breast cancer HER2 Noncleavable
Thioether linkerDM1 Roche 2013 4 Besponsa Inotuzumab ozogamicin Relapsed or refractory B-cell precursor acute lymphoblastic leukemia CD22 Cleavable
Hydrozone linkerCalicheamicin Pfizer 2017 5 Lumoxiti Moxetumomab pasudotox Relapsed or refractory hairy cell leukemia CD22 Fusion protein (antibody and payload) Pseudomonas exotoxin AstraZeneca 2018 6 Polivy Polatuzumab vedotin Relapsed or refractory diffuse large B-cell lymphoma CD79b Cleavable
Valine-citrulline linkerMMAE Roche 2019 7 Padcev Enfortumab vedotin Advanced or metastatic urothelial cancer Nectin-4 Cleavable
Maleimidocaproyl valine-citrulline linkerMMAE Seattle Genetics/ Astellas 2019 8 Enhertu Fam-trastuzumab deruxtecan
(DS-8201)1. Metastatic breast cancer
2. Locally advanced or metastatic gastric cancerHER2 Cleavable
Maleimide tetrapeptide linkerDxd AstraZeneca/Daiichi Sankyo 2019 9 Trodelvy Sacituzumab govitecan 1. Locally advanced or metastatic triple-negative breast cancer
2. Locally advanced or metastatic urothelial cancerTrop-2 Cleavable
Carbonate linkerSN-38 Immunomedics 2020 10 Blenrep Belantamab mafodotin Relapsed or refractory multiple myeloma BCMA Noncleavable
Maleimidocaproyl linkerMMAF GlaxoSmithKline 2020 11 Zynlonta Loncastuximab tesirine-lpyl Relapsed or refractory large B-cell lymphoma CD19 Cleavable
Valine-alanine linkerPyrrolobenzodiazepine (PBD) dimer ADC Therapeutics 2021 12 Tivdak Tisotumab vedotin-tftv Recurrent or metastatic cervical cancer Tissue factor Cleavable
Valine-citrulline linkerMMAE Seagen 2021 - TABLE 2
Overview of selected preclinical studies of new targets and associated ADC development
Target Cancer ADC Name Payload In Vitro Effect Tumor model In Vivo Effect Reference HER3 Overexpressed on various cancers (breast, gastric, and ovarian cancers and melanoma) U3-1402 DXd Efficient internalization and payload release in HER3+ cell lines (HCC1569, SK-BR-3, MDA-MB-175VII, MDA-MB-453, MDA-MB-361, and OVCAR-8) Human breast cancer cell line and patient-derived breast cancer xenograft mice 1. Antitumor activity dependent upon HER3 expression level
2. Tolerable safety profiles in rats and monkeysHashimoto et al., 2019 HER3 Overexpressed on various cancers (breast, gastric, and ovarian cancers and melanoma) EV20 MMAF Efficient proliferation inhibition in cell lines resistant to anti-HER2 therapies (BT474 cell) Trastuzumab-resistant HER2+ breast cancer xenograft mice HER3-dependent complete and long-lasting tumor regression (over 300 days) Gandullo-Sánchez et al., 2020 Anaplastic lymphoma kinase The most common somatically mutated gene in neuroblastoma CDX-0125-TEI NMS-P945 1. Efficient antigen binding and internalization
2. Cytotoxicity at pM concentrationsNeuroblastoma wild-type and mutant xenograft mice Dose-dependent antitumor effect and significant tumor growth delay Sano et al., 2019 CD205 Lymphoma, leukemia, and multiple myeloma MEN1309/OBT076 DM4 Antiproliferative activity against 42 types of B-cell lymphoma cell lines with a median IC50 of 200 pM TNBC, pancreatic, and bladder cancer cell lines xenograft mice Complete tumor regression at a dose of 5 mg/kg in all 8 model mice Eugenio et al., 2020 c-KIT (CD117) Gastrointestinal stromal tumors, small cell lung cancer, melanoma, non–small cell lung cancer, and acute myelogenous leukemia LOP628 DM1 Antiproliferative activity on c-KIT+ cell lines (GIST882, GIST430, GIST-T1, Kasumi-1, Kasumi-6, NCI-H526, and NCI-H1048) Gastrointestinal stromal tumors and small cell lung cancer xenograft mice 1. Superior antitumor activity against imatinib-resistant tumors and complete tumor regression for 130 days when coadministered with imatinib
2. Well tolerated in monkeys (dose of 30 mg/kg every 3 weeks)Abrams et al., 2018 Nectin-4 Re-expressed on various cancers N41mab-vcMMAE MMAE Dose-dependent cytotoxicity TNBC primary tumor, metastatic lesion, and local relapse Rapid, complete, and durable immune responses M-Rabet et al., 2017 cMet Amplified, mutated, or overexpressed cMet commonly seen in many human tumor types TR1801-PBD-ADC PBD 1. Antitumor activity at picomolar concentration
2. High toxicity to both cMet high-expression and medium-to-low expression cell linesPatient-derived xenograft mice models 1. Complete tumor regression in 90% of gastric, colorectal, and head and neck cancers
2. Good tolerability in rats (0.5, 1, 1.5, and 2 mg/kg)Gymnopoulos et al., 2020 cMet Amplified, mutated, or overexpressed cMet commonly seen in many human tumor types cIRCR201-dPBD PBD Antitumor activity on 47 different cancer cell lines in a cMet expression level dependent manner cMet-amplified cancer cells xenograft mice models Significant antitumor activity and complete tumor regression at a high dose of 0.8 mg/kg Min et al., 2020 IGF-1R Overexpression occurs in numerous tumor tissues hz208F2-4-W0101 Auristatin derivative IGF-1R expression-dependent cell cytotoxicity in various cancer cell lines Mouse models expressing different levels of IGF-1R Potent tumor regression correlated with IGF-1R expression level Akla et al., 2020 Death receptor 5 Overexpressed on various cancers Zapadcine-1 MMAD 1. Rapidly endocytosed into the lysosome of cancer cells
2. Antitumor effect against lymphocyte leukemia cells and solid tumor cellsPatient-derived xenografts of human acute leukemia and cell-derived xenografts of Jurkat E6-1, BALL-1 and Reh 1. Drastically eliminates the xenografts
2. Acceptable safety profile in rat and cynomolgus monkeyZhang et al., 2019b AXL Overexpressed on various cancers and plays important roles in formation, growth, and metastasis of tumors AXL-107-MMAE MMAE Efficient AXL-specific cytotoxicity in various cancer cells Patient-derived xenografts, including melanoma, lung, pancreas, and cervical cancer 1. Potent antitumor activity
2. Acceptable safety profile in cynomolgus monkeyBoshuizen et al., 2018 DLL3 Overexpressed in neuroendocrine prostate cancer and related to castration-resistant neuroendocrine prostate cancer SC16LD6.5 PBD NA DLL3-expressing prostate cancer xenografts Complete tumor regression and durable antitumor responses to DLL3 high expression xenografts Puca et al., 2019 GPC2 Differential expression in neuroblastoma and required for neuroblastoma proliferation D3-GPC2-PBD PBD Cytotoxic to human GPC2 expressing neuroblastoma cell lines GPC2-expressing neuroblastoma cell line xenografts 1. Efficacy against tumor growth with only a single dose
2. Significantly prolonged survival (80% of mice over 60 days)Bosse et al., 2017 Cadherin-6 Differential expression in ovarian and kidney cancers HKT288-DM4 DM4 NA Human ovarian and renal cancer xenografts 1. Durable tumor regression in ovarian and renal cancers
2. Acceptable tolerability profile in rats and nonhuman primatesBialucha et al., 2017 GPNMB Expressed on MAPK inhibitor-treated melanoma cells CDX-011 MMAE NA A375 and WM2664 melanoma cell xenograft model mice Melanoma regression and delayed recurrent melanoma growth when combined with MEK inhibitors trametinib Rose et al., 2016 β-1,3-N-acetylglucosaminyl transferase Overexpressed in breast cancers gPD-L1-ADC MMAE 1. Selectively suppressed tumors with PD-L1 antigen
2. Potent cytotoxic and bystander-killing effect to TNBCPD-L1 expressing mouse and human cancer cell xenograft model mice 1. Complete regression of 4T1-hPD-L1and EMT6-hPD-L1 tumors
2. Significantly better survival (about 75%) than glycosylated PD-L1 treated mice (about 30%)Li et al., 2018 Protein tyrosine kinase 7 Enriched on tumor-initiating cells in TNBC, ovarian cancer, and NSCLC PF-06647020 Aur0101 Strong cytotoxicity against H661, H446, and OVCAR3 cancer cell lines Human tumor xenograft (NSCLC, TNBC, and ovarian cancer) model mice 1. Sustained tumor regression for 200 days in BR22 xenograft and 150 days in most BR31 xenografts
2. Reduced tumor-initiating cell frequency 5.5-fold with respect to control ADC and 2.1-fold with respect to docetaxelDamelin et al., 2017 EphA2 Comprise a large family of receptor tyrosine kinases, low expression in normal adult tissue, but overexpression in a wide range of solid tumors BT5528 MMAE Successfully bind to the surface of HT-1080 cells with high EphA2 expression Murine xenograft models Decreased tumor burden (return to baseline values after three dosing cycles) and prolonged survival Bennett et al., 2020 5T4, trophoblast glycoprotein; Aur0101, an auristatin microtubule inhibitor; AXL, a tyrosine-protein kinase receptor; cMet, tyrosine-protein kinase Met; DM1/DM4, a maytansinoid microtubule disruptor; Dxd, a topoisomerase I inhibitor payload exatecan derivative; EphA2, erythropoietin-producing hepatocellular (Eph) receptor; MMAD, monomethyl auristatin D; NMS-P945, a DNA minor groove alkylating agent.
ADC ADCN Antibody requirement A single antibody is used to bind one target Multiple antibodies can be added to target heterogeneous and/or drug resistant tumors Linker influence Linkers affect payload potency and can cause side effects, especially with cleavable linkers Target binding and payload are not affected by linkers Payload requirement Highly potent drugs are needed Drugs with lower potency can be used DAR Has a limited DAR range (1–8) Higher amount of drug can be encapsulated
(can reach >100)Single/multiple-type payload One type of payload is primarily used Multiple types of payloads can be loaded Receptor clustering Regular receptor clustering
(in classic, monospecific antibodies)Potential for enhanced receptor clustering Preparation Precise chemical synthesis with multiple reaction steps Mainly relies on self-assembly
In this issue
Jump to section
- Article
- Visual Overview
- Abstract
- I. Introduction
- II. New Technology in the Development of Antibody Drug Conjugates
- III. New Targets of Drug Conjugates
- IV. New Types of Drug Conjugates
- V. Barriers to Clinical Translation
- VI. Conclusions and Perspectives
- Acknowledgments
- Authorship Contributions
- Footnotes
- Abbreviations
- References
- Figures & Data
- Info & Metrics
- eLetters