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 monkeys | Hashimoto 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 concentrations | Neuroblastoma 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 lines | Patient-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 cells | Patient-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 monkey | Zhang 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 monkey | Boshuizen 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 primates | Bialucha 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 TNBC | PD-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 docetaxel | Damelin 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.