Overview of selected preclinical studies of new targets and associated ADC development

TargetCancerADC NamePayloadIn Vitro EffectTumor modelIn Vivo EffectReference
HER3Overexpressed on various cancers (breast, gastric, and ovarian cancers and melanoma)U3-1402DXdEfficient 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 mice1. Antitumor activity dependent upon HER3 expression level
2. Tolerable safety profiles in rats and monkeys
Hashimoto et al., 2019
HER3Overexpressed on various cancers (breast, gastric, and ovarian cancers and melanoma)EV20MMAFEfficient proliferation inhibition in cell lines resistant to anti-HER2 therapies (BT474 cell)Trastuzumab-resistant HER2+ breast cancer xenograft miceHER3-dependent complete and long-lasting tumor regression (over 300 days)Gandullo-Sánchez et al., 2020
Anaplastic lymphoma kinaseThe most common somatically mutated gene in neuroblastomaCDX-0125-TEINMS-P9451. Efficient antigen binding and internalization
2. Cytotoxicity at pM concentrations
Neuroblastoma wild-type and mutant xenograft miceDose-dependent antitumor effect and significant tumor growth delaySano et al., 2019
CD205Lymphoma, leukemia, and multiple myelomaMEN1309/OBT076DM4Antiproliferative activity against 42 types of B-cell lymphoma cell lines with a median IC50 of 200 pMTNBC, pancreatic, and bladder cancer cell lines xenograft miceComplete tumor regression at a dose of 5 mg/kg in all 8 model miceEugenio et al., 2020
c-KIT (CD117)Gastrointestinal stromal tumors, small cell lung cancer, melanoma, non–small cell lung cancer, and acute myelogenous leukemiaLOP628DM1Antiproliferative 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 mice1. 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-4Re-expressed on various cancersN41mab-vcMMAEMMAEDose-dependent cytotoxicityTNBC primary tumor, metastatic lesion, and local relapseRapid, complete, and durable immune responsesM-Rabet et al., 2017
cMetAmplified, mutated, or overexpressed cMet commonly seen in many human tumor typesTR1801-PBD-ADCPBD1. Antitumor activity at picomolar concentration
2. High toxicity to both cMet high-expression and medium-to-low expression cell lines
Patient-derived xenograft mice models1. 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
cMetAmplified, mutated, or overexpressed cMet commonly seen in many human tumor typescIRCR201-dPBDPBDAntitumor activity on 47 different cancer cell lines in a cMet expression level dependent mannercMet-amplified cancer cells xenograft mice modelsSignificant antitumor activity and complete tumor regression at a high dose of 0.8 mg/kgMin et al., 2020
IGF-1ROverexpression occurs in numerous tumor tissueshz208F2-4-W0101Auristatin derivativeIGF-1R expression-dependent cell cytotoxicity in various cancer cell linesMouse models expressing different levels of IGF-1RPotent tumor regression correlated with IGF-1R expression levelAkla et al., 2020
Death receptor 5Overexpressed on various cancersZapadcine-1MMAD1. 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 Reh1. Drastically eliminates the xenografts
2. Acceptable safety profile in rat and cynomolgus monkey
Zhang et al., 2019b
AXLOverexpressed on various cancers and plays important roles in formation, growth, and metastasis of tumorsAXL-107-MMAEMMAEEfficient AXL-specific cytotoxicity in various cancer cellsPatient-derived xenografts, including melanoma, lung, pancreas, and cervical cancer1. Potent antitumor activity
2. Acceptable safety profile in cynomolgus monkey
Boshuizen et al., 2018
DLL3Overexpressed in neuroendocrine prostate cancer and related to castration-resistant neuroendocrine prostate cancerSC16LD6.5PBDNADLL3-expressing prostate cancer xenograftsComplete tumor regression and durable antitumor responses to DLL3 high expression xenograftsPuca et al., 2019
GPC2Differential expression in neuroblastoma and required for neuroblastoma proliferationD3-GPC2-PBDPBDCytotoxic to human GPC2 expressing neuroblastoma cell linesGPC2-expressing neuroblastoma cell line xenografts1. Efficacy against tumor growth with only a single dose
2. Significantly prolonged survival (80% of mice over 60 days)
Bosse et al., 2017
Cadherin-6Differential expression in ovarian and kidney cancersHKT288-DM4DM4NAHuman ovarian and renal cancer xenografts1. Durable tumor regression in ovarian and renal cancers
2. Acceptable tolerability profile in rats and nonhuman primates
Bialucha et al., 2017
GPNMBExpressed on MAPK inhibitor-treated melanoma cellsCDX-011MMAENAA375 and WM2664 melanoma cell xenograft model miceMelanoma regression and delayed recurrent melanoma growth when combined with MEK inhibitors trametinibRose et al., 2016
β-1,3-N-acetylglucosaminyl transferaseOverexpressed in breast cancersgPD-L1-ADCMMAE1. 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 mice1. 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 7Enriched on tumor-initiating cells in TNBC, ovarian cancer, and NSCLCPF-06647020Aur0101Strong cytotoxicity against H661, H446, and OVCAR3 cancer cell linesHuman tumor xenograft (NSCLC, TNBC, and ovarian cancer) model mice1. 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
EphA2Comprise a large family of receptor tyrosine kinases, low expression in normal adult tissue, but overexpression in a wide range of solid tumorsBT5528MMAESuccessfully bind to the surface of HT-1080 cells with high EphA2 expressionMurine xenograft modelsDecreased tumor burden (return to baseline values after three dosing cycles) and prolonged survivalBennett 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.