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Open Access

New Technologies Bloom Together for Bettering Cancer Drug Conjugates

Yiming Jin, Shahab Edalatian Zakeri, Raman Bahal and Andrew J. Wiemer
Eric Barker, ASSOCIATE EDITOR
Pharmacological Reviews July 2022, 74 (3) 680-713; DOI: https://doi.org/10.1124/pharmrev.121.000499
Yiming Jin
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut
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Shahab Edalatian Zakeri
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut
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Raman Bahal
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut
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Andrew J. Wiemer
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut
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Eric Barker
Roles: ASSOCIATE EDITOR
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    Fig. 1

    History, progress, and research stages of drug conjugates.

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    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.

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    Fig. 3

    Schematic diagram and features of some new linker technologies tested in ADC design.

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    Fig. 4

    The chemical structures and characteristics of new linker technologies mentioned in this section.

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    Fig. 5

    The chemical structures of payloads mentioned in this section.

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    Fig. 6

    Schematic diagram and features of some novel drug conjugates tested in preclinical studies.

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    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.

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    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

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    TABLE 1

    ADC drugs approved by FDA (up to March 2022)

    Brand NameADC NameIndicationTargetLinkerPayloadCompanyLaunch Year
    1MylotargGemtuzumab ozogamicin (GO)1. Newly-diagnosed CD33+ acute myeloid leukemia
    2. Relapsed or refractory CD33+ acute myeloid leukemia
    CD33Cleavable
    Hydrozone linker
    CalicheamicinPfizer2000
    Relaunched in 2017
    2AdcetrisBrentuximab vedotin (SGN-35)Hodgkin lymphoma, large cell lymphoma, T-cell lymphomasCD30Cleavable
    Valine-citrulline linker
    MMAESeattle Genetics/ Takeda2011
    3KadcylaTrastuzumab emtansine (T-DM1)HER2+ breast cancerHER2Noncleavable
    Thioether linker
    DM1Roche2013
    4BesponsaInotuzumab ozogamicinRelapsed or refractory B-cell precursor acute lymphoblastic leukemiaCD22Cleavable
    Hydrozone linker
    CalicheamicinPfizer2017
    5LumoxitiMoxetumomab pasudotoxRelapsed or refractory hairy cell leukemiaCD22Fusion protein (antibody and payload)Pseudomonas exotoxinAstraZeneca2018
    6PolivyPolatuzumab vedotinRelapsed or refractory diffuse large B-cell lymphomaCD79bCleavable
    Valine-citrulline linker
    MMAERoche2019
    7PadcevEnfortumab vedotinAdvanced or metastatic urothelial cancerNectin-4Cleavable
    Maleimidocaproyl valine-citrulline linker
    MMAESeattle Genetics/ Astellas2019
    8EnhertuFam-trastuzumab deruxtecan
    (DS-8201)
    1. Metastatic breast cancer
    2. Locally advanced or metastatic gastric cancer
    HER2Cleavable
    Maleimide tetrapeptide linker
    DxdAstraZeneca/Daiichi Sankyo2019
    9TrodelvySacituzumab govitecan1. Locally advanced or metastatic triple-negative breast cancer
    2. Locally advanced or metastatic urothelial cancer
    Trop-2Cleavable
    Carbonate linker
    SN-38Immunomedics2020
    10BlenrepBelantamab mafodotinRelapsed or refractory multiple myelomaBCMANoncleavable
    Maleimidocaproyl linker
    MMAFGlaxoSmithKline2020
    11ZynlontaLoncastuximab tesirine-lpylRelapsed or refractory large B-cell lymphomaCD19Cleavable
    Valine-alanine linker
    Pyrrolobenzodiazepine (PBD) dimerADC Therapeutics2021
    12TivdakTisotumab vedotin-tftvRecurrent or metastatic cervical cancerTissue factorCleavable
    Valine-citrulline linker
    MMAESeagen2021
    • View popup
    TABLE 2

    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.

    • View popup
    TABLE 3

    Comparison of ADC and ADCN features

    ADCADCN
    Antibody requirementA single antibody is used to bind one targetMultiple antibodies can be added to target heterogeneous and/or drug resistant tumors
    Linker influenceLinkers affect payload potency and can cause side effects, especially with cleavable linkersTarget binding and payload are not affected by linkers
    Payload requirementHighly potent drugs are neededDrugs with lower potency can be used
    DARHas a limited DAR range (1–8)Higher amount of drug can be encapsulated
    (can reach >100)
    Single/multiple-type payloadOne type of payload is primarily usedMultiple types of payloads can be loaded
    Receptor clusteringRegular receptor clustering
    (in classic, monospecific antibodies)
    Potential for enhanced receptor clustering
    PreparationPrecise chemical synthesis with multiple reaction stepsMainly relies on self-assembly
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Pharmacological Reviews: 74 (3)
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1 Jul 2022
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Review ArticleReview Article

Bettering Cancer Drug Conjugates

Yiming Jin, Shahab Edalatian Zakeri, Raman Bahal and Andrew J. Wiemer
Pharmacological Reviews July 1, 2022, 74 (3) 680-713; DOI: https://doi.org/10.1124/pharmrev.121.000499

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Review ArticleReview Article

Bettering Cancer Drug Conjugates

Yiming Jin, Shahab Edalatian Zakeri, Raman Bahal and Andrew J. Wiemer
Pharmacological Reviews July 1, 2022, 74 (3) 680-713; DOI: https://doi.org/10.1124/pharmrev.121.000499
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    • 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
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