Linkers: An Assurance for Controlled Delivery of Antibody-Drug Conjugate
Abstract
:1. Introduction
2. The Key Components of an ADC
2.1. Monoclonal Antibody (mAb)
2.2. Cytotoxic Drug
3. Linker Chemistry and Conjugation to Antibody
3.1. Cleavable Linkers
3.1.1. Chemically Labile Linkers
Acid-Cleavable/pH-Sensitive Linkers
Reducible Linkers
3.1.2. Enzyme-Cleavable Linkers
Peptide-Based Linkers
Glycosidase-Sensitive Linkers
Phosphatase-Cleavable Linkers
3.2. Non-Cleavable Linkers
3.3. Conjugation Strategies
4. Approved ADCs and ADCs in Clinical Trials
5. ADC Mechanism of Action
6. Conclusions and Prospects
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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ADC Structure | Linkage Type | Cleavage Mechanism | Products Formed | Cleavage Site |
---|---|---|---|---|
| pH sensitive | Hydrolysis | | Lysosome/Endosome [57,58,59,60] |
| Reduction sensitive | Reduction | | Cytoplasm [56,61,62,63] |
| Peptide based linkage | Proteolysis | | Lysosome [64,65,66,67] |
| β-glucoronide | Glyosidase 1, 6-Elimination | | Lysosome [68,69] |
| Phosphatase cleavage | Phosphatase | | Lysosome [70] |
| Carbamate | Esterase | | Lysosome [71,72] |
| Ester | Esterase | | Lysosome [72,73] |
API | Trade Name | Developer | mAb | Linker | Cytotoxin | Target Antigen | Indication(s) | Phase |
---|---|---|---|---|---|---|---|---|
Gemtuzumab ozogamicin | Mylotarg | Pfizer | Hp67.6 (Hz IgG4) | Hydrazone | Calicheamicin | CD33 | Acute myeloid leukemia | Approved 2000 [112], withdrawn 2010 [113]; reapproved 2017 [19]. |
Brentuximab vedotin (SGN-35) | Adcetris | Millennim/Takeda/Seattle Genetics | cAC10 (SGN-30, Ch-IgG1) | Dipeptide (VC) | MMAE | CD30 | Hodgkin lymphoma, systemic anaplastic large cell lymphoma | Accelerated approval 2011 [87]; full approval 2015 [114]. |
Trastuzumab emtansine | Kadcyla | Roche/Genetech | Trastuzumab (Hz IgG1) | Non-cleavable (SMCC) | DM1 | HER2 | HER2-positive breast cancer | Approved 2013 [115,116] |
Inotuzumab ozogamicin | Besponsa | Pfizer | G5/44 (Hz IgG4) | Hydrazone | Calicheamicin | CD22 | Acute lymphoblastic leukemia | Approved 2017 [117,118] |
Moxetumomab pasudotox-tdfk | Lumoxiti | AstraZeneca | Anti-CD22 | Hydrazone | Pasudotox-tdfk | CD22 | Relapsed hairy cell leukemia | Approved 2018 [119,120] |
Polatuzumab vedotin (RG7596, TAB-897, DCDS4501A | Polivy | Genentech/Roche | Anti-CD79b (Hz IgG1) | Dipeptide (VC) | MMAE | CD79b | Relapsed or refractory diffuse large B-cell lymphoma | Approved 2019 [19,121,122] |
Enfortumab vedotin | Padcev | Agensys/Astellas | Enfortumab | Dipeptide (VC) | MMAE | Nectin4 | Solid and urothelial tumors | Approved 2019 [122,123,124] |
Trastuzumab deruxtecan | Enhertu | AstraZeneca/Daiichi Sankyo | Trastuzumab (Herceptin) | Non-cleavable (mc) | Deruxtecan | HER2 | HER2-positive breast cancer | Approved 2019 [125,126] |
Sacituzumab govitecan | Trodelvy | Immunomedics | hRS7 IgGk | Acid-labile ester | SN-38 | Trop-2 | Triple-negative breast cancer, urothelial and other cancers | Approved May 2020 [127,128,129,130,131,132] |
Belantamab mafodotin-blmf | Blenrep | GlaxoSmithKline (GSK) | IgG1 | Non-cleavable (mc) | MMAE | BCMA | Multiple myeloma | Approved 2020 [132,133,134,135,136] |
Loncastuximab tesirine-lpyl | Zynlonta | ADC Therapeutics | Anti-CD19 | Dipeptide (VA) | PBD | CD19 | Large B-cell lymphoma | Approved 2021 [137,138] |
Tisotumab vedotin tftv | Tivdak | Seagen Inc | Tisotumab | Dipeptide (VC) | MMAE | Tissue factor | Metastatic cervical cancer | Approved 2021 [139,140] |
ADC Name | Developer | mAb | Linker | Cytotoxin | Target Antigen | Indication(s) | Phase |
---|---|---|---|---|---|---|---|
Rovalpituzumab tesirine | Sanofi/ImmunoGen | Anti-DLL3 (Rovalpituzumab) | Dipeptide (VC) | PBD dimer | DLL3 | Small-cell lung cancer | III [141,142,143] |
Glembatumumab vedotin | Seattle Genetics/Celldex/Progenics | CR-011 (Hu IgG2) | Cleavable dipeptide | MMAE | gpNMB | Metastatic breast cancer and melanoma | II/III [144,145] |
PSMA ADC | Seattle Genetics/Progenics | Anti-PSMA (Hu IgG1) | Cleavable dipeptide | MMAE | PSMA | Prostate cancer | II [121] |
Pinatuzumab vedotin | Roche/Genentech | Anti-CD22 (Hz IgG1) | Cleavable dipeptide | MMAE | CD22 | Diffuse large B-cell lymphoma, follicular non-Hodgkin lymphoma | II [121] |
Telisotuzumab vedotin | AbbVie/Pierre Fabre | ABT-700 | Cleavable dipeptide | MMAE | ABT-700 | Advanced solid tumors cancer and non-small cell lung cancer | II [146,147] |
Ladiratuzumab vedotin SGN-LIV1A | Seattle Genetics | Anti-LIV1 (Hz IgG1) | Cleavable dipeptide | MMAE | LIV-1 | Breast cancer, lung cancer | II [148] |
Mirvetuximab soravtansine | ImmunoGen | M9346A | Cleavable disulfide | DM4 | FOLR1 | Ovarian, endometrial, non-small cell lung cancer | III [149,150] |
Lorvotuzumab mertansine | ImmunoGen | huN901 (Hz IgG1) | Cleavable disulfide | DM1 | CD56 | Leukemia | II [88] |
Coltuximab ravtansine | ImmunoGen | huB4 (Hz IgG1) | Cleavable disulfide | DM4 | CD19 | Diffuse large B cell lymphoma, acute lymphocytic leukaemia | II [93,151,152] |
Indatuximab ravtansine | Biotest/ImmunoGen | Nbt062, Anti- CD138 (Ch IgG4) | Cleavable disulfide | DM4 | CD138 | Multiple myeloma | II [153] |
Anetumab ravtansine | Bayer Health Care | Antimesothelin (Hz IgG1) | Cleavable disulfide | DM4 | Mesothelin | Mesothelioma and other solid tumors | II [115,154] |
SAR566658 | Sanofi | DS6 (Hu IgG1) | Cleavable disulfide | DM4 | CA6 | Triple-negative breast cancer | II [155,156] |
Depatuxizumab mafodotin | AbbVie | ABT-806 | Non-cleavable (mc) | MMAF | EGFR | Glioblastoma and other EGFR-positive tumors | III [129] |
Naratuximab emtansine | ImmunoGen | K7153A humanized IgG1 | Non-cleavable (SMCC) | DM1 | CD37 | Diffuse large B cell lymphoma and follicular lymphoma | II [121] |
AGS-16C3F | Agensys/Astellas | Anti-AGS16 (Hu IgG2a) | Non-cleavable (mc) | ENPP3 | ENPP3 | Renal cell carcinoma | II [157] |
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Sheyi, R.; de la Torre, B.G.; Albericio, F. Linkers: An Assurance for Controlled Delivery of Antibody-Drug Conjugate. Pharmaceutics 2022, 14, 396. https://doi.org/10.3390/pharmaceutics14020396
Sheyi R, de la Torre BG, Albericio F. Linkers: An Assurance for Controlled Delivery of Antibody-Drug Conjugate. Pharmaceutics. 2022; 14(2):396. https://doi.org/10.3390/pharmaceutics14020396
Chicago/Turabian StyleSheyi, Rotimi, Beatriz G. de la Torre, and Fernando Albericio. 2022. "Linkers: An Assurance for Controlled Delivery of Antibody-Drug Conjugate" Pharmaceutics 14, no. 2: 396. https://doi.org/10.3390/pharmaceutics14020396