High Turnover of Tissue Factor Enables Efficient Intracellular Delivery of Antibody–Drug Conjugates
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| Názov: | High Turnover of Tissue Factor Enables Efficient Intracellular Delivery of Antibody–Drug Conjugates |
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| Autori: | Tong Zhu, Paul W. H. I. Parren, David Miao, Gary Chen, Richard Wubbolts, Claudia M. Freitag, Wim K. Bleeker, Patrick Van Berkel, Alisher Khasanov, Bart De Goeij, David Satijn |
| Prispievatelia: | Infection & Immunity, Fertility & Reproduction, dI&I I&I-2, dB&C I&I, LS Infectiebiologie (Bacteriologie) |
| Zdroj: | de Goeij, B E C G, Satijn, D, Freitag, C M, Wubbolts, R, Bleeker, W K, Khasanov, A, Zhu, T, Chen, G, Miao, D, van Berkel, P H C & Parren, P W H I 2015, ' High Turnover of Tissue Factor Enables Efficient Intracellular Delivery of Antibody-Drug Conjugates ', Molecular Cancer Therapeutics, vol. 14, no. 5, pp. 1130-1140 . https://doi.org/10.1158/1535-7163.MCT-14-0798 |
| Informácie o vydavateľovi: | American Association for Cancer Research (AACR), 2015. |
| Rok vydania: | 2015 |
| Predmety: | 0301 basic medicine, Receptor, ErbB-2, ErbB-2/immunology, Antineoplastic Agents, Apoptosis, Factor VIIa, Lysosomes/metabolism, Immunotoxins/administration & dosage, Antibodies, Cell Line, Mice, 03 medical and health sciences, ErbB Receptors/immunology, Drug Delivery Systems, SDG 3 - Good Health and Well-being, Neoplasms, Experimental/drug therapy, Neoplasms, Experimental/drug therapy, Cell Line, Tumor, Taverne, Animals, Humans, 2. Zero hunger, Tumor, Immunotoxins, GROWTH-FACTOR RECEPTOR FACTOR PATHWAY INHIBITOR FACTOR EXPRESSION FACTOR-VIIA TRASTUZUMAB EMTANSINE BREAST-CANCER MONOCLONAL-ANTIBODIES DOWN-REGULATION OVARIAN-CANCER CELLS, Neoplasms, Experimental, Xenograft Model Antitumor Assays, Antineoplastic Agents/administration & dosage, 3. Good health, Receptor, ErbB-2/immunology, ErbB Receptors, Factor VIIa/immunology, Lysosomes, Receptor |
| Popis: | Antibody–drug conjugates (ADC) are emerging as powerful cancer treatments that combine antibody-mediated tumor targeting with the potent cytotoxic activity of toxins. We recently reported the development of a novel ADC that delivers the cytotoxic payload monomethyl auristatin E (MMAE) to tumor cells expressing tissue factor (TF). By carefully selecting a TF-specific antibody that interferes with TF:FVIIa-dependent intracellular signaling, but not with the procoagulant activity of TF, an ADC was developed (TF-011-MMAE/HuMax-TF-ADC) that efficiently kills tumor cells, with an acceptable toxicology profile. To gain more insight in the efficacy of TF-directed ADC treatment, we compared the internalization characteristics and intracellular routing of TF with the EGFR and HER2. Both in absence and presence of antibody, TF demonstrated more efficient internalization, lysosomal targeting, and degradation than EGFR and HER2. By conjugating TF, EGFR, and HER2-specific antibodies with duostatin-3, a toxin that induces potent cytotoxicity upon antibody-mediated internalization but lacks the ability to induce bystander killing, we were able to compare cytotoxicity of ADCs with different tumor specificities. TF-ADC demonstrated effective killing against tumor cell lines with variable levels of target expression. In xenograft models, TF-ADC was relatively potent in reducing tumor growth compared with EGFR- and HER2-ADCs. We hypothesize that the constant turnover of TF on tumor cells makes this protein specifically suitable for an ADC approach. Mol Cancer Ther; 14(5); 1130–40. ©2015 AACR. |
| Druh dokumentu: | Article |
| Popis súboru: | application/pdf |
| Jazyk: | English |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-14-0798 |
| Prístupová URL adresa: | https://pubmed.ncbi.nlm.nih.gov/25724665 https://research-portal.uu.nl/en/publications/9173b47f-3ddc-40c6-bb0a-3423a8c24375 https://doi.org/10.1158/1535-7163.MCT-14-0798 http://mct.aacrjournals.org/content/molcanther/14/5/1130.full.pdf https://www.narcis.nl/publication/RecordID/oai%3Ascholarlypublications.universiteitleiden.nl%3Aitem_2995735 https://mct.aacrjournals.org/content/early/2015/02/25/1535-7163.MCT-14-0798.abstract https://europepmc.org/article/MED/25724665 https://mct.aacrjournals.org/content/molcanther/14/5/1130.full.pdf http://dspace.library.uu.nl/handle/1874/330565 https://hdl.handle.net/1887/104001 https://portal.findresearcher.sdu.dk/da/publications/31f8abde-4a9b-4143-9238-ccf0b185ed17 https://dspace.library.uu.nl/handle/1874/330565 |
| Rights: | taverne |
| Prístupové číslo: | edsair.doi.dedup.....e7a441b0d7cd19e988b2ef211eef8a7e |
| Databáza: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstrakt: | Antibody–drug conjugates (ADC) are emerging as powerful cancer treatments that combine antibody-mediated tumor targeting with the potent cytotoxic activity of toxins. We recently reported the development of a novel ADC that delivers the cytotoxic payload monomethyl auristatin E (MMAE) to tumor cells expressing tissue factor (TF). By carefully selecting a TF-specific antibody that interferes with TF:FVIIa-dependent intracellular signaling, but not with the procoagulant activity of TF, an ADC was developed (TF-011-MMAE/HuMax-TF-ADC) that efficiently kills tumor cells, with an acceptable toxicology profile. To gain more insight in the efficacy of TF-directed ADC treatment, we compared the internalization characteristics and intracellular routing of TF with the EGFR and HER2. Both in absence and presence of antibody, TF demonstrated more efficient internalization, lysosomal targeting, and degradation than EGFR and HER2. By conjugating TF, EGFR, and HER2-specific antibodies with duostatin-3, a toxin that induces potent cytotoxicity upon antibody-mediated internalization but lacks the ability to induce bystander killing, we were able to compare cytotoxicity of ADCs with different tumor specificities. TF-ADC demonstrated effective killing against tumor cell lines with variable levels of target expression. In xenograft models, TF-ADC was relatively potent in reducing tumor growth compared with EGFR- and HER2-ADCs. We hypothesize that the constant turnover of TF on tumor cells makes this protein specifically suitable for an ADC approach. Mol Cancer Ther; 14(5); 1130–40. ©2015 AACR. |
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| ISSN: | 15388514 15357163 |
| DOI: | 10.1158/1535-7163.mct-14-0798 |