Preclinical Antitumor Activity and Biodistribution of a Novel Anti-GCC Antibody–Drug Conjugate in Patient-derived Xenografts
| العنوان: | Preclinical Antitumor Activity and Biodistribution of a Novel Anti-GCC Antibody–Drug Conjugate in Patient-derived Xenografts |
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| المؤلفون: | Bradley Stringer, Kurt Eng, Katharine C. Lai, Mark G. Qian, Jennifer Fretland, Melissa Gallery, Robbie Robertson, Melissa Saylor Landen, Cindy Q. Xia, Adnan O. Abu-Yousif, O. Petter Veiby, Afrand Kamali, Maria Borland, Secil Koseoglu, Bret Bannerman, Andy Z. X. Zhu, Michelle L. Ganno, Thomas A. Keating, Michael D. Smith, Donna Cvet, Jayaprakasam Bolleddula |
| المصدر: | Molecular Cancer Therapeutics. 19:2079-2088 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Biodistribution, Immunoconjugates, medicine.drug_class, Mice, Nude, Monoclonal antibody, Mice, 03 medical and health sciences, 0302 clinical medicine, In vivo, medicine, Animals, Humans, Cytotoxic T cell, Tissue Distribution, Tight junction, Chemistry, Guanylate cyclase 2C, Xenograft Model Antitumor Assays, In vitro, HEK293 Cells, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, Female, Conjugate |
| الوصف: | Guanylyl cyclase C (GCC) is a unique therapeutic target with expression restricted to the apical side of epithelial cell tight junctions thought to be only accessible by intravenously administered agents on malignant tissues where GCC expression is aberrant. In this study, we sought to evaluate the therapeutic potential of a second-generation investigational antibody–dug conjugate (ADC), TAK-164, comprised of a human anti-GCC mAb conjugated via a peptide linker to the highly cytotoxic DNA alkylator, DGN549. The in vitro binding, payload release, and in vitro activity of TAK-164 was characterized motivating in vivo evaluation. The efficacy of TAK-164 and the relationship to exposure, pharmacodynamic marker activation, and biodistribution was evaluated in xenograft models and primary human tumor xenograft (PHTX) models. We demonstrate TAK-164 selectively binds to, is internalized by, and has potent cytotoxic effects against GCC-expressing cells in vitro. A single intravenous administration of TAK-164 (0.76 mg/kg) resulted in significant growth rate inhibition in PHTX models of metastatic colorectal cancer. Furthermore, imaging studies characterized TAK-164 uptake and activity and showed positive relationships between GCC expression and tumor uptake which correlated with antitumor activity. Collectively, our data suggest that TAK-164 is highly active in multiple GCC-positive tumors including those refractory to TAK-264, a GCC-targeted auristatin ADC. A strong relationship between uptake of 89Zr-labeled TAK-164, levels of GCC expression and, most notably, response to TAK-164 therapy in GCC-expressing xenografts and PHTX models. These data supported the clinical development of TAK-164 as part of a first-in-human clinical trial (NCT03449030). |
| تدمد: | 1538-8514 1535-7163 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f36fad95085a4edda953eff31247a4c7 https://doi.org/10.1158/1535-7163.mct-19-1102 |
| رقم الأكسشن: | edsair.doi.dedup.....f36fad95085a4edda953eff31247a4c7 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15388514 15357163 |
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