دورية أكاديمية
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: | Abu-Yousif AO; Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, Massachsetts. Adnan.Abu-Yousif@Takeda.com., Cvet D; Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, Massachsetts., Gallery M; Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, Massachsetts., Bannerman BM; Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, Massachsetts., Ganno ML; Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, Massachsetts., Smith MD; Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, Massachsetts., Lai KC; ImmunoGen, Inc. Waltham, Massachusetts., Keating TA; ImmunoGen, Inc. Waltham, Massachusetts., Stringer B; Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, Massachsetts., Kamali A; Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, Massachsetts., Eng K; Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, Massachsetts., Koseoglu S; Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, Massachsetts., Zhu A, Xia CQ; Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, Massachsetts., Landen MS; Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, Massachsetts., Borland M; Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, Massachsetts., Robertson R; Quanta Imaging, Boston, Massachusetts., Bolleddula J; Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, Massachsetts., Qian MG; Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, Massachsetts., Fretland J; Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, Massachsetts., Veiby OP; Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, Massachsetts. |
| المصدر: | Molecular cancer therapeutics [Mol Cancer Ther] 2020 Oct; Vol. 19 (10), pp. 2079-2088. Date of Electronic Publication: 2020 Aug 11. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research, Inc Country of Publication: United States NLM ID: 101132535 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-8514 (Electronic) Linking ISSN: 15357163 NLM ISO Abbreviation: Mol Cancer Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Philadelphia, PA : American Association for Cancer Research, Inc., c2001- |
| مواضيع طبية MeSH: | Immunoconjugates/*therapeutic use, Animals ; Female ; HEK293 Cells ; Humans ; Immunoconjugates/pharmacology ; Mice ; Mice, Nude ; Tissue Distribution ; Xenograft Model Antitumor Assays |
| مستخلص: | 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 89 Zr-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). (©2020 American Association for Cancer Research.) |
| سلسلة جزيئية: | ClinicalTrials.gov NCT03449030 |
| المشرفين على المادة: | 0 (Immunoconjugates) |
| تواريخ الأحداث: | Date Created: 20200814 Date Completed: 20210806 Latest Revision: 20210806 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1158/1535-7163.MCT-19-1102 |
| PMID: | 32788205 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1538-8514 |
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| DOI: | 10.1158/1535-7163.MCT-19-1102 |