Therapeutic Targeting of Tumor Cells Rich in LGR Stem Cell Receptors
| Autor: | Stephen B. Howell, Tim Vorberg, Xiying Shang, Joji Watanabe, Clara Wong, Songman Yu, Arisa Watanabe, Songyu Tian, Wannan Chen, Dennis P. Gately, Maria Carmen Mulero |
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| Rok vydání: | 2021 |
| Předmět: |
Population
Biomedical Engineering Pharmaceutical Science Bioengineering Antineoplastic Agents Receptors Cell Surface 02 engineering and technology 01 natural sciences Sortase Cell Line Tumor medicine Animals Humans education Receptor Chromatography High Pressure Liquid Pharmacology education.field_of_study 010405 organic chemistry Chemistry Stem Cells Organic Chemistry LGR5 021001 nanoscience & nanotechnology medicine.disease Xenograft Model Antitumor Assays 0104 chemical sciences HEK293 Cells Cell culture Cancer research Electrophoresis Polyacrylamide Gel Stem cell 0210 nano-technology Ovarian cancer Biotechnology Binding domain Half-Life |
| Zdroj: | Bioconjugate chemistry. 32(2) |
| ISSN: | 1520-4812 |
| Popis: | LGR5 and LGR6 mark epithelial stem cells in many niches including the ovarian surface and fallopian tube epithelia from which ovarian cancer arises. Human ovarian cancers express these receptors at high levels and express one of their ligands, RSPO1, at levels uniquely higher than all other tumor types except mesothelioma. Reasoning that these receptors are also important to tumor stem cells, arming the LGR binding domain of RSPO1 with a cytotoxin may permit depletion of the tumor stem cells. The Fu1-Fu2 receptor binding domain of RSPO1 (R1FF), containing a sortase recognition sequence at the C-terminal end, was produced in bacteria and a single molecule of MMAE was attached to each R1FF through a val-cit-PAB linker using the sortase reaction, thus producing a homogeneous population of armed molecules. R1FF-MMAE demonstrated (1) selective LGR-dependent binding, uptake, and cytotoxicity; (2) low nM cytotoxicity to multiple types of human tumor cell lines in vitro; (3) favorable plasma pharmacokinetic properties when administered iv with an elimination half-life of 27.8 h; (4) favorable absorption from the peritoneal cavity; and (5) therapeutic activity in aggressive xenograft models of ovarian cancer in the absence of any weight loss or other adverse events. These results demonstrate that the Fu1-Fu2 domain of RSPO1 can be exploited to deliver a potent cytotoxin to tumor cells that express the LGR4-6 family of stem cell receptors. |
| Databáze: | OpenAIRE |
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