A monomethyl auristatin E-conjugated antibody to guanylyl cyclase C is cytotoxic to target-expressing cells in vitro and in vivo
| Autor: | Tim Wyant, Melissa Gallery, Daniel Bradley, Adnan O. Abu-Yousif, Mark Williamson, Jose Estevam, Qing Zhu, Ping Li, Johnny J. Yang, Mark Manfredi, Claudia Rabino, Huay-Keng Loke, Edward A. Greenfield, O. Petter Veiby, Julie Zhang, Brad Stringer, Hadi Danaee, Donna Cvet, Pamela Brauer |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Immunoconjugates Physiology Cancer Treatment Receptors Enterotoxin lcsh:Medicine Mice SCID Biochemistry Mice chemistry.chemical_compound Spectrum Analysis Techniques 0302 clinical medicine Immune Physiology Medicine and Health Sciences Cytotoxic T cell Intestinal Mucosa lcsh:Science Immune System Proteins Multidisciplinary biology Reverse Transcriptase Polymerase Chain Reaction Antibodies Monoclonal Guanylate cyclase 2C Flow Cytometry Oncology Monomethyl auristatin E Spectrophotometry 030220 oncology & carcinogenesis Monoclonal Female Cytophotometry Anatomy Antibody Colorectal Neoplasms Oligopeptides Research Article Colon medicine.drug_class Immunology Blotting Western Research and Analysis Methods Antibodies Monoclonal Humanized Monoclonal antibody Antibodies 03 medical and health sciences Antigen In vivo medicine Animals Humans Immunohistochemistry Techniques Colorectal Cancer lcsh:R Biology and Life Sciences Proteins Cancers and Neoplasms Xenograft Model Antitumor Assays Monoclonal Antibodies Gastrointestinal Tract Histochemistry and Cytochemistry Techniques HEK293 Cells 030104 developmental biology Metastatic Tumors chemistry Immunologic Techniques Cancer research biology.protein lcsh:Q Digestive System |
| Zdroj: | PLoS ONE, Vol 13, Iss 1, p e0191046 (2018) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Guanylyl cyclase C (GCC) is a cell-surface protein that is expressed by normal intestinal epithelial cells, more than 95% of metastatic colorectal cancers (mCRC), and the majority of gastric and pancreatic cancers. Due to strict apical localization, systemically delivered GCC-targeting agents should not reach GCC in normal intestinal tissue, while accessing antigen in tumor. We generated an investigational antibody-drug conjugate (TAK-264, formerly MLN0264) comprising a fully human anti-GCC monoclonal antibody conjugated to monomethyl auristatin E via a protease-cleavable peptide linker. TAK-264 specifically bound, was internalized by, and killed GCC-expressing cells in vitro in an antigen-density-dependent manner. In GCC-expressing xenograft models with similar GCC expression levels/patterns observed in human mCRC samples, TAK-264 induced cell death, leading to tumor regressions and long-term tumor growth inhibition. TAK-264 antitumor activity was generally antigen-density-dependent, although some GCC-expressing tumors were refractory to TAK-264-targeted high local concentrations of payload. These data support further evaluation of TAK-264 in the treatment of GCC-expressing tumors. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
| Nepřihlášeným uživatelům se plný text nezobrazuje | K zobrazení výsledku je třeba se přihlásit. |