Details

Autor(en) / Beteiligte

• Gallery, Melissa
• Zhang, Julie
• Bradley, Daniel P
• Brauer, Pamela
• Cvet, Donna
• Estevam, Jose
• Danaee, Hadi
• Greenfield, Edward
• Li, Ping
• Manfredi, Mark
• Loke, Huay-Keng
• Rabino, Claudia
• Stringer, Brad
• Williamson, Mark
• Wyant, Tim
• Yang, Johnny
• Zhu, Qing
• Abu-Yousif, Adnan
• Veiby, O Petter
• Shiku, Hiroshi

Titel

A monomethyl auristatin E-conjugated antibody to guanylyl cyclase C is cytotoxic to target-expressing cells in vitro and in vivo

Ist Teil von

• PloS one, 2018-01, Vol.13 (1), p.e0191046-e0191046

Ort / Verlag

United States: Public Library of Science

Erscheinungsjahr

2018

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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.