Open AccessA monomethyl auristatin E-conjugated antibody to guanylyl cyclase C is cytotoxic to target-expressing cells in vitro and in vivo
Author(s) -
Melissa Gallery,
Julie Zhang,
Daniel P. Bradley,
Pamela P. Brauer,
Donna Cvet,
Jose Estevam,
Hadi Danaee,
Edward Greenfield,
Ping Li,
Mark Manfredi,
Huay-Keng Loke,
Claudia Rabino,
Brad Stringer,
Mark J. Williamson,
Tim Wyant,
Johnny Yang,
Qing Zhu,
Adnan O. Abu-Yousif,
O. Petter Veiby
Publication year - 2018
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0191046
Subject(s) - cytotoxic t cell , cancer research , in vivo , antibody drug conjugate , in vitro , antigen , monoclonal antibody , antibody , chemistry , biology , microbiology and biotechnology , immunology , biochemistry
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.