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

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

doi:10.1371/journal.pone.0191046

Melissa Gallery, Edward Greenfield + Show 17 more

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https://doi.org/10.1371/journal.pone.0191046

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Abstract

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.

Highlights

Gastrointestinal cancers are among the most common cancers in the United States, with an estimated 291,150 new cases of digestive system cancers in 2015; notably, colon/rectum and pancreatic cancers are the third and fourth most common causes of cancer-related deaths, with an estimated 49,700 and 40,560 deaths, respectively, in 2015 [1]
Guanylyl cyclase C (GCC) is a cell-surface protein that is expressed by normal intestinal epithelial cells, more than 95% of metastatic colorectal cancers, and the majority of gastric and pancreatic cancers
GCC is an intestinal epithelial-selective gene, as demonstrated in a panel of human tissues that was assessed by quantitative reverse transcription polymerase chain reaction (RT-PCR) (Fig 1A)

Summary

Introduction

Gastrointestinal cancers are among the most common cancers in the United States, with an estimated 291,150 new cases of digestive system cancers in 2015; notably, colon/rectum and pancreatic cancers are the third and fourth most common causes of cancer-related deaths, with an estimated 49,700 and 40,560 deaths, respectively, in 2015 [1]. Prognosis is poor with many gastrointestinal malignancies; for example, approximately one fifth of patients with colorectal cancer (CRC) have distant metastases [2,3,4,5]. Current chemotherapeutic options for metastatic CRC (mCRC) include combination chemotherapies and molecularly targeted monoclonal antibody therapies [6]; treatment options are expanding, 5-year survival for patients with distant metastases is only approximately 10% [5,6,7]. The tissue-restricted expression and consistent association with CRC has been exploited for use of GCC as a diagnostic and prognosis marker for this disease [10, 14, 18,19,20]. Recent studies have suggested GCC expression is a marker of therapeutic response in mCRC [11]

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