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Investigational Antibody-Drug Conjugate May Provide New Treatment Option for Pancreatic Cancer Patients

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Key Points

  • MLN0264 is an investigational antibody-drug conjugate targeting guanylyl cyclase C (GCC), which is expressed in subsets of pancreatic cancers.
  • The agent markedly inhibited the growth of five of seven different human pancreatic tumors transplanted into mice, and when combined with gemcitabine, caused greater tumor shrinkage than either drug alone.
  • Based on these preclinical data, a phase II study investigating the activity of the combination of MLN0264 and gemcitabine in patients with GCC-expressing pancreatic cancer is being planned.

Patients with pancreatic cancer may benefit from an investigational member of an emerging class of anticancer drugs called antibody-drug conjugates, according to preclinical results presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held October 19 to 23 in Boston (Abstract PR12/B194).

Antibody-drug conjugates are a new type of targeted anticancer therapy that uses an antibody to deliver an attached drug directly to cells displaying the antibody’s target on their surfaces. This precision reduces the side effects of the attached drug compared with conventional systemic administration. Currently, there are two U.S. Food and Drug Administration–approved antibody-drug conjugates used to treat particular cancers, brentuximab vedotin (Adcetris) and ado-trastuzumab emtansine (Kadcyla).

Drug Details

“Our investigational antibody-drug conjugate, MLN0264, is designed to selectively bring a highly potent cytotoxic payload to tumors that express guanyl cyclase C (GCC),” said Petter Veiby, PhD, Global Head of BioTherapeutics, Oncology Drug Development Unit at Takeda Pharmaceuticals International Co., in Boston. “Our findings in preclinical pancreatic tumor models support the testing of MLN0264 in combination with gemcitabine in patients with advanced pancreatic cancer.”

MLN0264 consists of the highly toxic agent monomethyl auristatin E (MMAE) attached to an antibody that recognizes GCC via a cleavable linker. When the antibody portion of the drug recognizes the protein GCC on tumor cells, the entire drug is taken up by the cells. Once inside the tumor cells, the linker that attaches MMAE to the antibody is severed, allowing the tumor cells to be exposed to the cytotoxic activity of MMAE.

Preclinical Study

According to Dr. Veiby, at least 50% of the pancreatic tumors he and his colleagues have examined express some level of GCC. They therefore investigated the activity of MLN0264 in preclinical models of pancreatic cancer that mimicked the various patterns of GCC expression observed in patient biopsies.

They found that MLN0264 markedly inhibited the growth of five of seven different human pancreatic tumors transplanted into mice.

Further analysis in two of the preclinical models, one in which MLN0264 had significantly inhibited tumor growth and one in which it had little effect, showed that a combination of MLN0264 and the traditional chemotherapy agent gemcitabine caused greater tumor shrinkage than either drug alone.

Based on their preclinical data, the researchers plan to investigate the activity of the combination of MLN0264 and gemcitabine in patients with GCC-expressing pancreatic cancer in a phase II study, which they hope will begin sometime in 2014. They are also evaluating the activity of MLN0264 in preclinical models of two other cancers known to frequently express GCC—metastatic colorectal cancer and gastric cancer.

Dr. Veiby is an employee of Takeda Pharmaceuticals International Co, which funded the study.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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