Antibody–Drug Conjugate May Inhibit Pancreatic Cancer

Patients with pancreatic cancer may benefit from the experimental antibody–drug conjugate (ADC) MLN0264, which markedly inhibited the growth of pancreatic tumors in preclinical studies, researchers announced at the 2013 International Conference on Molecular Targets and Cancer Therapeutics held in Boston, MA, October 19–23. The conference was hosted by the American Association for Cancer Research, the National Cancer Institute, and the European Organisation for Research and Treatment of Cancer.

Under development by Takeda Pharmaceuticals International, intravenously administered MLN0264 uses a protease-cleavable linker to join the highly toxic agent monomethyl auristatin E (MMAE) with a fully human monoclonal antibody that recognizes guanylyl cyclase C (GCC). The ADC selectively binds to GCC-expressing tumor cells, which internalize the drug. Once inside the cells, the linker that attaches MMAE to the antibody is severed and MMAE disrupts the formation of microtubules, inhibiting cell division and tumor growth.

Takeda licensed MMAE and the linker technology from Seattle Genetics of Bothell, WA, which uses the same components in its lymphoma drug Adcetris (brentuximab vedotin).

Petter Veiby, PhD, global head of BioTherapeutics, Oncology Drug Discovery Unit, at Takeda in Boston, MA, explained that earlier analyses showed GCC expression in about 95% of primary and metastatic colorectal tumors and about 75% of gastric tumors, two targets of MLN0264, for which the drug is already in clinical trials.

He and his research team decided to investigate whether pancreatic tumors also expressed the transmembrane cell surface receptor. They screened 218 primary and metastatic pancreatic tumor samples from patients and found that 137 expressed some level of GCC.

Next they examined the activity of two different doses of MLN0264 (7.5 mg/kg and 3.75 mg/kg) compared with the vehicle, MMAE, and a non–GCC-targeting ADC alone in seven mouse xenograft models of human pancreatic cancer with various levels of GCC expression. After the mice had received three treatments over 21 days, tumor growth inhibition ranged from 24% to 79% in the animals that received MLN0264, relative to the control animals, with the higher dose causing greater tumor inhibition than the lower dose, Veiby said.

However, in reference to MLN0264′s cell-killing ability, he noted that “we do not know what level of GCC in the tumors is required for the drug to be active.”

Further work in two of the xenografts—one in which MLN0264 significantly inhibited tumor growth and one in which it had a limited effect—showed that combining MLN0264 with the chemotherapy drug gemcitabine caused greater tumor shrinkage than using either drug alone. Veiby said this suggests that even though one of the models “was not sensitive to MLN0264 by itself, there is delivery of the payload to the tumor,” which seemed to enhance gemcitabine's effectiveness.

Based on this data, Veiby said that researchers hope to launch a clinical trial of the MLN0264–gemcitabine combination in patients with GCC-expressing pancreatic cancer next year.

A phase 1 dose-escalation study of MLN0264 alone is currently under way in patients with advanced gastrointestinal malignancies whose tumors express GCC, Veiby said. To date, 15 patients have enrolled in the trial, he said, including two with pancreatic cancer.