Antibody-drug conjugates are a new type of targeted anticancer therapy, which use an antibody to deliver an attached drug directly to those cells that display 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 for the treatment of certain cancers.
"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, global head of BioTherapeutics, Oncology DDU at Takeda Pharmaceuticals International Co. in Boston, Mass. "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.
According to Veiby, at least 50 percent 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.