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Antibody-drug conjugate demonstrated activity against guanylyl cyclase C in pancreatic cancer
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The antibody-drug conjugate MLN0264 demonstrated antitumor activity in pancreatic cancer xenograft models, according to study results presented at the International Conference on Molecular Targets and Cancer Therapeutics.
MLN0264 (Takeda), which targets the expression of guanylyl cyclase C (GCC) in tumors, is an antibody-drug conjugate that contains monomethyl auristatin.
“We have demonstrated through our preclinical work that GCC-targeting agents are not able to penetrate the intestinal wall and reach the site where GCC is normally found,” Petter Veiby, PhD, global head of BioTherapeutics, Oncology DDU at Takeda Pharmaceuticals International, said during a press conference. “Upon malignant transformation in colon cancer and other gastrointestinal malignancies, we see that the target continues to be expressed and, therefore, MLN0264 specially targets GCC on the tumors and not GCC on the normal cells.”
Veiby and colleagues screened for GCC expression in 218 metastatic pancreatic cancer tumor samples. Of them, 137 expressed GCC, and 58 of the samples demonstrated a combined cytoplasmic and apical H-score of at least 100.
In further analysis, five of seven primary human tumor xenograft models demonstrated tumor growth inhibition ranging from 24% (P=.17) to 79% (P<.001) by day 21 of treatment with MLN0264. Models treated with a 7.5 mg/kg dose demonstrated more significant results compared with those dosed with 3.75 mg/kg.
The treatment demonstrated low overall toxicity, with continued tumor growth inhibition after dosing ended, Veiby said.
Researchers then assessed a combination treatment with MLN0264 plus gemcitabine (Gemzar, Eli Lilly). Tumor growth inhibition reached 84% to 88% with the combination treatment.
“When we put these two together we found a dramatic increase in antitumor activity,” Veiby said. “This suggests that even though the tumor may not be sensitive to MLN0264 by itself, there is delivery of these payloads to the tumor leading to enhanced antitumor activity when we combine this with gemcitabine.”
Based on these data, researchers have designed a phase 2 trial to investigate MLN0264 plus gemcitabine in patients with pancreatic cancer who express GCC.
For more information:
Veiby P. Abstract #PR12/B194. Presented at: International Conference on Molecular Targets and Cancer Therapeutics; Oct. 19-23, 2013; Boston.
Disclosure: Researchers report employment with Takeda Pharmaceuticals International Co.