Proton pump inhibitors interfere with the anti-tumor potency of RC48ADC

Antibody-drug conjugates (ADCs) are a promising modality for cancers, but the interaction between them and proton pump inhibitors (PPIs), the common adjuvant drugs for cancer treatment, has not been understood. Here, the interactions between PPIs and RC48ADC, a novel HER2-targeting ADC, were quantified in vitro. CCK-8 assay showed that RC48ADC displayed a significant inhibitory effect on the proliferation of SK-BR-3, NCI-N87 and SK-OV-3 cells with the IC50 values of 4.91 +/- 1.15 ng/mL, 14.54 +/- 0.85 ng/mL and 11.28 +/- 0.68 ng/mL respectively. PPIs alone had no significant anti-tumor effect in the dose range of 1.37-1000 ng/mL. When used together, PPIs inhibited the anti-tumor activity of RC48ADC in a dose-dependent manner. And 1000 ng/mL (similar to Cmax) PPIs significantly recovered RC48ADC-inhibited cell proliferation by (32.85 +/- 2.81) % (p < 0.05). However, cimetidine, a non-PPIs gastric acid secretion inhibitor, had no significant inhibitory effect on RC48ADC. Furthermore, omeprazole, rather than cimetidine, significantly reduced the activity of vacuolar H+-ATPase and Cathepsin B compared with the control cells. These results, if confirmed in vivo, indicate that PPIs are antagonists of RC48ADC, even all ADCs, appearing to be due to inhibition of vacuolar H+-ATPase activity. Moreover, cimetidine combined with ADCs instead of PPIs can prevent an adverse drug interaction.

Automated summary

The study found that PPIs antagonized the effect of RC48ADC, potentially through inhibition of vacuolar H+-ATPase activity, while cimetidine did not have this effect. Therefore, the combination of cimetidine with ADCs could be a choice to prevent adverse drug interactions.