Targeted therapy of breast cancer using PLAC1 antibody-drug conjugate

Abstract

Abstract Background Placenta-specific 1 (PLAC1) is one of the oncoplacental genes ectopically expressed in a wide variety of cancers. Antibody drug conjugates (ADC) have the potential to substantially improve efficacy and reduce toxicity of treatment compared with cytotoxic small-molecule drugs and are recently being employed for treatment of cancers. Here, efficacy of a SN38-conjugated monoclonal anti-PLAC1 antibody was examined in breast cancer. Methods and Results Anti-human PLAC1 monoclonal antibodies were produced and characterized. SN38 was conjugated to an anti-PLAC1 antibody (clone: 2H12C12) and conjugation efficacy was evaluated by UV spectrophotometry. Post-conjugation reactivity was then tested using ELISA and flow cytometry. In vitro cytotoxicity profiling of 2H12C12-SN38 was examined on MDA-MB-231 breast cancer cells using a flourimetric assay. The effect of 2H12C12-SN38 on MDA-MB-231 tumor growth and angiogenesis ex vivo was tested by chorioallantoic membrane (CAM) assay followed by immunohistochemical analysis of tumor. Pharmacokinetics of 2H12C12-SN38 in mice was measured by successive venipuncture after ADC administration. Inhibitory effects of anti-PLAC1 ADC on tumor growth was assessed in nude mice xenograft model of human breast cancer. Anti-PLAC1 ADC exerted a substantial cytotoxicity on MDA-MB-231 cells starting from a concentration of about 33 nM. ADC also significantly decreased the growth of MDA-MB-231 tumors on CAM assay but did not show a significant effect on tumor angiogenesis. Pharmacokinetics of anti-PLAC1 ADC in mice showed an average half-life (t1/2) of about 80 hours. Treatment of nude mice with ADC resulted in a significant decrease in tumor size compared to isotype-matched antibody-SN38 conjugate, unconjugated anti-PLAC1 antibody or free SN38. Conclusion This is the first therapeutic application of anti-PLAC1 ADC in a xenograft model of human breast cancer. Our results reinforce on embryonic origin of cancers and shed light on the potential therapeutic benefits of targeting oncofetal antigens in human breast cancer.