Placenta-specific1 (PLAC1) is a potential target for antibody-drug conjugate-based prostate cancer immunotherapy

Mohammad-Reza Nejadmoghaddam,Roya Ghods,Ramin Ghahremanzadeh,Mohammad Hossein Ghahremani,Rassoul Dinarvand,Jafar Mahmoudian,Ali Anissian,Morteza Mahmoudi,Amir-Hassan Zarnani,Maryam Abolhasani,Maryam Yousefi,Mahboobeh Nazari

doi:10.1038/s41598-017-13682-9

Abstract

Our recent findings strongly support the idea of PLAC1 being as a potential immunotherapeutic target in prostate cancer (PCa). Here, we have generated and evaluated an anti-placenta-specific1 (PLAC1)-based antibody drug conjugate (ADC) for targeted immunotherapy of PCa. Prostate cancer cells express considerable levels of PLAC1. The Anti-PLAC1 clone, 2H12C12, showed high reactivity with recombinant PLAC1 and selectivity recognized PLAC1 in prostate cancer cells but not in LS180 cells, the negative control. PLAC1 binding induced rapid internalization of the antibody within a few minutes which reached to about 50% after 15 min and almost completed within an hour. After SN38 conjugation to antibody, a drug-antibody ratio (DAR) of about 5.5 was achieved without apparent negative effect on antibody affinity to cell surface antigen. The ADC retained intrinsic antibody activity and showed enhanced and selective cytotoxicity with an IC50 of 62 nM which was about 15-fold lower compared to free drug. Anti-PLAC1-ADC induced apoptosis in human primary prostate cancer cells and prostate cell lines. No apparent cytotoxic effect was observed in in vivo animal safety experiments. Our newly developed anti-PLAC1-based ADCs might pave the way for a reliable, efficient, and novel immunotherapeutic modality for patients with PCa.

Highlights

Prostate cancer (PCa) is the second leading cause of cancer death in men[1]
We hypothesized that utilizing advantages of cancer cell specificity of anti-placenta-specific 1 (PLAC1) antibodies and cytotoxic activity of a chemically supertoxic agent could be considered an ideal approach for generation of an antibody drug conjugate (ADC) platform for targeted immunotherapy of prostate cancer (PCa)
To pursue potential application of anti-PLAC1 antibodies for cancer immunotherapy, we developed an anti-PLAC1-ADC and assessed its potential efficacy in three human prostate cancer cell lines, namely LNCaP, DU145, and PC3

Summary

Introduction

Prostate cancer (PCa) is the second leading cause of cancer death in men[1]. Based on limitations of currently available prostate cancer markers, there is a steadily growing interest for discovery of new biomarkers to accurately diagnosis and treat PCa. Reactivity of the monoclonal anti-PLAC1 antibody, 2H12C12, with native target protein was tested in the step by flow cytometry in prostate cancer cell lines. Cytotoxicity profiling of anti-PLAC1-ADC in human primary prostate cancer cells and cell lines.

Results

Conclusion