Prostate cancer: development of PSMA-directed antibody-based molecules intended for immunotherapy

G. Das, Z. Nováková and C. Bařinka

Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Prumyslova 595, 252 50 Vestec, Czech Republic

Prostate cancer stands for very frequent death-causing malignancy in man population especially in countries with high standard of living. High mortality in progressed stages of disease triggers development of new reagents and medical treatments that aim to target prostate tumor and particularly tumor-derived metastases with high efficiency and specificity. Prostate-specific membrane antigen (PSMA) represents prominent biomarker of prostatic tumors since the level of its expression is highly correlated with progression of prostate cancer. Antibody-based molecules directed to PSMA have high potential to specifically target cancer cells with minor toxicity in non-target tissues.

Previously we developed and characterized PSMA-specific antibody, named 5D3, that reveals high specificity and affinity to native PSMA. Moreover, we proved suitability of 5D3 as well as its fragments for in vivo application using mouse model of xenografted prostate cancer. Here we show the strategy for protein engineering of bispecific molecules based on 5D3 that would engage host immune cells in the site of cancer. Bispecific molecules are intended to trigger specific anti-tumor activity of host immune system in close proximity to tumor cells resulting in their elimination. Accordingly, our pilot in vitro study shows that 5D3 fragment fused to anti-CD3 fragment has potential to trigger cell death in cancer cells via activity of associated T cells. Moreover, 5D3 fragment linked to cyclic peptide 33 is capable of enhancing production of reactive oxygen species by activated monocytes when localized in close proximity to PSMA antigen. Detailed characterization as well as testing of 5D3-derived molecules under in vivo conditions is currently on the run.