Targeting Prostate Cancer Cells Using Anti-Sortilin and Anti-Syndecan-1 Antibody Drug Conjugates.

Prostate cancer tissue usually involves either well formed glands, poorly formed glands or a combination of the two morphologies, which can be correlated with metabolic differences and tumor heterogeneity. This is particularly important for metastatic castration-resistant prostate cancer, where the heterogeneity and metabolic changes drive cancer progression and treatment refractory properties. Sortilin and syndecan-1 expression accurately define the two different morphologies in prostate cancer tissue, are critical to the process of metabolic regulation, and exhibit mechanistic/functional interactions during prostate cancer progression. As trans-membrane proteins that recycle from endocytic compartments to the cell surface, sortilin and syndecan-1 are attractive targets for therapeutic intervention that address the two major forms of prostate cancer. In this study, we describe an antibody-drug conjugate (ADC) strategy that utilizes monoclonal antibodies which bind to specific extracellular domains of these integral membrane proteins to elicit anticancer activity in prostate cancer cell lines. Anti-sortilin (clone 11H8) and anti-syndecan-1 (clone 6D11) monoclonal antibodies demonstrated high specificity for epitopes on the extracellular, N-terminal domains of these respective proteins and were effectively internalized into prostate cancer cell endocytic compartments. Monomethyl aurastatin E (MMAE)-conjugated ADCs exhibited low nanomolar cytotoxicity in LNCaP and PC-3 prostate cancer cells. Mechanistically, 11H8-MMAE and 6D11-MMAE triggered cytotoxicity and morphological alterations in androgen-sensitive and androgen-insensitive cells. However, the uptake of fluorescent labelled 11H8 and 6D11 antibodies appeared to be high, whereas the killing capacity of the MMAE-conjugated antibodies was less impressive, suggesting the need for further ADC development. These promising proof-of-concept ADCs are designed to exploit molecular and metabolic vulnerabilities in prostate cancer and may have utility for overcoming treatment resistance by simultaneously targeting different forms of the cancer.