Targeting Prostate Cancer Cells Using Anti-Sortilin and Anti-Syndecan-1 Antibody Drug Conjugates
Date
2025
Authors
Li, K.L.
Hickey, S.M.
Albrecht, H.
Logan, J.M.
Lazniewska, J.
Moore, C.R.
Brooks, R.D.
Johnson, I.R.D.
O'Leary, J.J.
Brooks, D.A.
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Advisors
Journal Title
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Journal article
Citation
International Journal of Molecular Sciences, 2025; 26(22):11145-1-11145-25
Statement of Responsibility
Ka Lok Li, Shane M. Hickey, Hugo Albrecht, Jessica M. Logan, Joanna Lazniewska, Courtney R. Moore, Robert D. Brooks, Ian R. D. Johnson, John J. O'Leary, Douglas A. Brooks
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Abstract
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.
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© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/ licenses/by/4.0/).