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

Ka Lok Li1, Shane M Hickey1, Hugo Albrecht1

  • 1Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia.

International Journal of Molecular Sciences
|November 27, 2025
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Summary
This summary is machine-generated.

This study explores antibody-drug conjugates (ADCs) targeting sortilin and syndecan-1 to treat prostate cancer. While ADCs showed promise in targeting cancer cells, further development is needed to improve their killing capacity.

Keywords:
advanced cancerantibody drug conjugatesmonoclonal antibodiesprostate cancertherapeutics

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Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Development

Background:

  • Prostate cancer exhibits heterogeneity, with distinct morphologies linked to metabolic differences and treatment resistance.
  • Metastatic castration-resistant prostate cancer (mCRPC) is driven by heterogeneity and metabolic changes, leading to treatment refractory properties.
  • Sortilin and syndecan-1 expression correlate with prostate cancer morphologies and are involved in metabolic regulation and cancer progression.

Purpose of the Study:

  • To develop and evaluate an antibody-drug conjugate (ADC) strategy targeting sortilin and syndecan-1 for prostate cancer therapy.
  • To assess the specificity, internalization, and anticancer activity of anti-sortilin and anti-syndecan-1 ADCs.
  • To investigate the potential of these ADCs in overcoming treatment resistance in prostate cancer.

Main Methods:

  • Development of monoclonal antibodies (mAbs) against extracellular domains of sortilin (11H8) and syndecan-1 (6D11).
  • Conjugation of mAbs to monomethyl aurastatin E (MMAE) to create ADCs (11H8-MMAE, 6D11-MMAE).
  • Assessment of ADC specificity, internalization, cytotoxicity, and morphological effects in prostate cancer cell lines (LNCaP, PC-3).

Main Results:

  • Anti-sortilin (11H8) and anti-syndecan-1 (6D11) mAbs showed high specificity and were internalized into prostate cancer cells.
  • MMAE-conjugated ADCs demonstrated low nanomolar cytotoxicity in both androgen-sensitive and androgen-insensitive prostate cancer cells.
  • While antibody uptake was high, the cytotoxic efficacy of the MMAE-conjugated ADCs was less impressive, indicating a need for further optimization.

Conclusions:

  • Proof-of-concept ADCs targeting sortilin and syndecan-1 show potential for treating prostate cancer by exploiting molecular and metabolic vulnerabilities.
  • These ADCs may offer a strategy to overcome treatment resistance by simultaneously targeting different prostate cancer forms.
  • Further ADC development is warranted to enhance the killing capacity and therapeutic utility against prostate cancer.