Targeting prostate cancer with site-specific antibody-drug conjugates enabled by tandemly fused ADP-ribosyl cyclases - 20/07/25

Doi : 10.1016/j.biopha.2025.118274

Lei Zhang ^a,^{^{1
These authors contributed equally to this work.}}, Mashael F. Aldossari ^a,^b,^{^{1
These authors contributed equally to this work.}}, Arshad J. Ansari ^a,^{^{1
These authors contributed equally to this work.}}, Guoyun Kao ^a, Sunny H. Kim ^a, Thuc Oanh Hoang ^a, Kaiyu Shen ^a, Zeyu Zhang ^a, Srinivasarao Singireddi ^a, Zekun Li ^a, Yuanteng Zhao ^a, Po-Wen Yu ^a, Fariborz Nasertorabi ^c, Benjamin B. Katz ^d, Ling Li ^e, Yong Zhang ^a,^f,^g,^h,^⁎

^a Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA

^b Department of Pharmaceutics, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia

^c Departments of Biological Sciences and Chemistry, Bridge Institute, Michelson Center for Convergent Bioscience, USC Structure Biology Center, University of Southern California, Los Angeles, CA 90089, USA

^d Department of Chemistry, University of California, Irvine, Irvine, CA 92697, USA

^e Department of Hematological Malignancies Translational Science, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA

^f Department of Chemistry, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90089, USA

^g Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA

^h Research Center for Liver Diseases, University of Southern California, Los Angeles, CA 90089, USA

^⁎ Corresponding author at: Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA. Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California Los Angeles CA 90089 USA

Abstract

Antibody-drug conjugates (ADCs) bring superior efficacy and safety profiles to the clinic by harnessing the power of biologics and chemotherapy. Despite numerous ADCs at different preclinical and clinical stages, homogeneous ADC with increased numbers of payloads conjugated at specific positions are still desired for enhanced pharmacological properties. To generate site-specifically conjugated ADCs with greater drug-to-antibody ratios (DARs), monoclonal antibodies targeting prostate-specific membrane antigens (PSMA) were genetically fused with tandem CD38 enzymes, a member of the ADP-ribosyl cyclase family. The resulting antibody-CD38 fusions coupled with its dinucleotide substrate-derived drug linker facilitate generation of A DP- r ibosyl c yclase-enable ADCs (ARC-ADCs) carrying 2, 4, 6, and 8 tubulin inhibitors. In vitro and in vivo studies indicated highly potent and selective cytotoxicity against human PSMA-expressing prostate cancer cells for the anti-PSMA ARC-ADC with a DAR of 6. This proof-of-concept study demonstrates feasibility of producing site-specific ARC-ADCs with increased DARs by tandemly fused CD38 and generates candidate ADCs for targeting prostate tumors.

Le texte complet de cet article est disponible en PDF.

Graphical Abstract

Le texte complet de cet article est disponible en PDF.

Highlights

•	Synthesis of ADCs with dinucleotide linkers by tandemly fused CD38 enzymes.
•	A new approach for generating site-specific ADCs with greater DARs.
•	Novel anti-PSMA ADCs targeting prostate cancer cells.
•	An ADC with a defined DAR of 6 and highly potent anti-tumor activity.

Le texte complet de cet article est disponible en PDF.

Keywords : Antibody-drug conjugate, Drug delivery, Targeted therapy, Prostate cancer, ADP-ribosyl cyclase

Plan

Introduction

Materials and methods

Materials

Chemical synthesis of linker and drug-linker conjugate

Molecular cloning of expression vectors

Protein expression and purification

Thermal shift assays

Gel filtration chromatography

Catalytic activity of CD38 extracellular domain and anti-PSMA IgG-CD38 fusions

Binding to recombinant human PSMA by ELISA

Synthesis of anti-PSMA ARC-ADCs and surrogates

Mass spectrometry of anti-PSMA IgG-CD38 fusions and ARC-ADCs

Flow cytometry

In vitro cytotoxicity of anti-PSMA ARC-ADCs

Pharmacokinetics of anti-PSMA ARC-ADC surrogates in mice

In vivo efficacy of anti-PSMA ARC-ADCs

ALT activities and creatinine concentrations in plasma

CRediT authorship contribution statement

Export

Vol 189

Article 118274- août 2025 Retour au numéro

Article précédent

Development of PDGF-BB-derived biomaterial: An ‘artificial’ concatemeric protein for regenerative applications
Milena Deptuła, Joanna Żebrowska, Agata Tymińska, Katarzyna Czerwiec, Aneta Skoniecka, Małgorzata Zawrzykraj, Przemysław Karpowicz, Paweł Wityk, Piotr Sass, Paweł Sosnowski, Jacek Zieliński, Leszek Kalinowski, Paweł Sachadyn, Sylwia Rodziewicz-Motowidło, Piotr M. Skowron, Michał Pikuła

| Article suivant

Cilostazol attenuates vascular inflammation via the regulation of TICAM1/IRF3 signaling pathway
Hui-Wen Chiu, Chun-Che Shih, Hung-Jin Huang, Tzu-Hsuan Huang, Li-Chin Sung

Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.

Déjà abonné à cette revue ?

connectez-vous ou créez un compte

Targeting prostate cancer with site-specific antibody-drug conjugates enabled by tandemly fused ADP-ribosyl cyclases - 20/07/25

Abstract

Graphical Abstract

Highlights

Plan

Export citations

Fichier

Contenu

Accès rapides

Mon compte

Aide & support

Plateformes Elsevier Masson

Déclaration CNIL