Prostatic Acid Phosphatase (PAP) Antibodies to Treat Castration-Resistant Prostate Cancer - Alexander Kirschenbaum et al.

Sep 22, 2026

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Prostate cancer (PCa) is the most common cancer and a leading cause of cancer death in American men. Most patients with metastatic disease respond initially to androgen deprivation therapy (ADT) but progress to castration-resistant prostate cancer (CRPC). Markers and drivers of metastatic CRPC (mCRPC) that persist under castration, are actionable surface targets, and are induced by hypoxia are needed for targeted therapy development. The study identifies prostatic acid phosphatase (PAP), especially its transmembrane form TMPAP, and evaluates a lead anti-TMPAP antibody clone 3D8 using antibody drug conjugates and xenograft testing.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages18

Reading Time45 min

AccessFree to download

Abstract

Background and clinical need

PAP/TMPAP as a therapeutic target

Antibody 3D8 and preclinical testing

Keywords

Article Prostatic Acid Phosphatase (PAP) Antibodies to Treat Castration-Resistant Prostate Cancer Alexander Kirschenbaum 1, Pamela Cheung 2, Shen Yao 2, J. Andrew Duty 3,4, Thomas Kraus 3, Thomas Moran 3 and Alice C. Levine 2, * Academic Editor: Shafiq Khan Received: 14 April 2026 Revised: 22 June 2026 Accepted: 3 July 2026 Published: 9 July 2026 Copyright: © 2026 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. 1 Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 2 Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 3 Laboratory of Therapeutic Antibody Development, Drug Discovery Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 4 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA * Correspondence: [alice.levine@mountsinai.org](alice.levine@mountsinai.org); Tel.: +1-212-241-3422 Abstract Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer death in American men. Most patients with metastatic disease respond initially to androgen deprivation therapy (ADT) but almost inevitably progress to castration-resistant prostate cancer (CRPC) . Identification of markers and drivers of Metastatic CRPC (mCRPC) that (a) represent a progenitor-type cancer cell population,(b) persist in castration-resistant disease,(c) are actionable targets expressed on the cell surface, and (d) are induced by hypoxia is required to facilitate the development of novel targeted therapies. We identified prostatic acid phosphatase (PAP), particularly the transmembrane form (TMPAP), as one such potential target. PAP is both a phosphatase and a 5′ ectonucleotidase that generates adenosine. PAP is a human tumor marker first described in 1936 and is still used as an important prognostic marker for advanced metastatic prostate cancer. Our group recently reported that the transmembrane form of the protein (TMPAP) is expressed in CRPC and can serve as a potential therapeutic target. We identified a lead human anti-TMPAP antibody clone 3D8 (3D8-Ab) . 3D8-ADCs (Antibody Drug Conjugates) and 3D8-Ab were tested for their ability to reduce tumor size/volume in a xenograft model. The human PAP-expressing PCa cell line VCaP, originally derived from a vertebral metastasis from a patient with CRPC, was inoculated subcutaneously into SCID mice. Treatment with either 3D8-Ab or 3D8-ADC significantly reduced tumor size and increased animal survival. These data indicate that targeting PAP with monoclonal antibodies either alone or conjugated to toxins has the potential to treat CRPC. Keywords: prostate cancer; transmembrane prostatic acid phosphatase; progenitor/stem cell; metastatic; castration-resistant; hypoxia; tumor microenvironment; 5′ ectonucleotidase; adenosine; adenosine receptors 1. Introduction Prostate cancer (PCa) is the second most common cancer among men in the United States and the second leading cause of cancer-related death in men, with an estimated 35,000 deaths annually in the U.S. [1] . For localized, clinically significant PCa, there are many treatment options, including focal therapy, surgery, and radiotherapy, with five-year survival approaching 100% . However, patients with locally advanced, high-grade PCa, treated with surgery or radiotherapy in conjunction with androgen deprivation therapy (ADT), have a high rate of progression leading to increased cancer-specific mortality. Patients with metastatic PCa, either hormone-naive or castration-resistant, have the poorest prognosis, and new therapeutic approaches are needed [2,3] . PAP is a protein phosphatase and 5′ ectonucleotidase expressed in normal and cancerous prostate epithelial cells that has served as

FAQs

Why is castration-resistant prostate cancer (CRPC) difficult to treat?

Most metastatic PCa initially responds to androgen deprivation therapy (ADT), but the disease almost inevitably progresses to CRPC. This progression drives a need for new targeted therapies.

What role does prostatic acid phosphatase (PAP), especially TMPAP, play in CRPC?

PAP is a phosphatase and 5′ ectonucleotidase that generates adenosine. The study highlights TMPAP as a potential surface-associated target expressed in CRPC and linked to mechanisms that support tumor progression.

How were anti-TMPAP antibody 3D8 and its ADC evaluated?

A lead anti-TMPAP antibody clone 3D8 (3D8-Ab) and 3D8-ADCs were tested in a xenograft model. The PAP-expressing VCaP cell line was inoculated into SCID mice, and treatment reduced tumor size and increased animal survival.

Sep 22, 2026

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