Abstract 4781: Generation and in vivo characterization of a novel antibody targeting Prostatic Acid Phosphatase (ACP-3)

Prostate cancer is the second deadliest tumor in men globally, despite the advent of novel drugs. Therapeutic modalities targeting Prostate Specific Membrane Antigen (PSMA) have provided benefit to patients but suffer from on-target off-tumor liabilities responsible for the side effects observed in clinical practice. These liabilities are a result of the expression of PSMA in healthy tissues, such as salivary glands, lacrimal glands, intestine, and kidneys. Innovative targeting ligands against better prostate cancer targets are therefore needed. Here, we present the generation and characterization of a first-in-class fully human antibody targeting ACP-3, a tyrosine phosphatase produced by prostate epithelial cells. Compared to PSMA, ACP-3 is expressed at significantly higher levels in the majority of prostate cancer lesions (both primary and metastatic), while being nearly undetectable in most healthy organs, including salivary glands, intestine and kidneys. A novel anti-ACP3 antibody was isolated from a phage display synthetic library containing 3 billion human single chain variable fragment clones. The antibody was thoroughly characterized, and its binding properties for the cognate target were studied in vitro using ELISA, flow cytometry and immunofluorescence on human prostate cancer specimens. Two orthogonal in vivo biodistribution studies were conducted in mice bearing HT1080 tumors stably transfected with human ACP-3. The first method relied on mass spectrometry to quantify the uptake antibody in tumors and healthy organs. The second method relied on the use of the immunofluorescence imaging to evaluate the microscopic distribution of the anti-ACP-3 antibody in tumors and healthy organs. The analyses were performed 24 hours post intravenous injection of the antibody. The results confirmed that the novel anti-ACP-3 antibody can selectively bind to its target in vitro and can preferentially localize to the tumor when injected intravaneously in tumor-bearing mice. In conclusion, given the exceptional binding selectivity and tumor-targeting performance, this novel anti-ACP-3 antibody promises to be an attractive scaffold for the generation of new best-in-class tumor targeted pharmaceuticals for the treatment of prostate cancer. Citation Format: Claudia Comacchio, Stefanie Pfister, Domenico Ravazza, Samuele Cazzamalli, Ettore Gilardoni, Emanuele Puca, Tobias Weiss, Michael Weller, Dario Neri, Roberto De Luca. Generation and in vivo characterization of a novel antibody targeting Prostatic Acid Phosphatase (ACP-3) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4781.