Abstract Background: Antibody-drug conjugates (ADCs), bispecific antibodies, and CAR-T cells offer tumor-selective cytotoxicity with reduced off-target toxicity. Their success depends on identifying cancer-specific surface antigens absent in normal tissues. The Oncotope Platform, developed by Cancer Antibodies Inc., enables high-throughput antigen discovery through rabbit immunization with cancer cell lines, filtration to remove cross-reactive antibodies, and protein microarray screening of 20,000 human proteins. This platform shortened discovery timelines and demonstrated selectivity by generating antibodies that killed breast cancer cells (Hs578T) while sparing matched normal cells (Hs578Bst). One lead antigen was SLC39A7 (ZIP7), a zinc transporter normally confined to the ER/Golgi but aberrantly expressed on the surface of malignant cells. In contrast to PSMA, which is expressed in salivary glands and kidneys and associated with significant toxicities in radioligand trials (e.g., 81% salivary, 25% renal), ZIP7 showed restricted expression in normal tissues, making it a promising target for safer therapeutics in breast and prostate cancer, including castration-resistant disease. Methods: ZIP7 was validated using in vitro and in situ approaches. Breast cancer cell lines were evaluated by flow cytometry for ZIP7 surface expression and by cytotoxicity assays for selective tumor killing. ZIP7 mRNA expression was assessed in 10 breast cancer cell lines representing Luminal A, HER2+, and TNBC subtypes. Immunofluorescence (IF) was performed on TNBC samples (n = 5; grades 2-3) and prostate cancer samples (n = 6; Gleason 3+4, 4+3, including CRPC). Each case included adjacent benign tissue as control. CyTOF imaging analyzed co-localization of ZIP7 with CD4+ and CD8+ T cells. IHC-DAB was used to evaluate ZIP7 expression in PSMA-negative (PC3) and PSMA-positive (LNCaP) xenografts and in normal kidney, spleen, and brain tissues. Results: In vitro, filtered antibodies killed ZIP7-expressing Hs578T cells while sparing Hs578Bst cells. ZIP7 was detected in 8/10 breast cancer cell lines, and ZIP7-specific antibodies bound selectively and induced cytotoxicity. Flow cytometry confirmed surface expression. In FFPE samples, IF showed ZIP7 staining in all TNBC tumors (5/5), absent in adjacent normal epithelium. In prostate cancer samples, ZIP7 expression was observed across all grades and CRPC, with enrichment at invasive margins and immune-infiltrated areas. CyTOF showed ZIP7+ cells in proximity to CD4+/CD8+ T cells. IHC-DAB confirmed ZIP7 in both PC3 and LNCaP xenografts. No ZIP7 expression was detected in normal kidney, spleen, or brain tissues. Conclusions: ZIP7 is a tumor-selective surface antigen with aberrant expression in breast and prostate cancers, including resistant subtypes. Its absence from essential normal tissues supports its safety as a therapeutic target. The Oncotope Platform enabled the rapid discovery and validation of ZIP7, demonstrating its power to uncover high-value, tumor-specific targets for antibody-based cancer therapies. Citation Format: J. S. Manavalan, A. Ahmad, D. Mor, J. Davis, R. Chakrabarti, A. Pollack, E. Davis. Slc39a7/zip7as a tumor-specific antigen enabling precision immunotherapy in breast and prostate cancers abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-04-27.
Manavalan et al. (Tue,) studied this question.