Abstract 445: Evaluation of HERV-K as an unusual cancer therapeutic target.

Abstract Human endogenous retroviruses (HERVs) are abundant genomic elements, transcriptionally repressed under normal physiological conditions. However, epigenetic alterations during disease reactivate HERV expression. HERV-K, specifically, has been identified as prevalent in numerous tumor types, including prostate, lung, breast, colon, and ovarian cancers and its presence correlates with tumor progression and protumoral signalling. In addition, HERV-K’s immunosuppressive role in the placenta, where it is usually expressed, points to a potential similar function within the tumor microenvironment, making it an attractive therapeutic target. We have comprehensively evaluated HERV-K as a potential target for T-cell Engagers (TCEs) and Antibody-Drug Conjugates (ADCs). This evaluation has been limited by the availability of tool antibodies. Employing flow cytometry and immunohistochemistry (IHC), HERV-K expression on the tumor cell surface was consistently low and unstable, often lost upon enzymatic cell detachment, indicating susceptibility to proteolytic cleavage. Receptor quantification on HERV-K+ tumor cell lines varied from 0-25,000 receptors per cell. IHC results confirmed low membranous staining across various tumor types, with a significant proportion of the protein detected in the cytoplasm, and thus, not available for antibody engagement. In vitro functional evaluation was performed by generating HERV-K tool TCEs and ADCs. While HERV-K TCEs demonstrated moderate and specific tumor cytotoxicity, HERV-K tool ADCs did not elicit HERV-K-dependent cytotoxic effects. In conclusion, while HERV-K presents an intriguing opportunity due to its tumor-selective expression, its inconsistent and labile surface presentation poses considerable challenges. Our findings suggest that HERV-K may be a viable target for TCE-based therapies, but less so for ADCs, primarily due to insufficient receptor density. Future efforts necessitate the development of high-quality specific antibodies to fully harness HERV-K’s therapeutic potential in cancer. Note: Human biological samples were sourced ethically, and their research use was in accord with the terms of the informed consents. IHC experiments were done by DLS. Citation Format: Monica Gordon, James H. Torpey, Andy D. Martin, Benjamin R. Miller, Marica Speranza, Kenneth W. Hance. Evaluation of HERV-K as an unusual cancer therapeutic target abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 445.