Abstract 1759: Targeting LRRC15 with an aptamer-drug conjugate achieves complete tumor growth inhibition

Abstract Antibody-drug conjugates (ADCs) have demonstrated the clinical potential of targeted payload delivery for cancer therapy. However, their large molecular size can limit tumor penetration, leaving regions of the tumor insufficiently exposed to the cytotoxic payload. To address this limitation, GRX2672 has been developed as a novel aptamer-drug conjugate (ApDC) designed to target LRRC15-expressing tumors while maintaining a small molecular size to enable deep tumor penetration. LRRC15 (leucine-rich repeat-containing protein 15) is a transmembrane member of the LRR superfamily involved in cell-cell and cell-matrix interactions. It is highly expressed in mesenchymal-derived tumors such as sarcoma, glioblastoma, and melanoma, making it an attractive target for therapeutic intervention. Aptamers are short, structured oligonucleotides that bind their targets with high affinity and specificity. Compared with monoclonal antibodies, their compact size enables superior tissue and tumor penetration. Moreover, aptamers can be engineered to neutralize oncogenic targets, deliver cytotoxic payloads, or achieve both simultaneously. Incorporating a proprietary half-life-extension moiety preserves the aptamer’s small size and tumor-penetrating capability while markedly improving its pharmacokinetic properties. Here, we describe an LRRC15-targeting aptamer with high affinity and selectivity that has been conjugated to 2DAR of a novel topoisomerase I inhibitor (PBX-7016) at the 5′ end and a half-life-extending fatty acid at the 3′ end. The resulting ApDC, GRX2672, selectively kills LRRC15-positive cells in vitro and achieves complete tumor growth inhibition in vivo without observed toxicity. These findings support the potential of LRRC15-targeted ApDCs as an emerging therapeutic strategy to improve outcomes for patients with LRRC15-positive tumors. Citation Format: Kristin Thompson, Aaron Ball, Jin Yuan, Yuxun Wang, Doo Young Jung, Shuhao Zhu. Targeting LRRC15 with an aptamer-drug conjugate achieves complete tumor growth inhibition 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 1759.