Abstract 4266: Discovery and characterization of a novel LRRC15-targeting antibody drug conjugate (ADC) for the treatment of solid tumors

Abstract Leucine-rich repeat-containing protein 15 (LRRC15) is a type I transmembrane protein involved in cell-cell and cell-extracellular matrix (ECM) interactions. It is overexpressed in various mesenchymal tumors such as sarcoma, glioblastoma and melanoma, where it promotes tumor metastasis. Additionally, LRRC15 is upregulated in cancer-associated fibroblasts (CAFs) across various cancer types, contributing to immune-excluded and immune-suppressive tumor microenvironment (TME). This makes LRRC15 an appealing target for cancer therapy. ZL-6201 is an innovative antibody-drug conjugate (ADC) targeting LRRC15, developed using the TME-activable linker-payload (TMALIN®) platform. This ADC comprises a humanized anti-LRRC15 antibody, a protease-cleavable linker, and a novel camptothecin derivative payload. It achieves a high drug-to-antibody ratio (DAR 8) with homogeneously conjugated, hydrophilic linker-payload combinations. ZL-6201 demonstrated strong and specific binding to human and cynomolgus LRRC15 without cross-reactivity to other LRRC family members. Its high affinity and specificity for LRRC15 on the cell surface led to target-mediated internalization and subsequent cytotoxicity in tumor cells upon payload release. Additionally, it exhibited potent bystander killing of LRRC15 negative tumor cells in an in vitro co-culture system. In in vivo efficacy studies, ZL-6201 was well-tolerated and effectively suppressed the growth of established human tumors in a dose-dependent manner in both tumor cell line-derived (CDX) and sarcoma patient sample-derived xenograft (PDX) models. In a human chondrosarcoma SA4109 PDX model, a significantly higher concentration of payload and ADC were detected in the tumors compared to mouse serum, indicating targeted delivery of the ADC. Collectively, these findings support advancing ZL-6201 into IND-enabling studies as a potential treatment for patients with sarcoma and other LRRC15-positive solid tumors. Citation Format: Shanshan Yan, Bing Wan, Donghui Li, Yue Ge, Wilson Peng, Jiaqing Yi, Ziruo Wen, Xinchuan Dai, Leo Xu, Lina Wang, Qiuping Ye, Peter Huang, Linda N. Liu. Discovery and characterization of a novel LRRC15-targeting antibody drug conjugate (ADC) for the treatment of solid tumors [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 4266.