Discovery of ZL-6201, a novel LRRC15-targeting antibody drug conjugate (ADC) for the treatment of sarcomas and epithelial solid tumors

Leucine-rich repeat-containing protein 15 (LRRC15) is a transmembrane protein involved in cell-cell and cell-extracellular matrix interactions. It is overexpressed in tumors of mesenchymal origin which include sarcomas, glioblastoma and melanoma, where its expression has been implicated in promoting metastasis. Additionally, LRRC15 is upregulated in cancer-associated fibroblasts (CAFs) that are found in the tumor microenvironment (TME) of multiple epithelial tumors. Its predominant expression in tumors and CAFs, coupled with minimal or absent expression in normal cells, makes LRRC15 a selective and potentially effective therapeutic target for antibody-drug conjugate (ADC) development. ZL-6201 is an innovative ADC targeting LRRC15, built on the tumor microenvironment-activable linker-payload (TMALIN ® ) platform. It comprises a humanized anti-LRRC15 antibody, a hydrophilic protease-cleavable linker, and a novel camptothecin-derived topoisomerase I inhibitor payload C24. Site-specific conjugation yields an average drug-to-antibody ratio (DAR) of 8. ZL-6201 binds human and cynomolgus monkey LRRC15 with high affinity and specificity. In vitro, cell-surface binding and target-dependent internalization selectively occurred in tumor cells expressing LRRC15. This resulted in C24 payload release, the induction of DNA damage response, cell cycle arrest, and ultimately cytotoxicity to tumor cells. The internalization of ZL-6201 in LRRC15-expressing human tumor cells and CAFs, followed by payload release and diffusion, mediated cytotoxicity against LRRC15-negative tumor cells in co-culture via the bystander effect. In vivo studies demonstrated efficacy of ZL-6201 in human patient-derived xenograft (PDX) sarcoma models expressing endogenous LRRC15. Additionally, CAF-mediated payload release and the resultant efficacy were evaluated in two model systems: (1) cell-derived xenograft (CDX) models with low or no endogenous LRRC15 expression in tumor cells but high LRRC15 expression in mouse-derived CAFs using a mouse-reactive ZL-6201 surrogate, and (2) syngeneic tumor models with human LRRC15 knock-in CAFs using ZL-6201. Both ZL-6201 and the surrogate were well tolerated and demonstrated dose-dependent anti-tumor activity. Finally, ZL-6201 showed acceptable toxicokinetic and safety profiles in non-human primates (NHP). Collectively, these data support advancing ZL-6201 into clinical development as a therapeutic candidate for sarcomas and epithelial solid tumors characterized by LRRC15 expression within the tumor microenvironment.