LRRC15 Is a Novel Mesenchymal Protein and Stromal Target for Antibody–Drug Conjugates

Abstract

Progress in understanding tumor stromal biology has been constrained in part because cancer-associated fibroblasts (CAF) are a heterogeneous population with limited cell-type-specific protein markers. Using RNA expression profiling, we identified the membrane protein leucine-rich repeat containing 15 (LRRC15) as highly expressed in multiple solid tumor indications with limited normal tissue expression. LRRC15 was expressed on stromal fibroblasts in many solid tumors (e.g., breast, head and neck, lung, pancreatic) as well as directly on a subset of cancer cells of mesenchymal origin (e.g., sarcoma, melanoma, glioblastoma). LRRC15 expression was induced by TGFβ on activated fibroblasts (αSMA) and on mesenchymal stem cells. These collective findings suggested LRRC15 as a novel CAF and mesenchymal marker with utility as a therapeutic target for the treatment of cancers with LRRC15-positive stromal desmoplasia or cancers of mesenchymal origin. ABBV-085 is a monomethyl auristatin E (MMAE)-containing antibody-drug conjugate (ADC) directed against LRRC15, and it demonstrated robust preclinical efficacy against LRRC15 stromal-positive/cancer-negative, and LRRC15 cancer-positive models as a monotherapy, or in combination with standard-of-care therapies. ABBV-085's unique mechanism of action relied upon the cell-permeable properties of MMAE to preferentially kill cancer cells over LRRC15-positive CAF while also increasing immune infiltrate (e.g., F4/80 macrophages) in the tumor microenvironment. In summary, these findings validate LRRC15 as a novel therapeutic target in multiple solid tumor indications and support the ongoing clinical development of the LRRC15-targeted ADC ABBV-085. These findings identify LRRC15 as a new marker of cancer-associated fibroblasts and cancers of mesenchymal origin and provide preclinical evidence for the efficacy of an antibody-drug conjugate targeting the tumor stroma. .

Genes associated with bowel metastases in ovarian cancer

“…Our study demonstrated that blocking LRRC15 expression may decrease both tumorigenicity and metastatic dissemination. This finding suggests that the LRRC15 protein may be a potential candidate as an antitumor target, a concept given further support by ongoing development of ABBV085 [41] an LRRC15-antibodytargeted drug conjugate.…”

Bioinformatics analysis of prognostic significance of COL10A1 in breast cancer

“…LRRC15 was found to be highly expressed on the cell surface of stromal fibroblasts in many solid tumors. Additionally, LRRC15 was considered as a new marker of cancer-associated fibroblasts and cancers of mesenchymal origin and might be applicated in antibody-drug conjugate targeting the tumor stroma [22].…”

Meflin-Positive Cancer-Associated Fibroblasts Inhibit Pancreatic Carcinogenesis

“…Thus, the biology of CAFs, including their origins, specific markers, functions, and clinical relevance, has gained increasing research interest in recent years (3)(4)(5)(6)(7)(8). Clinical trials of therapeutics that target CAFs are also emerging, with investigations on the underlying mechanisms (4,8,19,20).…”