Abstract
Background: LRRC15 is a member of the LRR (leucine-rich repeat) superfamily present on tumor-associated fibroblasts (CAFs) and stromal cells. The expression of LRRC15 is upregulated by the pro-inflammatory cytokine TGFβ. ABBV-085 is a monomethyl auristatin E (MMAE)-containing antibody-drug conjugate (ADC) designed to target LRRC15, and which has shown significant anti-tumor activity in several tumor models. This is the first focused examination of LRRC15 expression and ABBV-085 activity in soft-tissue sarcomas (STS). Methods: We analyzed the LRRC15 expression profile by immunohistochemistry in 711 STS cases, covering a broad spectrum of STS histologies and sub-classifications. In vivo experiments were carried out by using LRRC15-positive and LRRC15-negative patient-derived xenograft (PDX) models of STS. Results: In contrast to patterns observed in epithelial tumors, LRRC15 was expressed not only by stromal cells but also by cancer cells in multiple subsets of STS with significant variations noted between histological subtypes. Overexpression of LRRC15 is positively correlated with grade and independently associated with adverse outcome. ABBV-085 has robust preclinical efficacy against LRRC15 positive STS patient-derived xenograft (PDX) models. Conclusion: We provide the first preclinical evidence that LRRC15 targeting with an antibody-drug conjugate is a promising strategy in LRRC15-positive STS. ABBV-085 is being evaluated in an ongoing clinical trial in STS and other malignancies.
Highlights
Soft-tissue sarcomas (STS) represent approximately 1% of cancers in adults and 15% in children, and are among the most devastating of human malignancies
In contrast to the patterns observed in epithelial tumors, LRRC15 was expressed by normal stromal cells and by cancer cells
We report here the first large study assessing LRRC15 expression in mesenchymal malignancies and its potential therapeutic application in this indication
Summary
Soft-tissue sarcomas (STS) represent approximately 1% of cancers in adults and 15% in children, and are among the most devastating of human malignancies. Cancers 2020, 12, 757 overall survival of patients is only 12–18 months This poor outcome is in part explained by the limited sensitivity of STS to cytotoxic drugs [1]. ABBV-085 is a monomethyl auristatin E (MMAE)-containing antibody-drug conjugate (ADC) designed to target LRRC15, and which has shown significant anti-tumor activity in several tumor models. This is the first focused examination of LRRC15 expression and ABBV-085 activity in soft-tissue sarcomas (STS). Results: In contrast to patterns observed in epithelial tumors, LRRC15 was expressed by stromal cells and by cancer cells in multiple subsets of STS with significant variations noted between histological subtypes. ABBV-085 has robust preclinical efficacy against LRRC15 positive STS patient-derived xenograft (PDX) models.
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