LRRC15 Targeting in Soft-Tissue Sarcomas: Biological and Clinical Implications

Area of Science:

• Oncology
• Cancer Biology
• Pharmacology

Background:

• LRRC15, a leucine-rich repeat superfamily member, is found on tumor-associated fibroblasts and stromal cells, with expression upregulated by TGFβ.
• ABBV-085 is an antibody-drug conjugate targeting LRRC15, demonstrating anti-tumor activity in preclinical models.
• This study is the first to investigate LRRC15 expression and ABBV-085 activity specifically in soft-tissue sarcomas (STS).

Purpose of the Study:

• To analyze LRRC15 expression patterns across various soft-tissue sarcoma subtypes.
• To evaluate the preclinical efficacy of ABBV-085 in LRRC15-positive STS models.
• To establish LRRC15 as a potential therapeutic target in STS.

Main Methods:

• Immunohistochemistry was used to assess LRRC15 expression in 711 STS cases.
• Patient-derived xenograft (PDX) models, both LRRC15-positive and negative, were utilized for in vivo experiments.
• Analysis included diverse STS histologies and sub-classifications.

Main Results:

• LRRC15 expression was observed in both stromal and cancer cells in multiple STS subsets, differing from epithelial tumors.
• LRRC15 overexpression correlated with higher tumor grade and was independently associated with adverse outcomes.
• ABBV-085 demonstrated significant preclinical efficacy in LRRC15-positive STS PDX models.

Conclusions:

• Targeting LRRC15 with antibody-drug conjugates represents a promising therapeutic strategy for LRRC15-positive STS.
• These findings provide the first preclinical evidence supporting LRRC15 as a target in STS.
• ABBV-085 is currently under clinical investigation for STS and other cancers.