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ABBV-085, Antibody-Drug Conjugate Targeting LRRC15, Is Effective in Osteosarcoma: A Report by the Pediatric
Pooja Hingorani1, Michael E Roth1, Yifei Wang1
1Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, Texas.
Abstract:
Membrane protein leucine-rich repeat containing 15 (LRRC15) is known to be expressed in several solid tumors including osteosarcoma. ABBV-085, an antibody-drug conjugate against LRRC15, conjugated to monomethyl auristatin E (MMAE), was studied in osteosarcoma patient-derived xenografts (PDXs) by the Pediatric Preclinical Testing Consortium (PPTC). LRRC15 expression data were obtained from PPTC RNA-sequencing data for the PDX models. The TARGET database was mined for LRRC15 expression in human osteosarcoma. Protein expression was confirmed via IHC in three PDX models. Seven osteosarcoma PDX models (OS1, OS9, OS33, OS34, OS42, OS55, and OS60) with varying LRRC15 gene expression were studied. ABBV-085 was administered at 3 mg/kg (OS33), 6 mg/kg (all seven PDXs), and 12 mg/kg (OS60) weekly for 4 consecutive weeks via intraperitoneal injection. Control cohorts included vehicle and an isotype MMAE-linked antibody. Tumor volumes and responses were reported using PPTC statistical analysis. OS1, OS33, OS42, OS55, and OS60 had high LRRC15 expression while OS9 and OS34 had low LRRC15 expression. ABBV-085 inhibited tumor growth in six of seven PDX models as compared with vehicle control and significantly improved event-free survival in five of seven models as compared with isotype controls. Two models showed maintained complete responses while all others showed progressive disease. Response correlated with LRRC15 expression. ABBV-085's antitumor activity against osteosarcoma PDX suggests LRRC15 may be a rational target for pursuing clinical trials in patients with this disease.
Insights
The antibody-drug conjugate ABBV-085 targeting leucine-rich repeat containing 15 (LRRC15) showed significant antitumor activity in osteosarcoma patient-derived xenografts. This suggests LRRC15 is a promising target for osteosarcoma treatment.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Leucine-rich repeat containing 15 (LRRC15) is expressed in various solid tumors, including osteosarcoma.
- Targeting LRRC15 presents a potential therapeutic strategy for osteosarcoma.
Purpose of the Study:
- To evaluate the preclinical efficacy of ABBV-085, an antibody-drug conjugate targeting LRRC15, in osteosarcoma patient-derived xenografts (PDXs).
- To assess the correlation between LRRC15 expression levels and response to ABBV-085 treatment.
Main Methods:
- Seven osteosarcoma PDX models with varying LRRC15 gene expression were utilized.
- ABBV-085 was administered intraperitoneally at different doses.
- Tumor growth, event-free survival, and protein expression (via IHC) were analyzed.
Main Results:
- ABBV-085 demonstrated significant tumor growth inhibition in six of seven PDX models compared to vehicle control.
- Event-free survival was significantly improved in five of seven models compared to isotype controls.
- Treatment response correlated with LRRC15 expression levels, with higher expression linked to better outcomes.
Conclusions:
- ABBV-085 exhibits potent antitumor activity in preclinical osteosarcoma models.
- LRRC15 is a validated target for osteosarcoma, supporting further clinical investigation of ABBV-085.