ABBV-085, Antibody-Drug Conjugate Targeting LRRC15, Is Effective in Osteosarcoma: A Report by the Pediatric Preclinical Testing Consortium
Pooja Hingorani 1, Michael E Roth 1, Yifei Wang 1, Wendong Zhang 1, Jonathan B Gill 1, Douglas J Harrison 1, Beverly Teicher 2, Stephen Erickson 3, Gregory Gatto 3, Malcolm A Smith 2, Edward A Kolb 4, Richard Gorlick 5

Membrane protein leucine-wealthy repeat that contains 15 (LRRC15) is proven to be expressed in a number of 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) through the Pediatric Preclinical Testing Consortium (PPTC). LRRC15 expression data were acquired from PPTC RNA-sequencing data for that PDX models. The Prospective database was found 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 different 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 days via intraperitoneal injection. Control cohorts incorporated vehicle as well as an isotype MMAE-linked antibody. Tumor volumes and responses were reported using PPTC record analysis. OS1, OS33, OS42, OS55, and OS60 had high LRRC15 expression while OS9 and OS34 had low LRRC15 expression. ABBV-085 inhibited tumor development in six of seven PDX models compared to vehicle control and considerably improved event-free survival in five of seven models compared to isotype controls. Two models demonstrated maintained complete responses while others demonstrated progressive disease. Response correlated with LRRC15 expression. ABBV-085′s antitumor activity against osteosarcoma PDX suggests LRRC15 can be a rational target for going after numerous studies in patients with this particular disease.ABBV-CLS-484