ABBV-085, Antibody-Drug Conjugate Targeting LRRC15, Is Effective in Osteosarcoma: A Report by the Pediatric Preclinical Testing Consortium

• Published in: Molecular cancer therapeutics Vol. 20; no. 3; pp. 535 - 540
• Main Authors: Hingorani, Pooja, Roth, Michael E, Wang, Yifei, Zhang, Wendong, Gill, Jonathan B, Harrison, Douglas J, Teicher, Beverly, Erickson, Stephen, Gatto, Gregory, Smith, Malcolm A, Kolb, Edward A, Gorlick, Richard
• Format: Journal Article
• Language: English
• Published: United States 01.03.2021
• Subjects: Animals; Child; Female; Gene Expression - genetics; Humans; Immunoconjugates - therapeutic use; Membrane Proteins - metabolism; Mice; Osteosarcoma - drug therapy; Osteosarcoma - pathology
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-20-0406

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). expression data were obtained from PPTC RNA-sequencing data for the PDX models. The TARGET database was mined for 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 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 expression while OS9 and OS34 had low 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.