The antibody-drug conjugate targeting ROR1, NBE-002, is active in high-grade serous ovarian cancer preclinical models.

BACKGROUND: Novel therapeutics are urgently needed for high-grade serous ovarian cancer (HGSOC). We identified the receptor tyrosine kinase-like orphan receptor 1 (ROR1) as a therapeutic target. NBE-002, an antibody-drug conjugate (ADC) consisting of a humanised anti-ROR1 antibody, huXBR1-402, linked to a highly potent anthracycline-derivative (PNU), has activity in ROR1-positive haematologic malignancies. OBJECTIVES: This study explored the anti-cancer effects of NBE-002 alone and in combination with standard HGSOC therapies, carboplatin, paclitaxel and olaparib. DESIGN: A ROR1-ADC was tested in cell lines and in vivo models of HGSOC. METHODS: Different ROR1-targeting antibodies and payload compositions were constructed and tested in vitro. The dose effect of NBE-002 alone and in combination with carboplatin, paclitaxel or olaparib was analysed in ROR1+ HGSOC cell lines. Growth inhibition and apoptosis were monitored by live cell imaging and combination effects determined. Ten HGSOC PDX models were treated with NBE-002 alone, or in combination with carboplatin or olaparib, over 4 weeks and tumour volume and overall survival evaluated. RESULTS: Synergistic interaction was observed in two out of five HGSOC cell lines treated with NBE-002 and carboplatin (PEO4 and OC023, chemo-resistant), in one out of five treated with NBE-002 and olaparib (PEO1, BRCA2 mutated, HR deficient) and none of five treated with NBE-002 and paclitaxel. In vivo, NBE-002 exhibited activity in PA-1 xenografts and three HGSOC PDX models with high ROR1 expression, platinum sensitivity and homologous recombination DNA repair deficient (HRD). When NBE-002 was combined with carboplatin, activity was observed in 7 of 10 ROR1-expressing PDX models, regardless of platinum or HRD status. The activity was demonstrated in combination with olaparib in both PDX tested, one HRD and one HRD reverted. CONCLUSION: The ROR1-targeting ADC, NBE-002, has therapeutic potential in HGSOC, with single agent activity observed both in vitro and in vivo. Broader clinical applications were evident when NBE-002 was combined with carboplatin or olaparib.