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

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

  • Ther Adv Med Oncol. 2025 Apr 21:17:17588359251332471. doi: 10.1177/17588359251332471.
Dongli Liu 1,  Cassandra J Vandenberg 2 3,  Patrizia Sini 4,  Lorenz Waldmeier 5,  Rosa Baumgartinger 4,  Laura Pisarsky 4,  Georg Petroczi 4,  Gayanie Ratnayake 6,  Clare L Scott 2 3 6 7,  Caroline E Ford 8
Affiliations

Affiliations

  • 1 School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia.
  • 2 The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
  • 3 Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
  • 4 Boehringer Ingelheim RCV GmbH & Co KG, Wien, Austria.
  • 5 NBE Therapeutics AG, Basel, Switzerland.
  • 6 Royal Women's Hospital, Parkville, VIC, Australia.
  • 7 Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
  • 8 Gynaecological Cancer Research Group, Lowy Cancer Research Centre and School of Clinical Medicine, Faculty of Medicine and Health, Level 2 Lowy Cancer Research Centre, University of New South Wales, Kensington, NSW 2052, Australia.
PMID: 40297621 DOI: 10.1177/17588359251332471
Abstract

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.

Keywords

PARP inhibitors; antibody–drug conjugates; chemotherapy; chemotherapy resistance; drug screening; ovarian cancer; targeted therapy; translational research.

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