Poster Presentation Royal Australian Chemical Institute National Congress 2026

Development of Peptide-Based Theranostics Targeting the Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1) (#428)

Wenxiao Kay Yue 1 2 , Marwa Nadia Rahimi 1 2 , Marwa Nadia Rahimi 1 2 , Joseph Hilton-Proctor 1 2 , Jessica Van Zuylekom 3 , Benjamin Blyth 3 , Peter Roselt 1 2 , Katie Owen 1 , Katie Owen 1 , Michael Hofman 1 2 4 , Luc Furic 1 , Mohammad Haskali 1 2 , Toby Passioura 5
  1. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
  2. Cancer Imaging, The Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  3. Models of Cancer Translational Research Centre, The Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  4. Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), The Peter MacCallum Cancer Centre, Melbourne, VICTORIA, Australia
  5. The University of Sydney, Camperdown, New South Wales, Australia

Introduction: The receptor tyrosine kinase-like orphan receptor 1 (ROR1) has emerged as a promising therapeutic target due to its absence in healthy adult tissues and overexpression in many malignancies. Theranostics represents a personalised state-of-the-art approach to cancer treatment, which integrates diagnostic imaging with targeted therapy using paired radiopharmaceuticals. By visualising targets for diagnosis and staging, it confirms therapeutic delivery to tumours and enables effective treatment monitoring. Peptides as theranostic agents offer high binding affinity and specificity, favourable safety profiles, with rapid tumour uptake and renal clearance. This study aimed to develop ROR1-targeting peptide ligands for fit-for-purpose theranostic applications and clinical translation.

Methods: Utilising the Random non-standard Peptide Integrated Discovery (RaPID) mRNA display platform, we screened cyclic peptide libraries against recombinant ROR1 protein to identify high-affinity binders, and optimised lead candidates via structure–activity relationship studies. In vitro evaluations included surface plasmon resonance, cell binding and uptake assays, and assessment of lipophilicity and metabolic stability. In vivo studies were performed in a bilateral 22Rv1 xenograft model expressing ROR1-positive and ROR1-negative tumours. Imaging and biodistribution studies were conducted using 68Ga- and/or 177Lu-labelled ligands, with selected candidates further assessed for therapeutic efficacy.

Results & Discussion: Optimised ligands demonstrated significant improvements in ROR1 binding affinity (KD: 0.6–1.4 nM), cell uptake (20–40%), internalisation (10–20%), and metabolic stability. Imaging studies with 68Ga-labelled candidates showed high tumour uptake (12–18 %ID/g) with favourable biodistribution profiles. The 177Lu-labelled ligands exhibited excellent tumour targeting with improved uptake (10–19 %ID/g), retention (4–10 %ID/g at 24 h), fast renal clearance, reduced hepatobiliary uptake, and preliminary evidence of therapeutic efficacy.

Conclusion: These results demonstrate the effectiveness of combining RaPID mRNA display with structure-guided peptide optimisation for developing ROR1-targeted theranostics. The identified ligands exhibit strong imaging and therapeutic potential in preclinical models, supporting their future development toward clinical translation in ROR1-targeted cancers.