First clinical study of a pegylated diabody 124I-labeled PEG-AVP0458 in patients with tumor-associated glycoprotein 72 positive cancers

Andrew M. Scott, Timothy Akhurst, Fook Thean Lee, Marika Ciprotti, Ian D. Davis, Andrew J. Weickhardt, Hui K. Gan, Rodney J. Hicks, Sze Ting Lee, Pece Kocovski, Nancy Guo, Maggie Oh, Linda Mileshkin, Scott Williams, Declan Murphy, Kunthi Pathmaraj, Graeme J. O’Keefe, Sylvia J. Gong, John S. Pedersen, Fiona E. ScottMichael P. Wheatcroft, Peter J. Hudson

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6 Citations (Scopus)


Through protein engineering and a novel pegylation strategy, a diabody specific to tumor-associated glycoprotein 72 (TAG-72) (PEG-AVP0458) has been created to optimize pharmacokinetics and bioavailability to tumor. We report the preclinical and clinical translation of PEG-AVP0458 to a first-in-human clinical trial of a diabody. Methods: Clinical translation followed characterization of PEG-AVP0458 drug product and preclinical biodistribution and imaging assessments of Iodine-124 trace labeled PEG-AVP0458 (124I-PEG-AVP0458). The primary study objective of the first-in-human study was the safety of a single protein dose of 1.0 or 10 mg/m2 124I-PEG-AVP0458 in patients with TAG-72 positive relapsed/metastatic prostate or ovarian cancer. Secondary study objectives were evaluation of the biodistribution, tumor uptake, pharmacokinetics and immunogenicity. Patients were infused with a single-dose of 124I labeled PEG-AVP0458 (3-5 mCi (111-185 MBq) for positron emission tomography (PET) imaging, performed sequentially over a one-week period. Safety, pharmacokinetics, biodistribution, and immunogenicity were assessed up to 28 days after infusion. Results: PEG-AVP0458 was radiolabeled with 124I and shown to retain high TAG-72 affinity and excellent targeting of TAG-72 positive xenografts by biodistribution analysis and PET imaging. In the first-in-human trial, no adverse events or toxicity attributable to 124I-PEG-AVP0458 were observed. Imaging was evaluable in 5 patients, with rapid and highly specific targeting of tumor and minimal normal organ uptake, leading to high tumor:blood ratios. Serum concentration values of 124I-PEG-AVP0458 showed consistent values between patients, and there was no significant difference in T½α and T½β between dose levels with mean (± SD) results of T½α = 5.10 ± 4.58 hours, T½β = 46.19 ± 13.06 hours. Conclusions: These data demonstrates the safety and feasibility of using pegylated diabodies for selective tumor imaging and potential delivery of therapeutic payloads in cancer patients.

Original languageEnglish
Pages (from-to)11404-11415
Number of pages12
Issue number25
Publication statusPublished - 2020


  • Biodistribution
  • First-in-human
  • Pegylated diabody
  • PET imaging
  • TAG-72

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