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Theranostics 2020; 10(25):11404-11415. doi:10.7150/thno.49422 This issue Cite

Research Paper

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

Andrew M. Scott^1,2,3✉, Timothy Akhurst^4,5, Fook-Thean Lee¹, Marika Ciprotti³, Ian D. Davis^3,6,7, Andrew J. Weickhardt^1,8, Hui K. Gan^1,8, Rodney J. Hicks⁴, Sze Ting Lee^1,2, Pece Kocovski³, Nancy Guo¹, Maggie Oh⁹, Linda Mileshkin⁵, Scott Williams⁵, Declan Murphy⁵, Kunthi Pathmaraj², Graeme J. O'Keefe², Sylvia J. Gong², John S. Pedersen¹⁰, Fiona E. Scott¹, Michael P. Wheatcroft⁹, Peter J. Hudson⁹

1. Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia.
2. Department of Molecular Imaging and Therapy, Austin Hospital, and University of Melbourne, Heidelberg, Victoria 3084, Australia.
3. Ludwig Institute for Cancer Research, Melbourne Branch, Heidelberg, Victoria 3084, Australia.
4. Centre for Cancer Imaging, the Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.
5. The Sir Peter MacCallum Department of Oncology, the University of Melbourne Melbourne, Victoria 3000, Australia.
6. Eastern Health, Melbourne, Australia.
7. Monash University, Melbourne, Australia.
8. Department of Medical Oncology, Austin Health, Heidelberg, Victoria 3084, Australia.
9. Avipep Pty Ltd and the Victorian Cancer Biologics Consortium, Parkville, Victoria 3052, Australia.
10. TissuPath Specialist Pathology, Mount Waverley, Victoria 3149, Australia.

✉ Corresponding author: Prof. Andrew M. Scott. Olivia Newton-John Cancer Research Institute, Level 5, ONJCWC, Austin Hospital, Studley Rd, Heidelberg, Vic, 3084, Australia. E-mail: andrew.scottorg.au.

Abstract

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/m^{2 124}I-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.

Keywords: pegylated diabody, TAG-72, first-in-human, biodistribution, PET imaging

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