First clinical study of a pegylated diabody I-124-labeled PEG-AVP0458 in patients with tumor-associated glycoprotein 72 positive cancers
AuthorScott, AM; Akhurst, T; Lee, F-T; Ciprotti, M; Davis, ID; Weickhardt, AJ; Gan, HK; Hicks, RJ; Lee, ST; Kocovski, P; ...
PublisherIVYSPRING INT PUBL
University of Melbourne Author/sDavis, Ian; Mileshkin, Linda; Murphy, Declan; Hicks, Rodney; Williams, Scott; Scott, Andrew; Akhurst, Timothy; Weickhardt, Andrew; Gan, Hui; Lee, Sze Ting; ...
AffiliationSir Peter MacCallum Department of Oncology
School of Physics
Medicine (Austin & Northern Health)
Medicine (St Vincent's)
Surgery (St Vincent's)
Document TypeJournal Article
CitationsScott, A. M., Akhurst, T., Lee, F. -T., Ciprotti, M., Davis, I. D., Weickhardt, A. J., Gan, H. K., Hicks, R. J., Lee, S. T., Kocovski, P., Guo, N., Oh, M., Mileshkin, L., Williams, S., Murphy, D., Pathmaraj, K., O'Keefe, G. J., Gong, S. J., Pedersen, J. S. ,... Hudson, P. J. (2020). First clinical study of a pegylated diabody I-124-labeled PEG-AVP0458 in patients with tumor-associated glycoprotein 72 positive cancers. THERANOSTICS, 10 (25), pp.11404-11415. https://doi.org/10.7150/thno.49422.
Access StatusOpen Access
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.
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Publisher licenceCC BY
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