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

journal contribution
posted on 23.11.2020, 08:50 by Andrew ScottAndrew Scott, T Akhurst, Fook-Thean LeeFook-Thean Lee, M Ciprotti, ID Davis, Andrew WeickhardtAndrew Weickhardt, Hui GanHui Gan, RJ Hicks, Sze LeeSze Lee, Pece Kocovski, N Guo, M Oh, L Mileshkin, S Williams, Declan Murphy, Kunthi PathmarajKunthi Pathmaraj, GJ O’Keefe, Sylvia GongSylvia Gong, JS Pedersen, Fiona ScottFiona Scott, MP Wheatcroft, PJ Hudson
© The author(s). 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.

Funding

This work was supported by Avipep Pty Ltd, which was the lead agency of the Victorian Cancer Biologics Consortium funded by the Victorian Science Agenda Investment Fund of the Victorian State Government. We also acknowledge the Operational Infrastructure support program of the Victorian Government. This research was also undertaken using the Solid Targetry Laboratory, and ANSTO-AustinONJCRI partnership. AMS is supported by a NHMRC Senior Investigator Fellowship (APP1177837). IDD is supported by a NHMRC Practitioner Fellowship (APP1102604).

History

Publication Date

15/09/2020

Journal

Theranostics

Volume

10

Issue

25

Pagination

12p. (p. 11404-11415)

Publisher

Ivyspring International Publisher

ISSN

1838-7640

Rights Statement

The Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.