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First clinical study of a pegylated diabody 124I-labeled PEG-AVP0458 in patients with tumor-associated glycoprotein 72 positive cancers
- Source :
- Theranostics
- Publication Year :
- 2020
- Publisher :
- Ivyspring International Publisher, 2020.
-
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/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.
- Subjects :
- 0301 basic medicine
Male
Antibodies, Neoplasm
medicine.medical_treatment
PET imaging
Medicine (miscellaneous)
Pharmacology
Iodine Radioisotopes
Mice
0302 clinical medicine
first-in-human
Neoplasms
Positron Emission Tomography Computed Tomography
Antibodies, Bispecific
Tissue Distribution
Infusions, Intravenous
Pharmacology, Toxicology and Pharmaceutics (miscellaneous)
medicine.diagnostic_test
Recombinant Proteins
Positron emission tomography
TAG-72
030220 oncology & carcinogenesis
Radioimmunotherapy
Female
Tumor-associated glycoprotein 72
Research Paper
Adult
Biodistribution
Biological Availability
Antineoplastic Agents
pegylated diabody
03 medical and health sciences
Pharmacokinetics
Antigens, Neoplasm
Cell Line, Tumor
medicine
Animals
Humans
biodistribution
Dose-Response Relationship, Drug
business.industry
Cancer
medicine.disease
Xenograft Model Antitumor Assays
030104 developmental biology
PEGylation
Feasibility Studies
Radiopharmaceuticals
Ovarian cancer
business
Single-Chain Antibodies
Subjects
Details
- Language :
- English
- ISSN :
- 18387640
- Volume :
- 10
- Issue :
- 25
- Database :
- OpenAIRE
- Journal :
- Theranostics
- Accession number :
- edsair.doi.dedup.....f726408512d4503725f65bc59d4084b0