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

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 ( 124 I-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 124 I 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 124 I 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 124 I-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 124 I-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.

124I-Labeled Immuno-PET Targeting hTREM2 for the Diagnosis of Gastric Carcinoma

“…19−21 Scott et al used 124 I-PEG-AVP0458 (a pegylated diabody) for detecting tumorassociated glycoprotein in 72 positive cancer samples. 19 Wang et al demonstrated that 124 I-toripalimab was a safe tracer for PET with acceptable dosimetry. 20 Guo et al reported that 124 Itrastuzumab was feasible for the detection of HER2-positive lesions in primary and metastatic gastric cancer and to quantitatively differentiate HER2-positive and HER2-negative lesions.…”

“…Iodine-124 was selected as a medical positron radionuclide because it has a long half-life ( T 1/2 = 4.2 d) that matches the pharmacokinetics of the antibody in vivo. Furthermore, given its slow metabolism, iodine-124 is beneficial for obtaining images with low-radiation background. , The simplicity of labeling using the Iodogen method also provided an advantage; owing to these advantages, radioimmunoimaging with iodine-124 has been commonly used in clinical trials. − Scott et al used 124 I-PEG-AVP0458 (a pegylated diabody) for detecting tumor-associated glycoprotein in 72 positive cancer samples . Wang et al demonstrated that 124 I-toripalimab was a safe tracer for PET with acceptable dosimetry .…”

Survival Advantage Following TAG-72 Antigen-Directed Cancer Surgery in Patients With Colorectal Carcinoma: Proposed Mechanisms of Action

“…Testing our hypothesis could involve repeating our clinical studies using one of the humanized fragments of the mMoAb CC49 developed in the last decade ( 14 , 146 – 148 ). There are many radionuclides that can be used instead of 125 I, but it is critical to match the antibody’s clearance to that of the radionuclide.…”

Strategic Development of an Immunotoxin for the Treatment of Glioblastoma and Other Tumours Expressing the Calcitonin Receptor

“…To improve tumour penetration, several strategies have been adopted and integrated, including construction of smaller antibody derivatives such as scFv or diabodies and reducing renal clearance with incorporation of PEG. Further improvement of targeting antibodies and derivatives has been demonstrated for the pegylated diabody (Avibody) PEG-AVP0458, that targets the tumour-associated glycoprotein TAG-72 of ovarian and prostate cancers [ 46 ]. High tumour/blood ratios, a favourable bio-distribution (high tumour penetration with minimal organ uptake), and prolonged T 1/2 were reported.…”