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

Theranostics. 2020 Sep 15;10(25):11404-11415. doi: 10.7150/thno.49422. eCollection 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.

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

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antibodies, Bispecific / administration & dosage
  • Antibodies, Bispecific / adverse effects*
  • Antibodies, Bispecific / genetics
  • Antibodies, Bispecific / pharmacokinetics
  • Antibodies, Neoplasm / genetics
  • Antigens, Neoplasm / metabolism*
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Biological Availability
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Feasibility Studies
  • Female
  • Humans
  • Infusions, Intravenous
  • Iodine Radioisotopes / administration & dosage
  • Iodine Radioisotopes / adverse effects
  • Iodine Radioisotopes / pharmacokinetics
  • Male
  • Mice
  • Neoplasms / diagnosis
  • Neoplasms / drug therapy*
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Positron Emission Tomography Computed Tomography
  • Radiopharmaceuticals / administration & dosage
  • Radiopharmaceuticals / adverse effects*
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / pharmacokinetics
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / adverse effects
  • Recombinant Proteins / genetics
  • Recombinant Proteins / pharmacokinetics
  • Single-Chain Antibodies / administration & dosage
  • Single-Chain Antibodies / adverse effects
  • Single-Chain Antibodies / genetics
  • Single-Chain Antibodies / pharmacokinetics
  • Tissue Distribution
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Bispecific
  • Antibodies, Neoplasm
  • Antigens, Neoplasm
  • Antineoplastic Agents
  • B72.3 antibody
  • Iodine Radioisotopes
  • Iodine-124
  • Radiopharmaceuticals
  • Recombinant Proteins
  • Single-Chain Antibodies
  • tumor-associated antigen 72