In Vitro and In Vivo Comparison of 3,2-HOPO Versus Deferoxamine-Based Chelation of Zirconium-89 to the Antimesothelin Antibody Anetumab

Cancer Biother Radiopharm. 2021 May;36(4):316-325. doi: 10.1089/cbr.2020.4492.

Abstract

Introduction: [227Th]Th-3,2-HOPO-MSLN-mAb, a mesothelin (MSLN)-targeted thorium-227 therapeutic conjugate, is currently in phase I clinical trial; however, direct PET imaging using this conjugate is technically challenging. Thus, using the same MSLN antibody, we synthesized 3,2-HOPO and deferoxamine (DFO)-based zirconium-89 antibody conjugates, [89Zr]Zr-3,2-HOPO-MSLN-mAb and [89Zr]Zr-DFO-MSLN-mAb, respectively, and compared them in vitro and in vivo. Methods: [89Zr]Zr-3,2-HOPO-MSLN-mAb and [89Zr]Zr-DFO-MSLN-mAb were evaluated in vitro to determine binding affinity and immunoreactivity in HT29-MSLN and PDX (NCI-Meso16, NCI-Meso21) cells. For both the zirconium-89 conjugates, in vivo studies (biodistribution/imaging) were performed at days 1, 3, and 6, from which tissue uptake was determined. Results: Both the conjugates demonstrated a low nanomolar binding affinity for MSLN and >95% immunoreactivity. In all the three tumor types, biodistribution of [89Zr]Zr-DFO-MSLN-mAb resulted in higher tumor uptake(15.88-28-33%ID/g) at all time points compared with [89Zr]Zr-3,2-HOPO-MSLN-mAb(7-13.07%ID/g). [89Zr]Zr-3,2-HOPO-MSLN-mAb femur uptake was always higher than [89Zr]Zr-DFO-MSLN-mAb, and imaging results concurred with the biodistribution studies. Conclusions: Even though the conjugates exhibited a high binding affinity for MSLN, [89Zr]Zr-DFO-MSLN-mAb showed a higher tumor and lower femur uptake than [89Zr]Zr-3,2-HOPO-MSLN-mAb. Nevertheless, [89Zr]Zr-3,2-HOPO-MSLN-mAb could be used to study organ distribution and lesion uptake with the caveat of detecting MSLN-positive bone lesions. Clinical trial (NCT03507452).

Keywords: 32-HOPO; DFO; PET imaging; antibody conjugate; mesothelin; zirconium-89.

MeSH terms

  • Animals
  • Chelating Agents / pharmacology
  • Chelating Agents / therapeutic use*
  • Deferoxamine / pharmacology
  • Deferoxamine / therapeutic use*
  • Female
  • Humans
  • Immunoconjugates / pharmacology
  • Immunoconjugates / therapeutic use*
  • Maytansine / analogs & derivatives*
  • Maytansine / pharmacology
  • Maytansine / therapeutic use
  • Mice
  • Mice, Nude
  • Radioisotopes / pharmacology
  • Radioisotopes / therapeutic use*
  • Zirconium / pharmacology
  • Zirconium / therapeutic use*

Substances

  • Chelating Agents
  • Immunoconjugates
  • Radioisotopes
  • Maytansine
  • Zirconium
  • Deferoxamine
  • anetumab ravtansine
  • Zirconium-89

Associated data

  • ClinicalTrials.gov/NCT03507452