Preclinical radiolabeling, in vivo biodistribution and positron emission tomography of a novel pyrrolobenzodiazepine (PBD)-based antibody drug conjugate targeting ASCT2

Christian Werner Wichmann; Ingrid Julienne Georgette Burvenich; Nancy Guo; Angela Rigopoulos; Alexander McDonald; Diana Cao; Graeme Joseph O'Keefe; Sylvia Jie Gong; Hui Kong Gan; Fiona Elizabeth Scott; Nabendu Pore; Steven Coats; Andrew Mark Scott

doi:10.1016/j.nucmedbio.2023.108366

Preclinical radiolabeling, in vivo biodistribution and positron emission tomography of a novel pyrrolobenzodiazepine (PBD)-based antibody drug conjugate targeting ASCT2

Nucl Med Biol. 2023 Jul-Aug:122-123:108366. doi: 10.1016/j.nucmedbio.2023.108366. Epub 2023 Jul 14.

Affiliations

¹ Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia; School of Cancer Medicine, La Trobe University, Melbourne, Australia.
² Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia.
³ Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia.
⁴ Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia; School of Engineering and Mathematical Sciences, La Trobe University, Australia.
⁵ Early Oncology Research and Development, AstraZeneca, Gaithersburg, MD, USA.
⁶ Medimmune LLC, Gaithersburg, MD, USA.
⁷ Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia; School of Cancer Medicine, La Trobe University, Melbourne, Australia; Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia.

PMID: 37473513
DOI: 10.1016/j.nucmedbio.2023.108366

Abstract

Introduction: Anti-ASCT2 antibody drug conjugate (ADC) MEDI7247 has been under development as a potential anti-cancer therapy for patients with selected relapsed/refractory hematological malignancies and advanced solid tumors by MedImmune. Although promising efficacy was observed in the clinic, pharmacokinetic (PK) analyses observed low exposure of MEDI7247 in phase I hematological patients. To investigate the biodistribution properties of MEDI7247, MEDI7247 and control antibodies were radiolabeled with zirconium-89 and in vitro and in vivo properties characterized.

Methods: MEDI7247 (human anti-ASCT2 antibody conjugated with pyrrolobenzodiazepine (PBD)) and MEDI7519 (MEDI7247 without PBD drug conjugate) and an isotype control antibody drug conjugate construct were conjugated with p-isothiocyanatobenzyl-deferoxamine (Df) and radiolabeled with zirconium-89. In vitro studies included determining the radiochemical purity, protein integrity, immunoreactivity (Lindmo analysis), apparent antigen binding affinity for ASCT2-positive cells by Scatchard analysis and serum stability of the radiolabeled immunoconjugates. In vivo studies included biodistribution and PET/MRI imaging studies of the radiolabeled immunoconjugates in an ASCT2-positive tumor model, HT-29 colorectal carcinoma xenografts.

Results: Conditions for the Df-conjugation and radiolabeling of antibody constructs were determined to produce active radioimmunoconjugates. In vivo biodistribution and whole body PET/MRI imaging studies of [⁸⁹Zr]Zr-Df-MEDI7519 and [⁸⁹Zr]Zr-Df-MEDI7247 radioimmunoconjugates in HT-29 colon carcinoma xenografts in BALB/c nude mice demonstrated specific tumor localization. However, more rapid blood clearance and non-specific localization in liver was observed for [⁸⁹Zr]Zr-Df-MEDI7247 and [⁸⁹Zr]Zr-Df-MEDI7519 compared to isotype control ADC. Except for liver and bone, other normal tissues demonstrated clearance reflecting the blood clearance for all three constructs and no other abnormal tissue uptake.

Conclusions and advances in knowledge: Preclinical biodistribution analyses of [⁸⁹Zr]Zr-Df-MEDI7247 and [⁸⁹Zr]Zr-Df-MEDI7519 showed the biodistribution pattern of anti-ASCT2 ADC MEDI7247 was similar to parental MEDI7519, and both antibodies showed specific tumor uptake compared to an isotype control ADC. This study highlights an important role nuclear medicine imaging techniques can play in early preclinical assessment of drug specificity as part of the drug development pipeline.

Keywords: ASCT2; Antibody drug conjugate (ADC); MEDI7247; MEDI7519; Pyrrolobenzodiazepine (PBD); Zirconium-89.

MeSH terms

Animals
Cell Line, Tumor
Colonic Neoplasms*
Humans
Immunoconjugates* / pharmacokinetics
Mice
Mice, Nude
Positron-Emission Tomography / methods
Tissue Distribution
Zirconium / chemistry

Substances

Zirconium-89
pyrrolo(2,1-c)(1,4)benzodiazepine
Immunoconjugates
Zirconium