Pharmacokinetics and Biodistribution of 89Zr-Miltuximab and Its Antibody Fragments as Glypican-1 Targeting Immuno-PET Agents in Glioblastoma

• DOI: 10.1021/acs.molpharmaceut.2c00760
• Publication Date: 2023-01-05T11:08:47Z
• Authors: Saikat Ghosh; Nicholas L. Fletcher; Pie Huda; Zachary H. Houston; Christopher B. Ho...; Maria E. Lund; Yanling Lu; Douglas H. Campbell; Bradley J. Walsh; Kristofer J. Thur...
• Keywords: Biodistribution; Avidity; Molecular Imaging

Glioblastoma (GBM) is the most aggressive form of primary brain cancer, accounting for about 85% all central nervous system (CNS) tumors. With standard treatment strategies like surgery, radiation, and chemotherapy, median survival time patients with GBM only 12–15 months from diagnosis. The poor prognosis due to a very high tumor recurrence rate following initial treatment, indicating dire need improved diagnostic therapeutic alternatives this disease. Antibody-based immunotheranostics holds great promise in treating GBM, combining theranostic applications radioisotopes target-specificity antibodies. In study, we developed validated antibody-based positron emission tomography (PET) tracers targeting heparan sulfate proteoglycan, glypican-1 (GPC-1), noninvasive detection disease using molecular imaging. GPC-1 overexpressed multiple solid types, including promising biomarker novel immunotheranostics. Here, investigate zirconium-89 (89Zr)-conjugated Miltuximab (a clinical stage anti-GPC-1 monoclonal antibody by GlyTherix, Ltd.) engineered fragments their potential as immuno-PET detect GPC-1positive tumors preclinical models. We explore effects size, avidity, Fc-domain on pharmacokinetics biodistribution vivo, comparing parallel full-length (Miltuximab), Fab′2, Fab, single-chain variable fragment (scFv) formats. High radiolabeling efficiency (>95%) was demonstrated formats stability post-radiolabeling higher larger constructs Fab. Receptor-mediated internalization 89Zr-labeled observed human cell line vitro, while highest retention (5.7 ± 0.94% ID/g, day-9 postinjection (p.i.)) overall better tumor-to-background ratios than smaller Fc-less Results vivo PET image quantification ex scintillation counting were highly correlated. Altogether, 89Zr-DFO-Miltuximab appears be an effective imaging agent detecting such current results support utility Fc containing whole mAb format over target.