title: Apoptosis imaging for monitoring DR5 antibody accumulation and pharmacodynamics in brain tumors noninvasively.
abstract: High-grade gliomas often possess an impaired blood-brain barrier (BBB), which allows delivery of large molecules to brain tumors. However, achieving optimal drug concentrations in brain tumors remains a significant hurdle for treating patients successfully. Thus, detailed investigations of drug activities in gliomas are needed. To investigate BBB penetration, pharmacodynamics, and tumor retention kinetics of an agonistic DR5 antibody in a brain tumor xenograft model, we utilized a noninvasive imaging method for longitudinal monitoring of apoptosis induction. Brain tumors were induced by intracranial (i.c.) implantation of a luciferase-expressing tumor cell line as a reporter. To quantify accumulation of anti-DR5 in brain tumors, we generated a dosage-response curve for apoptosis induction after i.c. delivery of fluorescence-labeled anti-DR5 at different dosages. Assuming 100% drug delivery after i.c. application, the amount of accumulated antibody after i.v. application was calculated relative to its apoptosis induction. We found that up to 0.20% to 0.97% of antibody delivered i.v. reached the brain tumor, but that apoptosis induction declined quickly within 24 hours. These results were confirmed by three-dimensional fluorescence microscopy of antibody accumulation in explanted brains. Nonetheless, significant antitumor efficacy was documented after anti-DR5 delivery. We further demonstrated that antibody penetration was facilitated by an impaired BBB in brain tumors. These imaging methods enable the quantification of antibody accumulation and pharmacodynamics in brain tumors, offering a holistic approach for assessment of central nervous system-targeting drugs.
authors: Authors' Affiliations: Discovery Oncology, Pharmaceutical Research and Early Development (pRED), Roche Diagnostics GmbH, Penzberg, Germany; and Center for Molecular Imaging, Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors: Thomas G
authors: TG
authors: Weber
authors: Franz
authors: F
authors: Osl
authors: Anja
authors: A
authors: Renner
authors: Thomas
authors: T
authors: Pöschinger
authors: Stefanie
authors: S
authors: Galbán
authors: Alnawaz
authors: A
authors: Rehemtulla
authors: Werner
authors: W
authors: Scheuer
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000627:therapeutic use*; D017209:Apoptosis; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008812:Mice, Hairless; D008856:Microscopy, Fluorescence; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand