
==== Front
Neurooncol Adv
Neurooncol Adv
noa
Neuro-Oncology Advances
2632-2498
Oxford University Press US

10.1093/noajnl/vdae090.011
vdae090.011
Final Category: Basic Science Brain Metastases
AcademicSubjects/MED00300
AcademicSubjects/MED00310
BSBM-13 DISTINCT UPTAKE AND ELIMINATION PROFILES FOR TRASTUZUMAB, HUMAN IGG AND BIOCYTIN-TMR IN EXPERIMENTAL HER2+ BRAIN METASTASES OF BREAST CANCER
Silvestri Vanesa Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

Tran Andy Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
CCR Microscopy Core, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

Chung Monika Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
Rutgers New Jersey Medical School, Newark, NJ, USA

Chung Natalie Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
Lake Erie College of Osteopathic Medicine, Erie, PA, USA

Gril Brunilde Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
Tumor Metastasis Branch, Division of Cancer Biology, National Cancer Institute, Bethesda, MD, USA

Robinson Christina Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA

Difilippantonio Simone Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA

Wei Debbie Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

Kruhlak Michael Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
CCR Microscopy Core, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

Peer Cody Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
Amgen Inc., Rockville, MD, USA

Figg W Douglas Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

Khan Imran Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

Steeg Patricia Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

8 2024
02 8 2024
02 8 2024
6 Suppl 1 2024 SNO/ASCO CNS Metastases Conference i4i4
© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Abstract

The aim of this study is an improved understanding of drug distribution in brain metastases. Rather than single point snapshots, we analyzed the time course and route of drug/probe elimination (clearance), focusing on the intramural periarterial drainage (IPAD) pathway. Mice with JIMT1-BR HER2+ experimental brain metastases were injected with biocytin-TMR and either trastuzumab or human IgG. Drugs/probes circulated for 5 min to 48 h, followed by perfusion. Brain sections were stained for human IgG, vascular basement membrane proteins laminin or collagen IV, and periarterial α-SMA. A machine learning algorithm was developed to identify metastases, metastatic microenvironment, and uninvolved brain in confocally scanned brain sections. Drug/probe intensity over time and total imaged drug exposure (iAUC) were calculated for 27,249 lesions and co-immunofluorescence with IPAD-vascular matrix analyzed in 11,668 metastases. In metastases, peak trastuzumab levels were 5-fold higher than human IgG but 4-fold less than biocytin-TMR. The elimination phase constituted 85–93% of total iAUC for all drugs/probes tested. For trastuzumab, total iAUC during uptake was similar to the small molecule drug probe biocytin-TMR, but slower trastuzumab elimination resulted in a 1.7-fold higher total iAUC. During elimination trastuzumab and IgG were preferentially enriched in the α-SMA+ periarterial vascular matrix, consistent with the IPAD clearance route; biocytin-TMR showed heterogeneous elimination pathways. Drug/probe elimination is an important component of drug development for brain metastases. We identified a prolonged elimination pathway for systemically administered antibodies through the periarterial vascular matrix that may contribute to the sustained presence and efficacy of large antibody therapeutics.
==== Body
pmc
