Efficacy of Affibody-Based Ultrasound Molecular Imaging of Vascular B7-H3 for Breast Cancer Detection

Rakesh Bam, Patrick S. Lown, Lawrence A. Stern, Karina Sharma, Katheryne E. Wilson, Gregory R. Bean, Amelie M. Lutz, Ramasamy Paulmurugan, Benjamin J. Hackel, Jeremy Dahl, Jeremy Dahl, Lotfi Abou-Elkacem

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Purpose: Human B7-H3 (hB7-H3) is a promising molecular imaging target differentially expressed on the neovasculature of breast cancer and has been validated for preclinical ultrasound (US) imaging with anti-B7-H3-antibody-functionalized microbubbles (MB). However, smaller ligands such as affibodies (ABY) are more suitable for the design of clinical-grade targeted MB. Experimental Design: Binding of ABYB7-H3 was confirmed with soluble and cell-surface B7-H3 by flow cytometry. MB were functionalized with ABYB7-H3 or anti-B7-H3-antibody (AbB7-H3). Control and targeted MB were tested for binding to hB7-H3-expressing cells (MS1hB7-H3) under shear stress conditions. US imaging was performed with MBABY-B7-H3 in an orthotopic mouse model of human MDA-MB-231 coimplanted with MS1hB7-H3 or control MS1WT cells and a transgenic mouse model of breast cancer development. Results:ABYB7-H3 specifically binds to MS1hB7-H3 and murine- B7-H3-expressing monocytes. MBABY-B7-H3 (8.5 ± 1.4 MB/cell) and MBAb-B7-H3 (9.8 ± 1.3 MB/cell) showed significantly higher (P < 0.0001) binding to the MS1hB7-H3 cells compared with control MBNon-targeted (0.5 ± 0.1 MB/cell) under shear stress conditions. In vivo, MBABY-B7-H3 produced significantly higher (P < 0.04) imaging signal in orthotopic tumors coengrafted with MS1hB7-H3 (8.4 ± 3.3 a.u.) compared with tumors with MS1WT cells (1.4 ± 1.0 a.u.). In the transgenic mouse tumors, MBABY-B7-H3 (9.6 ± 2.0 a.u.) produced higher (P < 0.0002) imaging signal compared with MBNon-targeted (1.3 ± 0.3 a.u.), whereas MBABY-B7-H3 signal in normal mammary glands and tumors with B7-H3 blocking significantly reduced (P < 0.02) imaging signal. Conclusions: MBABY-B7-H3 enhances B7-H3 molecular signal in breast tumors, improving cancer detection, while offering the advantages of a small size ligand and easier production for clinical imaging.

Original languageEnglish (US)
Pages (from-to)2140-2150
Number of pages11
JournalClinical Cancer Research
Volume26
Issue number9
DOIs
StatePublished - May 1 2020

Bibliographical note

Funding Information:
We acknowledge the guidance and mentorship of the late Dr. Juergen K Willmann. We thank the Preclinical Imaging Core Facility and Proteomics Resource Facility at the Canary Center for Cancer Early Detection, Stanford University. IHC staining of human breast cancer specimens was performed at Human Pathology/Histology Service Center, Stanford University. This study was funded by the NCI under grant number R41-CA213544 and a Stanford Women's Cancer Center Innovation Award from the Stanford Cancer Institute, a NCI-designated Comprehensive Cancer Center.

Funding Information:
Weacknowledge the guidance andmentorship of the late Dr. JuergenKWillmann. We thank the Preclinical Imaging Core Facility and Proteomics Resource Facility at the Canary Center for Cancer Early Detection, Stanford University. IHC staining of human breast cancer specimens was performed at Human Pathology/Histology Service Center, Stanford University. This study was funded by the NCI under grant number R41-CA213544 and a Stanford Women's Cancer Center Innovation Award from the Stanford Cancer Institute, a NCI-designated Comprehensive Cancer Center

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