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Oncotarget. 2017 Nov 1;8(61):104303-104314. doi: 10.18632/oncotarget.22228. eCollection 2017 Nov 28.

Preclinical PET imaging of glycoprotein non-metastatic melanoma B in triple negative breast cancer: feasibility of an antibody-based companion diagnostic agent.

Author information

1
Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
2
Department of Radiology and Biomedical Imaging, PET Center, Yale University School of Medicine, New Haven, CT, USA.
3
Celldex Therapeutics, Hampton, NJ, USA.
4
The Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
5
Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
6
Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA.

Abstract

High levels of expression of glycoprotein non-metastatic B (gpNMB) in triple negative breast cancer (TNBC) and its association with metastasis and recurrence make it an attractive target for therapy with the antibody drug conjugate, glembatumumab vedotin (CDX-011). This report describes the development of a companion PET-based diagnostic imaging agent using 89Zr-labeled glembatumumab ([89Zr]DFO-CR011) to potentially aid in the selection of patients most likely to respond to targeted treatment with CDX-011. [89Zr]DFO-CR011 was characterized for its pharmacologic properties in TNBC cell lines. Preclinical studies determined that [89Zr]DFO-CR011 binds specifically to gpNMB with high affinity (Kd = 25 ± 5 nM), immunoreactivity of 2.2-fold less than the native CR011, and its cellular uptake correlates with gpNMB expression (r = 0.95). In PET studies at the optimal imaging timepoint of 7 days p.i., the [89Zr]DFO-CR011 tumor uptake in gpNMB-expressing MDA-MB-468 xenografts had a mean SUV of 2.9, while significantly lower in gpNMB-negative MDA-MB-231 tumors with a mean SUV of 1.9. [89Zr]DFO-CR011 was also evaluated in patient-derived xenograft models of TNBC, where tumor uptake in vivo had a positive correlation with total gpNMB protein expression via ELISA (r = 0.79), despite the heterogeneity of gpNMB expression within the same group of PDX mice. Lastly, the radiation dosimetry calculated from biodistribution studies in MDA-MB-468 xenografts determined the effective dose for human use would be 0.54 mSv/MBq. Overall, these studies demonstrate that [89Zr]DFO-CR011 is a potential companion diagnostic imaging agent for CDX-011 which targets gpNMB, an emerging biomarker for TNBC.

KEYWORDS:

PET imaging; dosimetry; glembatumumab; glycoprotein non-metastatic melanoma B; triple negative breast cancer

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