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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.

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


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.


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

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