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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Bernadette V. Marquez-Nostra1,3, Supum Lee1, Richard Laforest1, Laura Vitale4, Xingyu Nie1, Krzysztof Hyrc5, Tibor Keler4, Thomas Hawthorne4, Jeremy Hoog6, Shunqiang Li6, Farrokh Dehdashti1, Cynthia X. Ma6 and Suzanne E. Lapi2
1Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA
2Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA
3Department of Radiology and Biomedical Imaging, PET Center, Yale University School of Medicine, New Haven, CT, USA
4Celldex Therapeutics, Hampton, NJ, USA
5The Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
6Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
Suzanne E. Lapi, email: [email protected]
Bernadette V. Marquez-Nostra, email: [email protected]
Keywords: PET imaging; triple negative breast cancer; glycoprotein non-metastatic melanoma B; dosimetry; glembatumumab
Received: August 21, 2017 Accepted: October 13, 2017 Published: November 01, 2017
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.
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