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

// Bernadette V. Marquez-Nostra 1, 3 , Supum Lee 1 , Richard Laforest 1 , Laura Vitale 4 , Xingyu Nie 1 , Krzysztof Hyrc 5 , Tibor Keler 4 , Thomas Hawthorne 4 , Jeremy Hoog 6 , Shunqiang Li 6 , Farrokh Dehdashti 1 , Cynthia X. Ma 6 and Suzanne E. Lapi 2 1 Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA 2 Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA 3 Department of Radiology and Biomedical Imaging, PET Center, Yale University School of Medicine, New Haven, CT, USA 4 Celldex Therapeutics, Hampton, NJ, USA 5 The Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA 6 Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA Correspondence to: Suzanne E. Lapi, email: lapi@uab.edu Bernadette V. Marquez-Nostra, email: bernadette.marquez-nostra@yale.edu 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 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 89 Zr-labeled glembatumumab ([ 89 Zr]DFO-CR011) to potentially aid in the selection of patients most likely to respond to targeted treatment with CDX-011. [ 89 Zr]DFO-CR011 was characterized for its pharmacologic properties in TNBC cell lines. Preclinical studies determined that [ 89 Zr]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 [ 89 Zr]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. [ 89 Zr]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 [ 89 Zr]DFO-CR011 is a potential companion diagnostic imaging agent for CDX-011 which targets gpNMB, an emerging biomarker for TNBC.