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, Supum Lee, Richard Laforest, Laura Vitale, Xingyu Nie, Krzysztof Hyrc, Tibor Keler, Thomas Hawthorne, Jeremy Hoog, Shunqiang Li, Farrokh Dehdashti, Cynthia X. Ma, Suzanne E. Lapi

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish
Pages (from-to)104303-104314
Number of pages12
JournalOncotarget
Volume8
Issue number61
DOIs
StatePublished - 2017

Keywords

  • Dosimetry
  • Glembatumumab
  • Glycoprotein non-metastatic melanoma B
  • PET imaging
  • Triple negative breast cancer

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