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

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.

Development of Radiotracers for Breast Cancer—The Tumor Microenvironment as an Emerging Target

“…Moreover, this tracer has potential to visualize different levels of cell surface gpNMB expression on tumor cells. However, selective targeting of gpNMB in the tumor versus in normal organs could not be assessed in the animal study, since the CR011 antibody binds selectively to human gpNMB [ 30 ].…”

Triple Negative Breast Cancer: A Review of Present and Future Diagnostic Modalities

“…The discovery of ATL-836 antibody provides a promising platform for future diagnostics and therapeutics of TNBC as TF, otherwise known as platelet tissue factor/factor III, engages a crucial role in the signaling of cancer cells (apoptosis inhibition and cell migration promotion) and is found to be prominently presented on TNBC cells [ 106 , 107 ]. In 2017, another promising TNBC diagnostic imaging antibody agent targeting glycoprotein non-metastatic B (gpNMB)/osteoactivin was successfully developed in a TNBC xenograft animal model [ 108 ]. This discovery is crucial as gpNMB expression is significantly high in TNBC patients and, most importantly, in tumor progression reoccurrence [ 109 , 110 ].…”

Controllable Engineering and Functionalizing Nanoparticles with Specific Targeting Capability

“…GPNMB is a type I transmembrane glycoprotein and expressed in the tumor stroma of 64% of human breast tumors and in the tumor epithelium of an additional 10% of tumors 45 . Recent studies 45,46 have identi ed high GPNMB expression in TNBC and suggested GPNMB as a potential biomarker for clinical research 47,48 . In this work, using QD520 (with emission maximum at 520 nm) and QD620 (with emission maximum at 620 nm) as uorescent nanocores, GPNMB-speci c QD520@cMIP and HER2-speci c QD620@cMIP were prepared by the proposed ROSIC method for targeting TNBC cells (GPNMB+) and HER2+ breast cancer cells, respectively.…”