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

doi:10.18632/oncotarget.22228

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.

Highlights

The rise of companion diagnostic imaging agents, which are molecular imaging agents that provide information on the effective use of the corresponding drugs, is changing the paradigm of screening for targeted therapy in cancer
We evaluated its specificity for glycoprotein non-metastatic B (gpNMB), immunoreactivity, stability, imaging quality, pharmacokinetic properties, and dosimetry; all of which are required for an investigational new drug (IND) application to the FDA
fast protein liquid chromatography (FPLC) analysis showed the stability of [89Zr]DFO-CR011 with a retention time of 22.5 min, radiochemical purity of 100%, and antibody aggregation of 7% at t0 and 10% at 24 hrs (Supplementary Figure 2). This aggregation meets the specification of up to 20% aggregation based on the criterion used for the chemistry, manufacturing, and controls of an IND-approved [89Zr]trastuzumab, which means that an expiration time of 24 hrs can be used for injection into patients [23]

Summary

Introduction

The rise of companion diagnostic imaging agents, which are molecular imaging agents that provide information on the effective use of the corresponding drugs, is changing the paradigm of screening for targeted therapy in cancer. In breast cancer, [89Zr]DFOtrastuzumab is paving the way towards the selection of the human epidermal growth factor receptor 2 (HER2)positive patients for therapeutic antibodies that target this receptor. While this companion diagnostic imaging agent shows promise in stratifying patients who may benefit from the already established HER2-targeted therapies, there is currently no such approach for patients with the triple negative breast cancer (TNBC) subtype

Methods

Results

Conclusion