Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis. There is a clinical need for effective, targeted therapy strategies that destroy both differentiated TNBC cells and TNBC cancer initiating cells (CICs), as the latter are implicated in the metastasis and recurrence of TNBC. Chondroitin sulfate proteoglycan 4 (CSPG4) is overexpressed on differentiated tumor cells and CICs obtained from TNBC patient specimens, suggesting that CSPG4 may be a clinically relevant target for the imaging and therapy of TNBC. The purpose of this study was to determine whether α-particle radioimmunotherapy (RIT) targeting TNBC cells using the CSPG4-specific monoclonal antibody (mAb) 225.28 as a carrier was effective at eliminating TNBC tumors in preclinical models. To this end, mAb 225.28 labeled with 212Pb (212Pb-225.28) as a source of α-particles for RIT was used for in vitro Scatchard assays and clonogenic survival assays with human TNBC cells (SUM159 and 2LMP) grown as adherent cells or non-adherent CIC-enriched mammospheres. Immune-deficient mice bearing orthotopic SUM159 or 2LMP xenografts were injected i.v. with the targeted (225.28) or irrelevant isotype-matched control (F3-C25) mAbs, labeled with 99mTc, 125I, or 212Pb for in vivo imaging, biodistribution, or tumor growth inhibition studies. 212Pb-225.28 bound to adherent SUM159 and 2LMP cells and to CICs from SUM159 and 2LMP mammospheres with a mean affinity of 0.5 nM. Nearly ten times more binding sites per cell were present on SUM159 cells and CICs compared with 2LMP cells. 212Pb-225.28 was six to seven times more effective than 212Pb-F3-C25 at inhibiting SUM159 cell and CIC clonogenic survival (p < 0.05). Radiolabeled mAb 225.28 showed significantly higher uptake than radiolabeled mAb F3-C25 in SUM159 and 2LMP xenografts (p < 0.05), and the uptake of 212Pb-225.28 in TNBC xenografts was correlated with target epitope expression. 212Pb-225.28 caused dose-dependent growth inhibition of SUM159 xenografts; 0.30 MBq 212Pb-225.28 was significantly more effective than 0.33 MBq 212Pb-F3-C25 at inhibiting tumor growth (p < 0.01). These results suggest that CSPG4-specific 212Pb-225.28 is a useful reagent for RIT of CSPG4-expressing tumors, including metastatic TNBC.
Highlights
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by a lack of progesterone receptor and estrogen receptor alpha expression and by no or low amplification of human epidermal growth factor receptor 2 (HER-2) [1]
212Pb-225.28 bound to adherent SUM159 and 2LMP cells and to Cancer initiating cells (CICs) dissociated from SUM159 or 2LMP mammospheres with an affinity of 0.5 ± 0.1 nM and had a specific binding level above 83% (Table 1, Supplementary Figure S1)
This result indicates that the expression of the Chondroitin sulfate proteoglycan 4 (CSPG4) epitope defined by monoclonal antibody (mAb) 225.28 was higher on SUM159 cells than on 2LMP cells
Summary
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by a lack of progesterone receptor and estrogen receptor alpha expression and by no or low amplification of human epidermal growth factor receptor 2 (HER-2) [1]. There are currently no approved targeted therapies for TNBC, which contributes to the poor prognosis for the nearly 20% of patients with this subtype of breast cancer [1,2]. Standard chemotherapies (e.g., taxanes) have been shown to enrich the population of CICs in TNBC [7,8,9]. These surviving CICs are implicated in generating chemotherapy-resistant, recurrent, and metastatic disease [1,3,10]. There is a clinical need to develop novel, targeted approaches that kill both differentiated TNBC cells and CICs, in recurrent and metastatic lesions, to improve the outcomes for patients with TNBC
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