Effective treatment of ductal carcinoma in situ with a HER-2-targeted alpha-particle emitting radionuclide in a preclinical model of human breast cancer

Yoshida, Takahiro; Jin, Kideok; Song, Hong; Park, Sunju; Huso, David L.; Zhang, Zhe; Han, Lu; Zhu, Charles; Bruchertseifer, Frank; Morgenstern, Alfred; Sgouros, George; Sukumar, Saraswati

doi:10.18632/oncotarget.8949

Cited by 25 publications

(22 citation statements)

References 23 publications

(37 reference statements)

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“…As such the LD50 dose for rodents has been described to be in the range of 500 to 1000 rad (depending on the age of the animals) [ 45 ] in comparison to an LD50 of 500 rad in humans [ 46 ]. As expected from previous studies, no major findings were recorded in renal toxicity caused by accumulation of the daughter nuclides of 227 Th [ 44 ] in contrast to redistribution of 213 Bi formed from decay of 225 Ac-based radioimmunoconjugates [ 47 ].…”

Section: Discussionsupporting

confidence: 66%

Targeted alpha therapy using a novel CD70 targeted thorium-227 conjugate inin vitroandin vivomodels of renal cell carcinoma

et al. 2017

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The cell surface receptor CD70 has been previously reported as a promising target for B-cell lymphomas and several solid cancers including renal cell carcinoma. We describe herein the characterization and efficacy of a novel CD70 targeted thorium-227 conjugate (CD70-TTC) comprising the combination of the three components, a CD70 targeting antibody, a chelator moiety and the short-range, high-energy alpha-emitting radionuclide thorium-227 (227Th). In vitro analysis demonstrated that the CD70-TTC retained binding affinity to its target and displayed potent and specific cytotoxicity compared to an isotype control-TTC. A biodistribution study in subcutaneous tumor-bearing nude mice using the human renal cell carcinoma cell line 786-O demonstrated significant uptake and retention with 122 ± 42% of the injected dose of 227Th per gram (% ID/g) remaining in the tumor seven days post dose administration compared to only 3% ID/g for the isotype control-TTC. Tumor accumulation correlated with a dose dependent and statistically significant inhibition in tumor growth compared to vehicle and isotype control-TTC groups at radioactivity doses as low as 50 kBq/kg. The CD70-TTC was well tolerated as evidenced by only modest changes in hematology and normal gain in body weight of the mice. To our knowledge, this is the first report describing molecular targeting of CD70 expressing tumors using a targeted alpha-therapy (TAT).

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Section: Discussionsupporting

confidence: 66%

Targeted alpha therapy using a novel CD70 targeted thorium-227 conjugate inin vitroandin vivomodels of renal cell carcinoma

et al. 2017

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“…The cells’ relative sensitivities to 212 Pb-376.96 correlated to their expression of the B7-H3 epitope, as would be anticipated for targeted rather than non-specific binding of the RIC. The significantly greater sensitivity of the cells (three- to forty-fold) to a targeted RIC relative to a control RIC in these studies is equivalent to or greater than those reported for other cancer cells and radionuclides [16, 42-45]. The in vitro IC 50 concentrations of 212 Pb-376.96 against adherent ovarian cancer cells and CICs (1.6-33 kBq/mL) were lower than the maximum concentrations of alternative α-particle RICs calculated to be present in the peritoneum of ovarian cancer patients (42-100 kBq/mL) during clinical trials [15, 19, 21].…”

Section: Discussionmentioning

confidence: 66%

B7-H3-targeted 212Pb radioimmunotherapy of ovarian cancer in preclinical models

Kasten

Arend

Katre

et al. 2017

Nuclear Medicine and Biology

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Introduction Novel therapies that effectively kill both differentiated cancer cells and cancer initiating cells (CICs), which are implicated in causing chemotherapy-resistance and disease recurrence, are needed to reduce the morbidity and mortality of ovarian cancer. These studies used monoclonal antibody (mAb) 376.96, which recognizes a B7-H3 epitope expressed on ovarian cancer cells and CICs, as a carrier molecule for targeted α-particle radioimmunotherapy (RIT) in preclinical models of human ovarian cancer. Methods mAb 376.96 was conjugated to the chelate 2-(4-isothiocyanotobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoylmethyl)-cyclododecane (TCMC) and radiolabeled with 212Pb, a source of α-particles. In vitro Scatchard assays determined the specific binding of 212Pb-376.96 to adherent differentiated or non-adherent CIC-enriched ES-2 and A2780cp20 ovarian cancer cells. Adherent ovarian cancer cells and non-adherent CIC-enriched tumorspheres treated in vitro with 212Pb-376.96 or the irrelevant isotype-matched 212Pb-F3-C25 were assessed for clonogenic survival. Mice bearing i.p. ES-2 or A2780cp20 xenografts were injected i.p. with 0.17-0.70 MBq 212Pb-376.96 or 212Pb-F3-C25 and were used for in vivo imaging, ex vivo biodistribution, and therapeutic survival studies. Results 212Pb-376.96 was obtained in high yield and purity (>98%); Kd values ranged from 10.6-26.6 nM for ovarian cancer cells, with 104-105 binding sites/cell. 212Pb-376.96 inhibited the clonogenic survival of ovarian cancer cells up to 40 times more effectively than isotype-matched control 212Pb-F3-C25; combining 212Pb-376.96 with carboplatin significantly decreased clonogenic survival compared to either agent alone. In vivo imaging and biodistribution analysis 24 h after i.p. injection of 212Pb-376.96 showed high peritoneal retention and tumor tissue accumulation (28.7% ID/g in ES-2 ascites, 73.1% ID/g in A2780cp20 tumors); normal tissues showed lower and comparable uptake for 212Pb-376.96 and 212Pb-F3-C25. Tumor-bearing mice treated with 212Pb-376.96 alone or combined with carboplatin survived 2-3 times longer than mice treated with 212Pb-F3-C25 or non-treated controls. Conclusion These results support additional RIT studies with 212Pb-376.96 for future evaluation in patients with ovarian cancer.

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“…Due to the inability of 223 Ra to accumulate in primary tumors or non-skeletal metastases, alternative radionuclides and targeting strategies are required to be effective against primary TNBC and metastases to other organs. Many monoclonal antibodies (mAbs) that specifically bind to antigens overexpressed on malignant cells have been used as carriers for α-particle emitting nuclides in targeted radioimmunotherapy (RIT) studies against preclinical in vitro and in vivo models of breast cancer [ 11 , 12 , 14 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. However, no existing mAbs or radioimmunoconjugates (RICs) that simultaneously target differentiated, bulk tumor cells and CICs are approved for TNBC or other types of breast cancer.…”

Section: Introductionmentioning

confidence: 99%

212Pb-Labeled Antibody 225.28 Targeted to Chondroitin Sulfate Proteoglycan 4 for Triple-Negative Breast Cancer Therapy in Mouse Models

Kasten

Oliver

Kim

et al. 2018

IJMS

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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.

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Effective treatment of ductal carcinoma in situ with a HER-2-targeted alpha-particle emitting radionuclide in a preclinical model of human breast cancer

Cited by 25 publications

References 23 publications

Targeted alpha therapy using a novel CD70 targeted thorium-227 conjugate inin vitroandin vivomodels of renal cell carcinoma

Targeted alpha therapy using a novel CD70 targeted thorium-227 conjugate inin vitroandin vivomodels of renal cell carcinoma

B7-H3-targeted 212Pb radioimmunotherapy of ovarian cancer in preclinical models

212Pb-Labeled Antibody 225.28 Targeted to Chondroitin Sulfate Proteoglycan 4 for Triple-Negative Breast Cancer Therapy in Mouse Models

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