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

Abstract

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 0.17-0.70MBq 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 10.6-26.6nM 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 24h 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.

• Authors: Benjamin B Kasten, Rebecca C Arend, Ashwini A Katre, Harrison Kim, Jinda Fan, Soldano Ferrone, Kurt R Zinn, Donald J Buchsbaum
• Journal: Nuclear medicine and biology (Nucl Med Biol) Vol. 47 Pg. 23-30 (Apr 2017) ISSN: 1872-9614 [Electronic] United States
• PMID: 28104527 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Antibodies, Monoclonal
• B7 Antigens
• CD276 protein, human
• Epitopes
• Lead Radioisotopes

Topics

• Animals
• Antibodies, Monoclonal (immunology, therapeutic use)
• B7 Antigens (immunology)
• Cell Differentiation
• Cell Line, Tumor
• Cell Survival
• Cell Transformation, Neoplastic
• Epitopes (immunology)
• Female
• Humans
• Lead Radioisotopes (therapeutic use)
• Mice
• Ovarian Neoplasms (pathology, radiotherapy)
• Radioimmunotherapy (methods)