title: B7-H3-targeted212Pb radioimmunotherapy of ovarian cancer in preclinical models.
abstract: BACKGROUND
  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 with212Pb, a source of α-particles. In vitro Scatchard assays determined the specific binding of212Pb-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 with212Pb-376.96 or the irrelevant isotype-matched212Pb-F3-C25 were assessed for clonogenic survival. Mice bearing i.p. ES-2 or A2780cp20 xenografts were injected i.p. with 0.17-0.70MBq212Pb-376.96 or212Pb-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%); Kdvalues ranged from 10.6-26.6nM for ovarian cancer cells, with 104-105binding sites/cell.212Pb-376.96 inhibited the clonogenic survival of ovarian cancer cells up to 40 times more effectively than isotype-matched control212Pb-F3-C25; combining212Pb-376.96 with carboplatin significantly decreased clonogenic survival compared to either agent alone. In vivo imaging and biodistribution analysis 24h after i.p. injection of212Pb-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 for212Pb-376.96 and212Pb-F3-C25. Tumor-bearing mice treated with212Pb-376.96 alone or combined with carboplatin survived 2-3 times longer than mice treated with212Pb-F3-C25 or non-treated controls.
  
  
  CONCLUSIONS
  These results support additional RIT studies with212Pb-376.96 for future evaluation in patients with ovarian cancer.
authors.affiliation: Department of Radiology, University of Alabama at Birmingham, Birmingham, AL. Electronic address: benjaminkasten@uabmc.edu.
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Kasten
authors.affiliation: Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Arend
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Ashwini A
authors.initials: AA
authors.lastname: Katre
authors.affiliation: Department of Radiology, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Harrison
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Radiology, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Jinda
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Soldano
authors.initials: S
authors.lastname: Ferrone
authors.affiliation: Department of Radiology, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Zinn
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Buchsbaum
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D060887:B7 Antigens / Q000276:immunology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D000939:Epitopes / Q000276:immunology*; D005260:Female; D006801:Humans; D007856:Lead Radioisotopes / Q000627:therapeutic use*; D051379:Mice; D010051:Ovarian Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D016499:Radioimmunotherapy / Q000379:methods*
chemical_list: D000911:Antibodies, Monoclonal; D060887:B7 Antigens; C423237:CD276 protein, human; D000939:Epitopes; D007856:Lead Radioisotopes
keywords: (212)Pb; B7-H3; Ovarian cancer; Radioimmunotherapy