B7-H3-targeted Pb Radioimmunotherapy of Ovarian Cancer in Preclinical Models

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 Pb, a source of α-particles. In vitro Scatchard assays determined the specific binding of Pb-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 Pb-376.96 or the irrelevant isotype-matched Pb-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 Pb-376.96 or Pb-F3-C25 and were used for in vivo imaging, ex vivo biodistribution, and therapeutic survival studies.

Results: Pb-376.96 was obtained in high yield and purity (>98%); K values ranged from 10.6-26.6nM for ovarian cancer cells, with 10-10 binding sites/cell. Pb-376.96 inhibited the clonogenic survival of ovarian cancer cells up to 40 times more effectively than isotype-matched control Pb-F3-C25; combining Pb-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 Pb-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 Pb-376.96 and Pb-F3-C25. Tumor-bearing mice treated with Pb-376.96 alone or combined with carboplatin survived 2-3 times longer than mice treated with Pb-F3-C25 or non-treated controls.

Conclusion: These results support additional RIT studies with Pb-376.96 for future evaluation in patients with ovarian cancer.