Effectiveness and normal tissue toxicity of Auger electron (AE) radioimmunotherapy (RIT) with [111In]In-Bn-DTPA-nimotuzumab in mice with triple-negative or trastuzumab-resistant human breast cancer xenografts that overexpress EGFR

Our objective was to evaluate the effectiveness and normal tissue toxicity of nimotuzumab labeled with the Auger electron (AE)-emitter, 111In ([111In]In-Bn-DTPA-nimotuzumab) for radioimmunotherapy (RIT) of human triple-negative breast cancer (TNBC) or trastuzumab-resistant HER2-positive BC tumors overexpressing epidermal growth factor receptors (EGFR) in athymic mice. Normal tissue toxicity was studied in non-tumor-bearing Balb/c mice i.v. administered 9.0 or 28.6 MBq (3 mg/kg) of [111In]In-Bn-DTPA-nimotuzumab, unlabeled nimotuzumab (3 mg/kg) or normal saline. A complete blood cell count (CBC) and serum alanine aminotransferase (ALT) and creatinine (Cr) were measured at 14 days. Body weight was monitored. RIT studies were performed in CD-1 athymic mice engrafted s.c. with MDA-MB-468 human TNBC tumors or TrR1 HER2-positive but trastuzumab-resistant BC tumors. Mice were i.v. administered two amounts (15.5 MBq; 3 mg/kg) of [111In]In-Bn-DTPA-nimotuzumab separated by 14 days. Control mice received unlabeled Bn-DTPA-nimotuzumab (3 mg/kg) or anti-HER2 [111In]In-Bn-DTPA-trastuzumab or normal saline. Tumor growth and body weight were measured for 6 weeks. A tumor growth index (TGI) and body weight index (BWI) were calculated to compare the tumor size and body weight post-treatment with the pre-treatment values. A tumor doubling ratio (TDR) was calculated for each treatment group compared to control mice receiving normal saline. There was no loss of body weight or decreased red blood cells (RBC) or platelets (PLT) or increased serum ALT or Cr in Balb/c mice administered 9.0 or 28.6 MBq (3 mg/kg) of [111In]In-Bn-DTPA-nimotuzumab compared to mice treated with unlabeled Bn-DTPA-nimotuzumab (3 mg/kg) or normal saline. There was a significant decrease in white blood cell (WBC) counts in Balb/c mice receiving 28.6 MBq but not 9.0 MBq of [111In]In-Bn-DTPA-nimotuzumab. Based on these results, an administered amount of 15.5 MBq (3 mg/kg) was selected for RIT studies. Administration of two amounts (15.5 MBq; 3 mg/kg) separated by 14 days to CD-1 athymic mice with s.c. MDA-MB-468 xenografts strongly inhibited tumor growth. The TDR for mice treated with [111In]In-Bn-DTPA-nimotuzumab was 2.15 compared to control mice receiving normal saline. In contrast, treatment with unlabeled Bn-DTPA-nimotuzumab or [111In]In-Bn-DTPA-trastuzumab had no significant effect on tumor growth (TDR = 0.96 and 1.08, respectively). RIT with [111In]In-Bn-DTPA-nimotuzumab also strongly inhibited the grow