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

Nucl Med Biol. 2020 Jan-Feb;80-81:37-44. doi: 10.1016/j.nucmedbio.2019.10.001. Epub 2019 Oct 22.


Introduction: 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.

Methods: 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.

Results: 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 growth of TrR1 tumors in athymic mice (TDR = 2.13) compared to unlabeled Bn-DTPA-nimotuzumab (TDR = 0.91). There were no losses in body weight over 6 weeks in tumor bearing mice receiving [111In]In-Bn-DTPA-nimotuzumab, unlabeled Bn-DTPA-nimotuzumab, [111In]In-Bn-DTPA-trastuzumab or normal saline.

Conclusions: [111In]In-Bn-DTPA-nimotuzumab was effective for treatment of TNBC or trastuzumab-resistant HER2-positive human BC tumors in mice that overexpress EGFR at administered amounts that caused no decrease in body weight or normal tissue toxicity in non-tumor-bearing Balb/c mice.

Advances in knowledge and implications for patient care: Our results suggest that Auger electron RIT with [111In]In-Bn-DTPA-nimotuzumab may provide a novel therapeutic option for patients with TNBC or trastuzumab-resistant HER2-positive BC that overexpresses EGFR. The low normal tissue toxicity of this approach may allow combination with other targeted therapies such as antibody-drug conjugates (ADCs).

Keywords: Auger electrons; Epidermal growth factor receptors (EGFR); Indium-111; Nimotuzumab; Radioimmunotherapy; Trastuzumab resistant HER2-positive breast cancer; Triple-negative breast cancer (TNBC).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / adverse effects*
  • Antibodies, Monoclonal, Humanized / pharmacokinetics
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / immunology
  • Drug Resistance, Neoplasm / radiation effects*
  • Electrons / adverse effects
  • Electrons / therapeutic use
  • ErbB Receptors / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic / radiation effects
  • Humans
  • Immunoconjugates / adverse effects
  • Immunoconjugates / pharmacokinetics
  • Immunoconjugates / therapeutic use
  • Indium Radioisotopes / therapeutic use*
  • Mice
  • Pentetic Acid / chemistry*
  • Phenotype
  • Radioimmunotherapy / adverse effects*
  • Tissue Distribution
  • Trastuzumab / pharmacology
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / pathology
  • Triple Negative Breast Neoplasms / radiotherapy*


  • Antibodies, Monoclonal, Humanized
  • Immunoconjugates
  • Indium Radioisotopes
  • nimotuzumab
  • Pentetic Acid
  • Indium-111
  • ErbB Receptors
  • Trastuzumab