111 In- and 225 Ac-Labeled Cixutumumab for Imaging and α-Particle Radiotherapy of IGF-1R Positive Triple-Negative Breast Cancer

Mol Pharm. 2019 Dec 2;16(12):4807-4816. doi: 10.1021/acs.molpharmaceut.9b00542. Epub 2019 Nov 5.


Insulin growth factor receptor (IGF-1R) is overexpressed in many cancers of epithelial origin, where it confers enhanced proliferation and resistance to therapies targeted at other receptors. Anti-IGF-1R monoclonal antibodies have not demonstrated significant improvements in patient outcomes in clinical trials. Humanized monoclonal antibody cixutumumab (IMC-A12) binds to IGF-1R with low nM affinity. In this study, cixutumumab was conjugated with p-SCN-Bn-DOTA and radiolabeled with 111In or 225Ac for imaging or radiotherapy using a triple-negative breast cancer (TNBC) model SUM149PT. The antibody conjugate showed low nM affinity to IGF-1R, which was not affected by conjugation and radiolabeling procedures. Cixutumumab immunoconjugates were effectively internalized in SUM149PT and were cytotoxic to the cells with an EC50 of 225Ac-cixutumumab (0.02 nM) that was almost 5000-fold less than that of unlabeled cixutumumab (95.2 nM). MicroSPECT imaging of the SUM149PT xenograft showed the highest tumor uptake occurred at 48 h post injection and was 9.9 ± 0.5% injected activity per gram (%IA/cc). In radiotherapy studies, we evaluated the effect of the specific activity of 225Ac-cixutumumab on efficacy following a tail vein injection of two doses (days 0 and 10) of the investigation agent or controls. Cixutumumab (2.5 mg/kg) prolonged the survival of the SUM149PT tumor-bearing mice with a median survival of 87 days compared to the PBS control group (median survival of 62 days). Median survival of high specific activity 225Ac-cixutumumab (8 kBq/μg, 225 nCi, 0.05 mg/kg) was 103.5 days compared to 122 days for low specific activity 225Ac-cixutumumab (0.15 kBq/μg, 225 nCi, 2.5 mg/kg). Additionally, low specific activity radioimmunoconjugate led to complete tumor remission in 2/6 mice. The data suggest that the efficacy of cixutumumab can be enhanced by radiolabeling with 225Ac at a low specific activity.

Keywords: cixutumumab; insulin growth factor receptor type I (IGF-1R); microSPECT imaging; triple-negative breast cancer; α-particle radiotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actinium / chemistry*
  • Animals
  • Antibodies, Monoclonal, Humanized / chemistry*
  • Biopolymers / chemistry
  • Female
  • Flow Cytometry
  • Humans
  • Indium / chemistry*
  • MCF-7 Cells
  • Mice
  • Radiation-Sensitizing Agents / chemistry*
  • Radioimmunotherapy / methods
  • Receptor, IGF Type 1 / metabolism*
  • Triple Negative Breast Neoplasms / metabolism*
  • Triple Negative Breast Neoplasms / radiotherapy*


  • Actinium-225
  • Antibodies, Monoclonal, Humanized
  • Biopolymers
  • Radiation-Sensitizing Agents
  • Indium
  • cixutumumab
  • Receptor, IGF Type 1
  • Actinium