Biodistribution, pharmacokinetics and radioimmunotherapy of 188Re-cetuximab in NCI-H292 human lung tumor-bearing nude mice

Summary

Background Cetuximab is a fully humanized IgG1 subclass monoclonal that binds specifically to the human epidermal growth factor receptor (EGFR). Although EGFR is expressed in normal cells, the overexpression of EGFR is detected in many human cancers, such as colon, rectum and lung tumors. In this study, cetuximab with a combination of radiotherapy nuclear 188Re achieved better therapeutic effect on lung cancer. Methods188Re-cetuximab administered by the i.v. route in human NCI-H292 lung tumor-bearing mice was investigated. NanoSPECT/CT images were taken to evaluate the distribution and tumor targeting of 188Re-cetuximab in mice. The anti-tumor effect of 188Re-cetuximab was assessed by the tumor growth inhibition, survival ratio. Results For nanoSPECT/CT imaging, a significant uptake in tumor was observed at 24 and 48 h following the injection of 188Re-cetuximab. The anti-tumor effect of 188Re-cetuximab was assessed by tumor growth inhibition and the survival ratio. The tumor-bearing mice treated with 188Re-cetuximab showed a better mean tumor growth inhibition rate (MGI = 0.049) and longer median survival time and lifespan (62.50 d; 70.07%) than those treated with 188Re-perrhenate and cetuximab only by single injection. A synergistic effect of tumor growth inhibition was observed with the combination index exceeding one for 188Re-cetuximab (CI = 6.135 and 9.276). Conclusion The tumor targeting and localization of 188Re-cetuximab were confirmed in this study. Synergistic therapeutic efficacy was demonstrated for the radioimmunotherapy of 188Re-cetuximab. The results of this study reveal the potential advantage and benefit obtained from 188Re-cetuximab for diagnosis and therapy of oncology applications in the future.

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Abbreviations

AUC:

Area under the curve

CI:

Combination index

Cl:

Clearance

CR:

Complete response

CRC:

Colorectal cancer

Cmax :

The maximum concentration

EGFR:

Epidermal growth factor receptor

FLEX:

First-line erbitux in lung cancer

IR:

Inhibition rate

mAbs:

Monoclonal antibodies

MAA:

Maximum administered activity

MGI:

Growth inhibition rate

MTD:

Maximum tolerated dose

NCA:

Noncompartmental analysis

NHL:

Non-Hodgkin’s lymphoma

ORR:

Overall response rate

RIT:

Radioimmunotherapy

ROI:

Region of interest

T1/2z :

Elimination half-life

VOIs:

Volumes of interest

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Acknowledgements

The authors would like to thank C. C. Liang, W. L. Lo, Y. R. Huang and M. W. Chen for help with the biodistribution study of 188Re-cetuximab.

Grants

This study was supported by the grants from Ministry of Economic Affairs of Taiwan (Grant Number 107-EC-17-A-22-1309) and Taipei Veterans General Hospital (Grant Number V106D29–003-MY3–2).

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Correspondence to Chih-Hsien Chang.

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Chang, Y., Ho, C., Cheng, K. et al. Biodistribution, pharmacokinetics and radioimmunotherapy of 188Re-cetuximab in NCI-H292 human lung tumor-bearing nude mice. Invest New Drugs 37, 961–972 (2019). https://doi.org/10.1007/s10637-018-00718-8

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Keywords

  • 188Re
  • Cetuximab
  • Radioimmunotherapy