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


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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Area under the curve


Combination index




Complete response


Colorectal cancer

Cmax :

The maximum concentration


Epidermal growth factor receptor


First-line erbitux in lung cancer


Inhibition rate


Monoclonal antibodies


Maximum administered activity


Growth inhibition rate


Maximum tolerated dose


Noncompartmental analysis


Non-Hodgkin’s lymphoma


Overall response rate




Region of interest

T1/2z :

Elimination half-life


Volumes of interest


  1. 1.

    Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA (2008) Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 83(5):584–594.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Privitera G, Luca T, Musso N, Vancheri C, Crimi N, Barresi V, Condorelli D, Castorina S (2016) In vitro antiproliferative effect of trastuzumab (Herceptin((R))) combined with cetuximab (Erbitux((R))) in a model of human non-small cell lung cancer expressing EGFR and HER2. Clin Exp Med 16(2):161–168.

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    Patil N, Abba M, Allgayer H (2012) Cetuximab and biomarkers in non-small-cell lung carcinoma. Biologics 6:221–231.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Pujol JL, Pirker R, Lynch TJ, Butts CA, Rosell R, Shepherd FA, Vansteenkiste J, O'Byrne KJ, de Blas B, Heighway J, von Heydebreck A, Thatcher N (2014) Meta-analysis of individual patient data from randomized trials of chemotherapy plus cetuximab as first-line treatment for advanced non-small cell lung cancer. Lung Cancer 83(2):211–218.

    Article  Google Scholar 

  5. 5.

    Kim SM, Kim JS, Kim JH, Yun CO, Kim EM, Kim HK, Solca F, Choi SY, Cho BC (2010) Acquired resistance to cetuximab is mediated by increased PTEN instability and leads cross-resistance to gefitinib in HCC827 NSCLC cells. Cancer Lett 296(2):150–159.

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Pirker R, Pereira JR, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, Vynnychenko I, Park K, Yu CT, Ganul V, Roh JK, Bajetta E, O'Byrne K, de Marinis F, Eberhardt W, Goddemeier T, Emig M, Gatzemeier U, Team FS (2009) Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 373(9674):1525–1531.

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Rosell R, Robinet G, Szczesna A, Ramlau R, Constenla M, Mennecier BC, Pfeifer W, O'Byrne KJ, Welte T, Kolb R, Pirker R, Chemaissani A, Perol M, Ranson MR, Ellis PA, Pilz K, Reck M (2008) Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer. Annals of oncology : official journal of the European Society for. Med Oncol 19(2):362–369.

    CAS  Article  Google Scholar 

  8. 8.

    Gatzemeier U, von Pawel J, Vynnychenko I, Zatloukal P, de Marinis F, Eberhardt WE, Paz-Ares L, Schumacher KM, Goddemeier T, O'Byrne KJ, Pirker R (2011) First-cycle rash and survival in patients with advanced non-small-cell lung cancer receiving cetuximab in combination with first-line chemotherapy: a subgroup analysis of data from the FLEX phase 3 study. Lancet Oncol 12(1):30–37.

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Milenic DE, Brady ED, Brechbiel MW (2004) Antibody-targeted radiation cancer therapy. Nat Rev Drug Discov 3(6):488–499.

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Ting G, Chang CH, Wang HE, Lee TW (2010) Nanotargeted radionuclides for cancer nuclear imaging and internal radiotherapy. J Biomed Biotechnol 2010:1–17.

    Article  CAS  Google Scholar 

  11. 11.

    Davis TA, Kaminski MS, Leonard JP, Hsu FJ, Wilkinson M, Zelenetz A, Wahl RL, Kroll S, Coleman M, Goris M, Levy R, Knox SJ (2004) The radioisotope contributes significantly to the activity of radioimmunotherapy. Clin Cancer Res 10(23):7792–7798.

  12. 12.

    Witzig TE, Gordon LI, Cabanillas F, Czuczman MS, Emmanouilides C, Joyce R, Pohlman BL, Bartlett NL, Wiseman GA, Padre N, Grillo-Lopez AJ, Multani P, White CA (2002) Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol 20(10):2453–2463.

  13. 13.

    Gordon LI, Witzig T, Molina A, Czuczman M, Emmanouilides C, Joyce R, Vo K, Theuer C, Pohlman B, Bartlett N, Wiseman G, Darif M, White C (2004) Yttrium 90-labeled ibritumomab tiuxetan radioimmunotherapy produces high response rates and durable remissions in patients with previously treated B-cell lymphoma. Clin Lymphoma 5(2):98–101

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Bonner JA (2016) Cetuximab or cisplatin as a radiosensitizer in locoregionally advanced head and neck cancer: recent results. Transl Cancer Res 5(3):234–237.

  15. 15.

    Bianco C, Tortora G, Bianco R, Caputo R, Veneziani BM, Caputo R, Damiano V, Troiani T, Fontanini G, Raben D, Pepe S, Bianco AR, Ciardiello F (2002) Enhancement of antitumor activity of ionizing radiation by combined treatment with the selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 (Iressa). Clin Cancer Res 8(10):3250–3258

  16. 16.

    Chinnaiyan P, Huang S, Vallabhaneni G, Armstrong E, Varambally S, Tomlins SA, Chinnaiyan AM, Harari PM (2005) Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva). Cancer Res 65(8):3328–3335.

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Raben D, Helfrich B, Chan DC, Ciardiello F, Zhao L, Franklin W, Baron AE, Zeng C, Johnson TK, Bunn PA Jr (2005) The effects of cetuximab alone and in combination with radiation and/or chemotherapy in lung cancer. Clin Cancer Res 11(2 Pt 1):795–805

  18. 18.

    Milas L, Mason K, Hunter N, Petersen S, Yamakawa M, Ang K, Mendelsohn J, Fan Z (2000) In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody. Clin Cancer Res 6(2):701–708

  19. 19.

    Huang SM, Bock JM, Harari PM (1999) Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res 59(8):1935–1940

    CAS  PubMed  Google Scholar 

  20. 20.

    Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, Baselga J, Youssoufian H, Amellal N, Rowinsky EK, Ang KK (2006) Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354(6):567–578.

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, Raben D, Baselga J, Spencer SA, Zhu J, Youssoufian H, Rowinsky EK, Ang KK (2010) Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 11(1):21–28.

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Stabin MG, Siegel JA (2003) Physical models and dose factors for use in internal dose assessment. Health Phys 85(3):294–310

    Article  CAS  PubMed  Google Scholar 

  23. 23.

    Molina-Trinidad EM, de Murphy CA, Ferro-Flores G, Murphy-Stack E, Jung-Cook H (2006) Radiopharmacokinetic and dosimetric parameters of 188Re-lanreotide in athymic mice with induced human cancer tumors. Int J Pharm 310(1–2):125–130.

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Lin YY, Chang CH, Li JJ, Stabin MG, Chang YJ, Chen LC, Lin MH, Tseng YL, Lin WJ, Lee TW, Ting G, Chang CA, Chen FD, Wang HE (2011) Pharmacokinetics and dosimetry of 111In/188Re-labeled PEGylated liposomal drugs in two colon carcinoma-bearing mouse models. Cancer Biother Radiopharm 26(3):373–380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Chang CH, Stabin MG, Chang YJ, Chen LC, Chen MH, Chang TJ, Lee TW, Ting G (2008) Comparative dosimetric evaluation of nanotargeted 188Re-(DXR)-liposome for internal radiotherapy. Cancer Biother Radiopharm 23(6):749–758.

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Bentel GCNC, Noell KT (1989) Treatment planning and dose calculation in radiation oncology. Pergamon Press, Oxford

    Google Scholar 

  27. 27.

    O'Donoghue JA, Baidoo N, Deland D, Welt S, Divgi CR, Sgouros G (2002) Hematologic toxicity in radioimmunotherapy: dose-response relationships for I-131 labeled antibody therapy. Cancer Biother Radiopharm 17(4):435–443

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Cao S, Rustum YM (2000) Synergistic antitumor activity of irinotecan in combination with 5-fluorouracil in rats bearing advanced colorectal cancer: role of drug sequence and dose. Cancer Res 60(14):3717–3721

    CAS  PubMed  Google Scholar 

  29. 29.

    Reilly RM, Chen P, Wang J, Scollard D, Cameron R, Vallis KA (2006) Preclinical pharmacokinetic, biodistribution, toxicology, and dosimetry studies of 111In-DTPA-human epidermal growth factor: an auger electron-emitting radiotherapeutic agent for epidermal growth factor receptor-positive breast cancer. J Nucl Med 47(6):1023–1031

  30. 30.

    Morgillo F, Kim WY, Kim ES, Ciardiello F, Hong WK, Lee HY (2007) Implication of the insulin-like growth factor-IR pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib. Clin Cancer Res 13(9):2795–2803.

  31. 31.

    Maddalena ME, Fox J, Chen J, Feng W, Cagnolini A, Linder KE, Tweedle MF, Nunn AD, Lantry LE (2009) 177Lu-AMBA biodistribution, radiotherapeutic efficacy, imaging, and autoradiography in prostate cancer models with low GRP-R expression. J Nucl Med 50(12):2017–2024

  32. 32.

    Goetz M, Hoetker MS, Diken M, Galle PR, Kiesslich R (2013) In vivo molecular imaging with cetuximab, an anti-EGFR antibody, for prediction of response in xenograft models of human colorectal cancer. Endoscopy 45(6):469–477.

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    van Dijk LK, Hoeben BA, Kaanders JH, Franssen GM, Boerman OC, Bussink J (2013) Imaging of epidermal growth factor receptor expression in head and neck cancer with SPECT/CT and 111In-labeled cetuximab-F(ab')2. J Nucl Med 54(12):2118–2124.

  34. 34.

    Shih YH, Peng CL, Lee SY, Chiang PF, Yao CJ, Lin WJ, Luo TY, Shieh MJ (2015) 111In-cetuximab as a diagnostic agent by accessible epidermal growth factor (EGF) receptor targeting in human metastatic colorectal carcinoma. Oncotarget 6(18):16601–16610.

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Hoeben BA, Molkenboer-Kuenen JD, Oyen WJ, Peeters WJ, Kaanders JH, Bussink J, Boerman OC (2011) Radiolabeled cetuximab: dose optimization for epidermal growth factor receptor imaging in a head-and-neck squamous cell carcinoma model. Int J Cancer 129(4):870–878.

    Article  CAS  Google Scholar 

  36. 36.

    Shih BB, Chang YF, Cheng CC, Yang HJ, Chang KW, Ho AS, Lin HC, Yeh C, Chang CC (2017) SPECT imaging evaluation of 111indium-chelated cetuximab for diagnosing EGFR-positive tumor in an HCT-15-induced colorectal xenograft. J Chin Med Assoc 80(12):766–773.

  37. 37.

    Makris NE, Boellaard R, van Lingen A, Lammertsma AA, van Dongen GA, Verheul HM, Menke CW, Huisman MC (2015) PET/CT-derived whole-body and bone marrow dosimetry of 89Zr-cetuximab. J Nucl Med 56(2):249–254.

  38. 38.

    Perk LR, Visser GW, Vosjan MJ, Stigter-van Walsum M, Tijink BM, Leemans CR, van Dongen GA (2005) 89Zr as a PET surrogate radioisotope for scouting biodistribution of the therapeutic radiometals 90Y and 177Lu in tumor-bearing nude mice after coupling to the internalizing antibody cetuximab. J Nucl Med 46(11):1898–1906

  39. 39.

    van Dijk LK, Yim CB, Franssen GM, Kaanders JH, Rajander J, Solin O, Gronroos TJ, Boerman OC, Bussink J (2016) PET of EGFR with 64Cu-cetuximab-F(ab')2 in mice with head and neck squamous cell carcinoma xenografts. Contrast Media Mol Imaging 11(1):65–70.

  40. 40.

    Guo Y, Parry JJ, Laforest R, Rogers BE, Anderson CJ (2013) The role of p53 in combination radioimmunotherapy with 64Cu-DOTA-cetuximab and cisplatin in a mouse model of colorectal cancer. J Nucl Med 54(9):1621–1629.

  41. 41.

    Schechter NR, Wendt RE 3rd, Yang DJ, Azhdarinia A, Erwin WD, Stachowiak AM, Broemeling LD, Kim EE, Cox JD, Podoloff DA, Ang KK (2004) Radiation dosimetry of 99mTc-labeled C225 in patients with squamous cell carcinoma of the head and neck. J Nucl Med 45(10):1683–1687

  42. 42.

    Chakravarty R, Chakraborty S, Sarma HD, Nair KV, Rajeswari A, Dash A (2016) 90Y/177Lu-labelled Cetuximab immunoconjugates: radiochemistry optimization to clinical dose formulation. J Label Compd Radiopharm 59(9):354–363.

    Article  CAS  Google Scholar 

  43. 43.

    Song IH, Lee TS, Park YS, Lee JS, Lee BC, Moon BS, An GI, Lee HW, Kim KI, Lee YJ, Kang JH, Lim SM (2016) Immuno-PET imaging and Radioimmunotherapy of 64Cu-/177Lu-labeled anti-EGFR antibody in esophageal squamous cell carcinoma model. J Nucl Med 57(7):1105–1111.

  44. 44.

    Iznaga-Escobar N (1998) 188Re-direct labeling of monoclonal antibodies for radioimmunotherapy of solid tumors: biodistribution, normal organ dosimetry, and toxicology. Nucl Med Biol 25(5):441–447

    Article  CAS  PubMed  Google Scholar 

  45. 45.

    O'Donoghue JA, Bardies M, Wheldon TE (1995) Relationships between tumor size and curability for uniformly targeted therapy with beta-emitting radionuclides. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 36(10):1902–1909

    CAS  Google Scholar 

  46. 46.

    Wang HY, Lin WY, Chen MC, Lin T, Chao CH, Hsu FN, Lin E, Huang CY, Luo TY, Lin H (2013) Inhibitory effects of Rhenium-188-labeled Herceptin on prostate cancer cell growth: a possible radioimmunotherapy to prostate carcinoma. Int J Radiat Biol 89(5):346–355.

    Article  CAS  PubMed  Google Scholar 

  47. 47.

    Li G, Wang Y, Huang K, Zhang H, Peng W, Zhang C (2005) The experimental study on the radioimmunotherapy of the nasopharyngeal carcinoma overexpressing HER2/neu in nude mice model with intratumoral injection of 188Re-herceptin. Nucl Med Biol 32(1):59–65.

    Article  CAS  PubMed  Google Scholar 

  48. 48.

    Dittmann K, Mayer C, Fehrenbacher B, Schaller M, Raju U, Milas L, Chen DJ, Kehlbach R, Rodemann HP (2005) Radiation-induced epidermal growth factor receptor nuclear import is linked to activation of DNA-dependent protein kinase. J Biol Chem 280(35):31182–31189.

    Article  CAS  PubMed  Google Scholar 

  49. 49.

    Dittmann K, Mayer C, Fehrenbacher B, Schaller M, Kehlbach R, Rodemann HP (2011) Nuclear epidermal growth factor receptor modulates cellular radio-sensitivity by regulation of chromatin access. Radiother Oncol 99(3):317–322.

  50. 50.

    Morgan MA, Parsels LA, Kollar LE, Normolle DP, Maybaum J, Lawrence TS (2008) The combination of epidermal growth factor receptor inhibitors with gemcitabine and radiation in pancreatic cancer. Clin Cancer Res 14(16):5142–5149.

  51. 51.

    Kimple RJ, Vaseva AV, Cox AD, Baerman KM, Calvo BF, Tepper JE, Shields JM, Sartor CI (2010) Radiosensitization of epidermal growth factor receptor/HER2-positive pancreatic cancer is mediated by inhibition of Akt independent of ras mutational status. Clin Cancer Res 16(3):912–923.

  52. 52.

    Rembielak AI, Jain P, Jackson AS, Green MM, Santorelli GR, Whitfield GA, Crellin A, Garcia-Alonso A, Radhakrishna G, Cullen J, Taylor MB, Swindell R, West CM, Valle J, Saleem A, Price PM (2014) Phase II trial of Cetuximab and conformal radiotherapy only in locally advanced pancreatic Cancer with concurrent tissue sampling feasibility study. Transl Oncol 7(1):55–64

    Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Bonner JA, Trummell HQ, Bonner AB, Willey CD, Bredel M, Yang ES (2015) Enhancement of Cetuximab-induced Radiosensitization by JAK-1 inhibition. BMC Cancer 15:673.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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.


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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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).

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  • 188Re
  • Cetuximab
  • Radioimmunotherapy