Advertisement

Molecular Imaging and Biology

, Volume 18, Issue 2, pp 232–242 | Cite as

Biodistribution Study of Intravenously Injected Cetuximab-IRDye700DX in Cynomolgus Macaques

  • E. de Boer
  • S. Samuel
  • D. N. French
  • J. M. Warram
  • T. R. Schoeb
  • E. L. Rosenthal
  • K. R. Zinn
Research Article

Abstract

Purpose

The use of receptor-targeted antibodies conjugated to photosensitizers is actively being explored to enhance treatment efficacy. To facilitate clinical testing, we evaluated cetuximab conjugated to IRDye700DX (IR700) in cynomolgus macaques.

Procedures

Total IR700 and intact cetuximab-IR700 were measured in 51 tissues at 2 and 14 days after intravenous injection of 40 and 80 mg/kg cetuximab-IR700, respectively, and compared with an unlabeled cetuximab-dosed control group (two each per sex per time point per group).

Results

The IR700 retrieved from all tissues at 2 and 14 days after dosing was estimated at 34.9 ± 1.8 and 2.53 ± 0.67 % of the total dose, respectively. The tissues with the highest levels of intact cetuximab-IR700 at 2 days after dosing were the blood, lung, and skin. Formalin-fixed paraffin-embedded tissue sections at 2 days after dosing showed the highest IR700 signals in the axillary lymph node, mammary gland, and gall bladder.

Conclusions

Both IR700 and intact cetuximab-IR700 biodistributions were consistent with known epidermal growth factor receptor (EGFR) expression, and changes between 2 and 14 days were consistent with rapid metabolism and excretion of the cetuximab-IR700.

Key words

Photoimmunotherapy Biodistribution Macaques Cetuximab IRDye700DX 

Notes

Acknowledgments

This work was supported by Aspyrian Therapeutics LLC, the UAB Comprehensive Cancer Center small animal imaging shared facility (5P30CA013148), and an equipment loan from LI-COR Biosciences. Authors would like to thank Miguel Garcia-Guzman for his input in this study.

Compliance with Ethical Standards

Conflict of Interest

Dr. K. R. Zinn reports grants from Aspyrian Therapeutics, during the conduct of the study.

Ethical Approval

All applicable institutional and/or national guidelines for the care and use of animals were followed.

Supplementary material

11307_2015_892_MOESM1_ESM.pdf (2.9 mb)
Supplemental Figure 1 (PDF 2947 kb)

References

  1. 1.
    van Dam GM, Themelis G, Crane LM et al (2011) Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results. Nat Med 17:1315–1319CrossRefPubMedGoogle Scholar
  2. 2.
    Zinn KR, Korb M, Samuel S et al (2015) IND-directed safety and biodistribution study of intravenously injected cetuximab-IRDye800 in cynomolgus macaques. Mol Imaging Biol 17:49–57CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Day KE, Sweeny L, Kulbersh B et al (2013) Preclinical comparison of near-infrared-labeled cetuximab and panitumumab for optical imaging of head and neck squamous cell carcinoma. Mol Imaging Biol 15:722–729CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Heath CH, Deep NL, Sweeny L et al (2012) Use of panitumumab-IRDye800 to image microscopic head and neck cancer in an orthotopic surgical model. Ann Surg Oncol 19:3879–3887CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Terwisscha van Scheltinga AG, van Dam GM, Nagengast WB et al (2011) Intraoperative near-infrared fluorescence tumor imaging with vascular endothelial growth factor and human epidermal growth factor receptor 2 targeting antibodies. J Nucl Med 52:1778–1785CrossRefPubMedGoogle Scholar
  6. 6.
    Korb ML, Hartman YE, Kovar J et al (2014) Use of monoclonal antibody-IRDye800CW bioconjugates in the resection of breast cancer. J Surg Res 188:119–128CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    van Dongen GA, Visser GW, Vrouenraets MB (2004) Photosensitizer-antibody conjugates for detection and therapy of cancer. Adv Drug Deliv Rev 56:31–52CrossRefPubMedGoogle Scholar
  8. 8.
    Mitsunaga M, Ogawa M, Kosaka N et al (2011) Cancer cell-selective in vivo near infrared photoimmunotherapy targeting specific membrane molecules. Nat Med 17:1685–1691CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    de Boer E, Warram JM, Hartmans E et al (2014) A standardized light-emitting diode device for photoimmunotherapy. J Nucl Med 55:1893–1898CrossRefPubMedGoogle Scholar
  10. 10.
    Mitsunaga M, Nakajima T, Sano K et al (2012) Immediate in vivo target-specific cancer cell death after near infrared photoimmunotherapy. BMC Cancer 12:1471–2407CrossRefGoogle Scholar
  11. 11.
    Nakajima T, Sano K, Choyke PL, Kobayashi H (2013) Improving the efficacy of photoimmunotherapy (PIT) using a cocktail of antibody conjugates in a multiple antigen tumor model. Theranostics 3:357–365CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Rogers SJ, Harrington KJ, Rhys-Evans P et al (2005) Biological significance of c-erbB family oncogenes in head and neck cancer. Cancer Metastasis Rev 24:47–69CrossRefPubMedGoogle Scholar
  13. 13.
    Giusti RM, Shastri KA, Cohen MH et al (2007) FDA drug approval summary: panitumumab (Vectibix). Oncologist 12:577–583CrossRefPubMedGoogle Scholar
  14. 14.
    Kim H, Chaudhuri TR, Buchsbaum DJ et al (2007) High-resolution single-photon emission computed tomography and X-ray computed tomography imaging of Tc-99m-labeled anti-DR5 antibody in breast tumor xenografts. Mol Cancer Ther 6:866–875CrossRefPubMedGoogle Scholar
  15. 15.
    de Boer E, Warram JM, Tucker MD et al (2015) In vivo fluorescence immunohistochemistry: localization of fluorescently labeled cetuximab in squamous cell carcinomas. Sci Rep 5:10169CrossRefPubMedGoogle Scholar
  16. 16.
    Tichauer KM, Samkoe KS, Gunn JR et al (2014) Microscopic lymph node tumor burden quantified by macroscopic dual-tracer molecular imaging. Nat Med 20:1348–1353CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© World Molecular Imaging Society 2015

Authors and Affiliations

  • E. de Boer
    • 1
    • 2
  • S. Samuel
    • 3
  • D. N. French
    • 3
  • J. M. Warram
    • 1
  • T. R. Schoeb
    • 4
  • E. L. Rosenthal
    • 5
  • K. R. Zinn
    • 3
  1. 1.Department of SurgeryUniversity of Alabama at BirminghamBirminghamUSA
  2. 2.Department of Surgery, University of GroningenUniversity Medical Centrum GroningenGroningenThe Netherlands
  3. 3.Department of RadiologyUniversity of Alabama at BirminghamBirminghamUSA
  4. 4.Department of GeneticsUniversity of Alabama at BirminghamBirminghamUSA
  5. 5.Department of Otolaryngology-Head and Neck SurgeryStanford UniversityStanfordUSA

Personalised recommendations