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OtherBasic Science (Animal or Phantoms)

CC49 diabody pretargeting using click chemistry in vivo

Sander van Duijnhoven, Raffaella Rossin, Sandra van den Bosch, Michael Wheatcroft, Peter Hudson and Marc Robillard
Journal of Nuclear Medicine July 2015, jnumed.115.159145; DOI: https://doi.org/10.2967/jnumed.115.159145
Sander van Duijnhoven
1 Tagworks Pharmaceuticals, Netherlands;
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Raffaella Rossin
1 Tagworks Pharmaceuticals, Netherlands;
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Sandra van den Bosch
2 Philips Research, Netherlands;
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Michael Wheatcroft
3 Avipep, Netherlands
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Peter Hudson
3 Avipep, Netherlands
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Marc Robillard
1 Tagworks Pharmaceuticals, Netherlands;
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Abstract

Radioimmunotherapy and nuclear imaging (Immuno-PET/SPECT) of cancer using radiometal-labeled antibody fragments or peptides is hampered by low tumor-to-kidney ratios due to high renal radiometal retention. Therefore, we developed and evaluated a pretargeting strategy using click chemistry in vivo to reduce kidney uptake and avoid unwanted radiation toxicity. We focused on the bioorthogonal reaction between a trans-cyclooctene (TCO) functionalized TAG72 tumor targeting diabody, AVP04-07, and a low-molecular weight radiolabeled tetrazine probe, which previously showed low kidney retention and relative fast renal clearance. Methods: AVP04-07 diabodies were functionalized with TCO tags and in vitro immunoreactivity towards bovine submaxillary mucin and tetrazine reactivity was assessed. Next, pretargeting biodistribution studies were performed in LS174T-tumor bearing mice with AVP04-07-TCO(n) and radiolabeled tetrazine to optimize the TCO modification grade (0 vs. 1.8 vs. 4.7 TCOs/diabody) and 177Lu-tetrazine dose (0.1 vs. 1.0 vs. 10 equivalents with respect to diabody). Radiolabeled tetrazine was injected 47h post-diabody injection and mice were euthanized 3h later. A pretargeting SPECT/CT study with 111In-tetrazine was carried out employing the optimized conditions. Results: Immunoreactivity for native and TCO-functionalized AVP04-07 was similar and the latter reacted efficiently with radiolabeled tetrazine in vitro. The combination of the pretargeting components AVP04-07 functionalized with 4.7 TCOs and 1 equivalent of 177Lu-tetrazine with respect to diabody showed the most promising biodistribution. Specifically, high 177Lu-tetrazine tumor uptake (6.9 %ID/g) was observed with low renal retention yielding a tumor-to-kidney ratio of 5.7. SPECT/CT imaging confirmed predominant accumulation of radiolabeled tetrazine in tumor with low non-tumor retention. Conclusion: Pretargeting provides an alternative radioimmunotherapy strategy by overcoming the high renal retention of low molecular weight radiometal tumor-homing agents through the separate administration of the tumor-homing agent and a fast clearing radioactive probe.

  • Animal Imaging
  • Molecular Imaging
  • Monoclonal Antibodies
  • Oncology: General
  • Oncology: GI
  • Radiochemistry
  • Radioimmunoimaging
  • Radionuclide Therapy
  • Radiopharmaceuticals
  • SPECT/CT
  • Click
  • Diabody
  • Diels-Alder
  • Pretargeting
  • Copyright © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
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Journal of Nuclear Medicine: 64 (5)
Journal of Nuclear Medicine
Vol. 64, Issue 5
May 1, 2023
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CC49 diabody pretargeting using click chemistry in vivo
Sander van Duijnhoven, Raffaella Rossin, Sandra van den Bosch, Michael Wheatcroft, Peter Hudson, Marc Robillard
Journal of Nuclear Medicine Jul 2015, jnumed.115.159145; DOI: 10.2967/jnumed.115.159145

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CC49 diabody pretargeting using click chemistry in vivo
Sander van Duijnhoven, Raffaella Rossin, Sandra van den Bosch, Michael Wheatcroft, Peter Hudson, Marc Robillard
Journal of Nuclear Medicine Jul 2015, jnumed.115.159145; DOI: 10.2967/jnumed.115.159145
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Keywords

  • Animal Imaging
  • Molecular Imaging
  • Monoclonal Antibodies
  • Oncology: General
  • Oncology: GI
  • Radiochemistry
  • Radioimmunoimaging
  • radionuclide therapy
  • radiopharmaceuticals
  • SPECT/CT
  • Click
  • diabody
  • Diels-Alder
  • pretargeting
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