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Molecules 2018, 23(5), 1223; https://doi.org/10.3390/molecules23051223

d-Amino Acid Peptide Residualizing Agents for Protein Radioiodination: Effect of Aspartate for Glutamate Substitution

1
Department of Radiology, Duke University Medical Center, Durham, NC 27710, USA
2
Present address: Institute of Nuclear Chemistry and Technology, 03-195 Warsaw, Poland
3
Present address: Korea Institute of Radiological and Medical Sciences, Seoul 01812, Korea
4
Present address: Laboratory for Translational and Molecular Imaging, Duke-National University of Singapore Medical School, Singapore 169857, Singapore
*
Authors to whom correspondence should be addressed.
Received: 23 April 2018 / Revised: 15 May 2018 / Accepted: 17 May 2018 / Published: 20 May 2018
(This article belongs to the Section Bioorganic Chemistry)
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Abstract

The residualizing prosthetic agent Nε-(3-[*I]iodobenzoyl)-Lys5-Nα-maleimido-Gly1-d-GEEEK ([*I]IB-Mal-d-GEEEK) showed promise for the radioiodination of monoclonal antibodies (mAbs) that bind to internalizing molecular targets. Although enhanced tumor uptake was achieved in these studies, elevated kidney accumulation also was observed, particularly with low-molecular-weight, single-domain antibody fragments (sdAbs). Here, we developed an analogous agent (IB-Mal-d-GDDDK), in which glutamate residues (E) were replaced with aspartates (D) to determine whether this modification could decrease renal uptake. [125I]IB-Mal-d-GDDDK and [131I]IB-Mal-d-GEEEK were synthesized with similar radiochemical yields (60–80%) and coupled to the anti-HER2 sdAb 5F7 at 50–60% efficiency. Paired-label internalization assays in vitro indicated similar levels of intracellular activity residualization in HER2-expressing BT474M1 cells for [125I]IB-Mal-d-GDDDK-5F7 and [131I]IB-Mal-d-GEEEK-5F7. A paired-label biodistribution comparison of the two labeled conjugates was performed in mice with HER2-expressing SKOV-3 xenografts, and the results of this study indicated that renal uptake at 1 h was 127.5 ± 18.7% ID/g and 271.4 ± 66.6% ID/g for [125I]IB-Mal-d-GDDDK-5F7 and [131I]IB-Mal-d-GEEEK-5F7, respectively. The tumor uptake of the two radioconjugates was not significantly different. These results demonstrate that substitution of E with D in the IB-Mal-d-GEEEK construct reduced kidney accumulation of the sdAb. However, renal activity levels need to be reduced further if d-amino acid derived prosthetic agents are to be of practical value for labeling low molecular weight biomolecules such as sdAbs. View Full-Text
Keywords: radioiodination; VHH; HER2; residualizing label; breast cancer radioiodination; VHH; HER2; residualizing label; breast cancer
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Pruszynski, M.; Kang, C.M.; Koumarianou, E.; Vaidyanathan, G.; Zalutsky, M.R. d-Amino Acid Peptide Residualizing Agents for Protein Radioiodination: Effect of Aspartate for Glutamate Substitution. Molecules 2018, 23, 1223.

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