The ionic charge of Copper-64 complexes conjugated to an engineered antibody effects biodistribution
Abstract
The development of biomolecules as imaging probes requires radiolabeling methods that do not significantly influence their biodistribution. Sarcophagine (Sar) chelators form extremely stable complexes with copper, and are therefore a promising option for labeling proteins with ⁶⁴Cu. However, initial studies using the first-generation sarcophagine bifunctional chelator SarAr to label the engineered antibody fragment ch14.18-ΔCH2 (MW 120 kDa) with ⁶⁴Cu showed high tracer retention in the kidneys,(>38% injected dose per gram (ID/g) 48 h post-injection), presumably because the high local positive charge on the CuII-SarAr moiety resulted in increased binding of the labeled protein to the negatively charged basal cells of the glomerulus. To test this hypothesis, ch14.18-ΔCH2 was conjugated with a series of Sar derivatives of decreasing positive charge and three commonly used macrocyclic polyaza polycarboxylate (PAC) BFCs. The immunoconjugates were labeled with ⁶⁴Cu and injected into mice, and PET/CT images were obtained at 24 and 48 h post injection (p.i.). At 48 h p.i., ex vivo biodistribution was carried out. In addition, to demonstrate the potential of metastasis detection using ⁶⁴Cu-labeled ch14.18-ΔCH2, a preclinical imaging study of intrahepatic neuroblastoma tumors was performed carried out. Reducing the positive charge on the Sar chelators decreased kidney uptake of Cu-labeled ch14.18-ΔCH2 bymore »
- Authors:
-
- Boston Children's Hospital, Boston, MA (United States); Harvard Medical School, Boston, MA (United States)
- Brookhaven National Lab. (BNL), Upton, NY (United States)
- Univ. of Melbourne (Australia)
- Boston Children's Hospital, Boston, MA (United States)
- The Antibody Society & Huston BioConsulting LLC, Boston, MA (United States)
- Publication Date:
- Research Org.:
- Brookhaven National Laboratory (BNL), Upton, NY (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Nuclear Physics (NP)
- OSTI Identifier:
- 1201357
- Report Number(s):
- BNL-108158-2015-JA
Journal ID: ISSN 1043-1802; R&D Project: KBCH139; 00600; KB0202011
- Grant/Contract Number:
- SC00112704
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Bioconjugate Chemistry
- Additional Journal Information:
- Journal Volume: 26; Journal Issue: 4; Journal ID: ISSN 1043-1802
- Publisher:
- American Chemical Society
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 43 PARTICLE ACCELERATORS; bifunctional chelator; ΔCH2; sarcophagine; radioimmunoimaging; NOTA; ⁶⁴Cu
Citation Formats
Dearling, Jason L. J., Smith, Suzanne V., Paterson, Brett M., Akurathi, Vamisidhar, Betanzos-Lara, Soledad, Treves, S. Ted, Voss, Stephan D., White, Jonathan M., Huston, James S., Donnelly, Paul S., and Packard, Alan B. The ionic charge of Copper-64 complexes conjugated to an engineered antibody effects biodistribution. United States: N. p., 2015.
Web. doi:10.1021/acs.bioconjchem.5b00049.
Dearling, Jason L. J., Smith, Suzanne V., Paterson, Brett M., Akurathi, Vamisidhar, Betanzos-Lara, Soledad, Treves, S. Ted, Voss, Stephan D., White, Jonathan M., Huston, James S., Donnelly, Paul S., & Packard, Alan B. The ionic charge of Copper-64 complexes conjugated to an engineered antibody effects biodistribution. United States. https://doi.org/10.1021/acs.bioconjchem.5b00049
Dearling, Jason L. J., Smith, Suzanne V., Paterson, Brett M., Akurathi, Vamisidhar, Betanzos-Lara, Soledad, Treves, S. Ted, Voss, Stephan D., White, Jonathan M., Huston, James S., Donnelly, Paul S., and Packard, Alan B. Wed .
"The ionic charge of Copper-64 complexes conjugated to an engineered antibody effects biodistribution". United States. https://doi.org/10.1021/acs.bioconjchem.5b00049. https://www.osti.gov/servlets/purl/1201357.
@article{osti_1201357,
title = {The ionic charge of Copper-64 complexes conjugated to an engineered antibody effects biodistribution},
author = {Dearling, Jason L. J. and Smith, Suzanne V. and Paterson, Brett M. and Akurathi, Vamisidhar and Betanzos-Lara, Soledad and Treves, S. Ted and Voss, Stephan D. and White, Jonathan M. and Huston, James S. and Donnelly, Paul S. and Packard, Alan B.},
abstractNote = {The development of biomolecules as imaging probes requires radiolabeling methods that do not significantly influence their biodistribution. Sarcophagine (Sar) chelators form extremely stable complexes with copper, and are therefore a promising option for labeling proteins with ⁶⁴Cu. However, initial studies using the first-generation sarcophagine bifunctional chelator SarAr to label the engineered antibody fragment ch14.18-ΔCH2 (MW 120 kDa) with ⁶⁴Cu showed high tracer retention in the kidneys,(>38% injected dose per gram (ID/g) 48 h post-injection), presumably because the high local positive charge on the CuII-SarAr moiety resulted in increased binding of the labeled protein to the negatively charged basal cells of the glomerulus. To test this hypothesis, ch14.18-ΔCH2 was conjugated with a series of Sar derivatives of decreasing positive charge and three commonly used macrocyclic polyaza polycarboxylate (PAC) BFCs. The immunoconjugates were labeled with ⁶⁴Cu and injected into mice, and PET/CT images were obtained at 24 and 48 h post injection (p.i.). At 48 h p.i., ex vivo biodistribution was carried out. In addition, to demonstrate the potential of metastasis detection using ⁶⁴Cu-labeled ch14.18-ΔCH2, a preclinical imaging study of intrahepatic neuroblastoma tumors was performed carried out. Reducing the positive charge on the Sar chelators decreased kidney uptake of Cu-labeled ch14.18-ΔCH2 by more than 6-fold, from >45 ID/g to <6% ID/g, while the uptake in most other tissues, including liver, was relatively unchanged. However, despite this dramatic decrease, the renal uptake of the PAC BFCs was generally lower than that of the Sar derivatives, as was the liver uptake. Uptake of ⁶⁴Cu-labeled ch14.18-ΔCH2 in neuroblastoma hepatic metastases was detected using PET.},
doi = {10.1021/acs.bioconjchem.5b00049},
journal = {Bioconjugate Chemistry},
number = 4,
volume = 26,
place = {United States},
year = {Wed Apr 15 00:00:00 EDT 2015},
month = {Wed Apr 15 00:00:00 EDT 2015}
}
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Figures / Tables:
Figure 1: Structures of the whole antibody ch14.18 and the engineered form used in this study, ch14.18-ΔCH2 (green arrows show the antigen-binding regions).
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