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}
}
Web of Science
Figures / Tables:
Works referenced in this record:
Follow-up in Neuroblastoma: Comparison of Metaiodobenzylguanidine and a Chimeric Anti-GD2 Antibody for Detection of Tumor Relapse and Therapy Response
journal, January 2001
- Reuland, Peter; Geiger, Livia; Thelen, Marcel H.
- Journal of Pediatric Hematology/Oncology, Vol. 23, Issue 7
WinGX suite for small-molecule single-crystal crystallography
journal, August 1999
- Farrugia, Louis J.
- Journal of Applied Crystallography, Vol. 32, Issue 4
Conjugation and radiolabeling of monoclonal antibodies with zirconium-89 for PET imaging using the bifunctional chelate p-isothiocyanatobenzyl-desferrioxamine
journal, March 2010
- Vosjan, Maria J. W. D.; Perk, Lars R.; Visser, Gerard W. M.
- Nature Protocols, Vol. 5, Issue 4
Conjugation of antibodies with bifunctional chelating agents: Isothiocyanate and bromoacetamide reagents, methods of analysis, and subsequent addition of metal ions
journal, October 1984
- Meares, Claude F.; McCall, Michael J.; Reardan, Dayton T.
- Analytical Biochemistry, Vol. 142, Issue 1
Pharmacokinetics and Tumor Localization of 111 In-Labeled HuCC49ΔC H 2 in BALB/c Mice and Athymic Murine Colon Carcinoma Xenograft
journal, April 2006
- Chinn, Paul C.; Morena, Ron A.; Santoro, Denise A.
- Cancer Biotherapy and Radiopharmaceuticals, Vol. 21, Issue 2
Detection of Neuroblastoma cells in CD34+ selected peripheral stem cells using a combination of tyrosine hydroxylase nested RT–PCR and anti-Ganglioside GD2 immunocytochemistry
journal, October 1997
- Lode, H. N.; Handgretinger, R.; Schuermann, U.
- European Journal of Cancer, Vol. 33, Issue 12
Tailoring the Pharmacokinetics and Positron Emission Tomography Imaging Properties of Anti–Carcinoembryonic Antigen Single-Chain Fv-Fc Antibody Fragments
journal, January 2005
- Kenanova, Vania; Olafsen, Tove; Crow, Desiree M.
- Cancer Research, Vol. 65, Issue 2
Anti-GD2 Antibody with GM-CSF, Interleukin-2, and Isotretinoin for Neuroblastoma
journal, September 2010
- Yu, Alice L.; Gilman, Andrew L.; Ozkaynak, M. Fevzi
- New England Journal of Medicine, Vol. 363, Issue 14
Neuroblastoma and Other Neuroendocrine Tumors
journal, July 2007
- Howman-Giles, Robert; Shaw, Peter J.; Uren, Roger F.
- Seminars in Nuclear Medicine, Vol. 37, Issue 4
Simplified method for conjugating macrocyclic bifunctional chelating agents to antibodies via 2-iminothiolane
journal, May 1990
- McCall, Michael J.; Diril, Habibe; Meares, Claude F.
- Bioconjugate Chemistry, Vol. 1, Issue 3
New 64Cu PET imaging agents for personalised medicine and drug development using the hexa-aza cage, SarAr
journal, January 2006
- Di Bartolo, Nadine; Sargeson, Alan M.; Smith, Suzanne V.
- Organic & Biomolecular Chemistry, Vol. 4, Issue 17
Antigen binding and biological activities of engineered mutant chimeric antibodies with human tumor specificities
journal, April 1990
- Gillies, Stephen D.; Wesolowski, John S.
- Human Antibodies, Vol. 1, Issue 1
PET imaging of tumours with a 64 Cu labeled macrobicyclic cage amine ligand tethered to Tyr 3 -octreotate
journal, January 2014
- Paterson, Brett M.; Roselt, Peter; Denoyer, Delphine
- Dalton Trans., Vol. 43, Issue 3
AMIDE: A Free Software Tool for Multimodality Medical Image Analysis
journal, July 2003
- Loening, Andreas Markus; Gambhir, Sanjiv Sam
- Molecular Imaging, Vol. 2, Issue 3
Serum half-life and tumor localization of a chimeric antibody deleted of the CH2 domain and directed against the disialoganglioside GD2.
journal, August 1990
- Mueller, B. M.; Reisfeld, R. A.; Gillies, S. D.
- Proceedings of the National Academy of Sciences, Vol. 87, Issue 15
Correlation of Early Metastatic Response by 123 I-Metaiodobenzylguanidine Scintigraphy With Overall Response and Event-Free Survival in Stage IV Neuroblastoma
journal, July 2003
- Matthay, Katherine K.; Edeline, Veronique; Lumbroso, Jean
- Journal of Clinical Oncology, Vol. 21, Issue 13
Synthesis of a new cage ligand, SarAr, and its complexation with selected transition metal ions for potential use in radioimaging†
journal, January 2001
- Di Bartolo, Nadine M.; Sargeson, Alan M.; Donlevy, Therese M.
- Journal of the Chemical Society, Dalton Transactions, Issue 15
Primary bioassay of human tumor stem cells
journal, July 1977
- Hamburger, A.; Salmon, S.
- Science, Vol. 197, Issue 4302
Technological Advances in Radioimmunotherapy
journal, August 2007
- Dearling, J. L. J.; Pedley, R. B.
- Clinical Oncology, Vol. 19, Issue 6
Mechanism of Amide Formation by Carbodiimide for Bioconjugation in Aqueous Media
journal, January 1995
- Nakajima, Naoki; Ikada, Yoshito
- Bioconjugate Chemistry, Vol. 6, Issue 1
Positron emission tomography (PET) imaging of neuroblastoma and melanoma with 64Cu-SarAr immunoconjugates
journal, October 2007
- Voss, S. D.; Smith, S. V.; DiBartolo, N.
- Proceedings of the National Academy of Sciences, Vol. 104, Issue 44
Comparison of 64 Cu-Complexing Bifunctional Chelators for Radioimmunoconjugation: Labeling Efficiency, Specific Activity, and in Vitro / in Vivo Stability
journal, April 2012
- Cooper, Maggie S.; Ma, Michelle T.; Sunassee, Kavitha
- Bioconjugate Chemistry, Vol. 23, Issue 5
Imaging cancer using PET — the effect of the bifunctional chelator on the biodistribution of a 64Cu-labeled antibody
journal, January 2011
- Dearling, Jason L. J.; Voss, Stephan D.; Dunning, Patricia
- Nuclear Medicine and Biology, Vol. 38, Issue 1
99mTc-monoclonal antibody radiolabeled via hydrazino nicotinamide derivative for imaging disialoganglioside GD2-positive tumors
journal, August 1999
- Fonti, Rosa; Cheung, Nai-Kong V.; Bridger, Gary J.
- Nuclear Medicine and Biology, Vol. 26, Issue 6
Measurement of the rate of copper(II) exchange for 64Cu complexes of bifunctional chelators
journal, December 2012
- Maheshwari, Vidhi; Dearling, Jason L. J.; Treves, S. Ted
- Inorganica Chimica Acta, Vol. 393
Molecular imaging with copper-64
journal, November 2004
- Smith, Suzanne V.
- Journal of Inorganic Biochemistry, Vol. 98, Issue 11, p. 1874-1901
A semi-automated system for the routine production of copper-64
journal, August 2012
- Kume, Maiko; Carey, Paul C.; Gaehle, Gregory
- Applied Radiation and Isotopes, Vol. 70, Issue 8
A new bifunctional chelator for copper radiopharmaceuticals: a cage amine ligand with a carboxylate functional group for conjugation to peptides
journal, January 2009
- Ma, Michelle T.; Karas, John A.; White, Jonathan M.
- Chemical Communications, Issue 22
ORTEP -3 for Windows - a version of ORTEP -III with a Graphical User Interface (GUI)
journal, October 1997
- Farrugia, L. J.
- Journal of Applied Crystallography, Vol. 30, Issue 5
Measuring circulating neuroblastoma cells by quantitative reverse transcriptase-polymerase chain reaction analysis: Correlation with its paired bone marrow and standard disease markers
journal, January 2004
- Cheung, Irene Y.; Sahota, Arvind; Cheung, Nai-Kong V.
- Cancer, Vol. 101, Issue 10
Evaluation of catecholamine metabolites, mIBG scan, and bone marrow cytology as response markers in stage 4 neuroblastoma
journal, January 2001
- Hero, B.; Hunneman, D. H.; Gahr, M.
- Medical and Pediatric Oncology, Vol. 36, Issue 1
Works referencing / citing this record:
New pathogen-specific immunoPET/MR tracer for molecular imaging of a systemic bacterial infection
journal, February 2016
- Wiehr, Stefan; Warnke, Philipp; Rolle, Anna-Maria
- Oncotarget, Vol. 7, Issue 10
Bispidines for radiopharmaceuticals
journal, January 2018
- Comba, Peter; Kerscher, Marion; Rück, Katharina
- Dalton Transactions, Vol. 47, Issue 28
Site-Specific In Vivo Bioorthogonal Ligation via Chemical Modulation
journal, August 2016
- Koo, Heebeom; Lee, Jeong Heon; Bao, Kai
- Advanced Healthcare Materials, Vol. 5, Issue 19
Synthesis, 64 Cu-labeling and PET imaging of 1,4,7-triazacyclononane derived chelators with pendant azaheterocyclic arms
journal, January 2016
- Gotzmann, Carla; Braun, Friederike; Bartholomä, Mark D.
- RSC Advances, Vol. 6, Issue 1
Improving the stability and inertness of Cu( ii ) and Cu( i ) complexes with methylthiazolyl ligands by tuning the macrocyclic structure
journal, January 2016
- Le Fur, Mariane; Beyler, Maryline; Le Poul, Nicolas
- Dalton Transactions, Vol. 45, Issue 17
Figures / Tables found in this record: