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Title: The ionic charge of Copper-64 complexes conjugated to an engineered antibody effects biodistribution

Journal Article · · Bioconjugate Chemistry
 [1];  [2];  [3];  [1];  [4];  [1];  [1];  [3];  [5];  [3];  [1]
  1. Boston Children's Hospital, Boston, MA (United States); Harvard Medical School, Boston, MA (United States)
  2. Brookhaven National Lab. (BNL), Upton, NY (United States)
  3. Univ. of Melbourne (Australia)
  4. Boston Children's Hospital, Boston, MA (United States)
  5. The Antibody Society & Huston BioConsulting LLC, Boston, MA (United States)

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.

Research Organization:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Nuclear Physics (NP)
Grant/Contract Number:
SC00112704
OSTI ID:
1201357
Report Number(s):
BNL-108158-2015-JA; R&D Project: KBCH139; 00600; KB0202011
Journal Information:
Bioconjugate Chemistry, Vol. 26, Issue 4; ISSN 1043-1802
Publisher:
American Chemical SocietyCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 28 works
Citation information provided by
Web of Science

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Figures / Tables (8)