Radioiodinated versus Radiometal-Labeled Anti–Carcinoembryonic Antigen Single-Chain Fv-Fc Antibody Fragments: Optimal Pharmacokinetics for Therapy
- 15 January 2007
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 67 (2), 718-726
- https://doi.org/10.1158/0008-5472.can-06-0454
Abstract
Antibody fragments with optimized pharmacokinetic profiles hold potential for detection and therapy of tumor malignancies. We studied the behavior of three anti–carcinoembryonic antigen (CEA) single-chain Fv-Fc (scFv-Fc) variants (I253A, H310A, and H310A/H435Q; Kabat numbering system) that exhibited differential serum persistence. Biodistribution studies done on CEA-positive tumor xenografted mice revealed that the 111In-labeled I253A fragment with the slowest clearance kinetics (T1/2β, 27.7 h) achieved the highest tumor uptake (44.6% ID/g at 24 h), whereas the radiometal-labeled H310A/H435Q fragment with the most rapid elimination (T1/2β, 7.05 h) reached a maximum of 28.0% ID/g at 12 h postinjection. The H310A protein was characterized by both intermediate serum half-life and tumor uptake. The 111In-based biodistribution studies showed that all three fragments were eliminated primarily through the liver, and hepatic radiometal activity correlated with the rate of fragment clearance. The 111In-labeled H310A/H435Q protein exhibited the highest liver uptake (23.5% ID/g at 24 h). Metabolism of the 125I-labeled scFv-Fc proteins resulted in low normal organ activity. Finally, the 125I/111In biodistribution data allowed for dose estimations, which suggest the 131I-labeled scFv-Fc H310A/H435Q as a promising candidate for radioimmunotherapy. [Cancer Res 2007;67(2):718–26]This publication has 26 references indexed in Scilit:
- A two-tiered physiologically based model for dually labeled single-chain Fv-Fc antibody fragmentsMolecular Cancer Therapeutics, 2006
- Tailoring antibodies for radionuclide deliveryExpert Opinion on Drug Delivery, 2005
- Arming antibodies: prospects and challenges for immunoconjugatesNature Biotechnology, 2005
- Pilot Trial Evaluating an 123I-Labeled 80-Kilodalton Engineered Anticarcinoembryonic Antigen Antibody Fragment (cT84.66 Minibody) in Patients with Colorectal CancerClinical Cancer Research, 2004
- Crystal Structure at 2.8 Å of an FcRn/Heterodimeric Fc Complex: Mechanism of pH-Dependent BindingMolecular Cell, 2001
- Tumor Targeting of Radiometal Labeled Anti-CEA Recombinant T84.66 Diabody and T84.66 Minibody: Comparison to Radioiodinated FragmentsBioconjugate Chemistry, 2001
- Numerical Selection of Optimal Tumor Imaging Agents with Application to Engineered AntibodiesCancer Biotherapy & Radiopharmaceuticals, 2001
- Crystal Structure and Immunoglobulin G Binding Properties of the Human Major Histocompatibility Complex-Related Fc Receptor,Biochemistry, 2000
- Increased clearance of IgG in mice that lack β2‐microglobulin: possible protective role of FcRnImmunology, 1996
- A program package for simulation and parameter estimation in pharmacokinetic systemsComputer Programs in Biomedicine, 1979