Abstract
P-cadherin is overexpressed in various cancers and can be a target for radioimmunotherapy. We investigated the preclinical pharmacokinetics and pharmacology of FF-21101, an indium-111 (111In)- or yttrium-90 (90Y)-conjugated monoclonal antibody against P-cadherin, to evaluate its clinical applications. Methods: The radiochemical purity, binding affinity, and in vitro serum stability of 111In/90Y-labeled FF-21101 were evaluated. The pharmacokinetics of 111In/90Y-FF-21101 were compared in normal mice. Tumor accumulation after 111In-FF-21101 administration was investigated in mice bearing subcutaneous tumors with high (NCI-H1373), moderate (EBC-1), and negative (A549) P-cadherin expression. The tumor suppression effect following a single intravenous injection of 90Y-FF-21101 was assessed in NCI-H1373 and EBC-1 mouse xenograft models. The relationship between antibody dose and tumor accumulation was investigated in the NCI-H1373 mouse xenograft model. The radiation-absorbed dose in humans after injection of 90Y-FF-21101 was estimated using gamma camera images of cynomolgus monkeys. Results: The radiochemical purities of 111In- and 90Y-FF-21101 were 98.2% ± 2.5% (n = 9) and 99.3% ± 0.6% (n = 5), respectively. The dissociation constant values were 1.083 nM for 111In-FF-21101 and 1.367 nM for 90Y-FF-21101. Both 111In- and 90Y-FF-21101 were stable in human serum after 96 h of incubation and exhibited similar pharmacokinetics in normal mice. The tumor accumulation of 111In-FF-21101 was closely related to intensity of P-cadherin expression in the cells. 90Y-FF-21101 showed significant tumor growth inhibition, implying NCI-H1373 and EBC-1 recurrence were not observed after the intravenous administration of 90Y-FF-21101 3.7 and 7.4 MBq per animal, respectively. The tumor uptake in the mouse xenograft model and the estimated radiation-absorbed doses in the spleen of monkeys decreased with increasing antibody doses of 111In-FF-21101. Conversely, the estimated radiation-absorbed dose in the red marrow increased with increasing antibody dose. An antibody dose of 4.8 mg/m2 was considered appropriate for humans based on efficacy and safety. The estimated maximum tolerated radiation dose at this antibody dose was 2,886 MBq/human. Conclusion: FF-21101 radioimmunotherapy exhibited high antitumor affinity and antitumor efficacy in mouse xenograft models. Extrapolation of the pharmacokinetics in monkeys to humans suggests the potential for clinical application of FF-21101 for treating P-cadherin expressing tumor.
- Monoclonal Antibodies
- Radiobiology/Dosimetry
- Radionuclide Therapy
- CDH3
- antibody
- dosimetry
- targeted radionuclide therapy
- theranostics
Footnotes
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