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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 111 In- or 90 Y-conjugated monoclonal antibody against P-cadherin, to evaluate its clinical applications. Methods: The radiochemical purity, binding affinity, and in vitro serum stability of 111 In or 90 Y-labeled FF-21101 were evaluated. The pharmacokinetics of 111 In or 90 Y-FF-21101 were compared in normal mice. Tumor accumulation after 111 In-FF-21101 administration was investigated in mice bearing subcutaneous tumors with high (NCI-H1373), moderate (EBC-1), or no (A549) P-cadherin expression. The tumor suppression effect after a single intravenous injection of 90 Y-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 absorbed radiation dose in humans after injection of 90 Y-FF-21101 was estimated using γ-camera images of cynomolgus monkeys. Results: The radiochemical purities of 111 In- and 90 Y-FF-21101 were 98.2% ± 2.5% ( n = 9) and 99.3% ± 0.6% ( n = 5), respectively. The dissociation constants were 1.083 nM for 111 In-FF-21101 and 1.367 nM for 90 Y-FF-21101. Both 111 In- and 90 Y-FF-21101 were stable in human serum after 96 h of incubation and exhibited similar pharmacokinetics in normal mice. The tumor accumulation of 111 In-FF-21101 was closely related to the intensity of P-cadherin expression in the cells. 90 Y-FF-21101 showed significant tumor growth inhibition, indicating that NCI-H1373 and EBC-1 recurrence was not observed after intravenous administration of 3.7 and 7.4 MBq, respectively of 90 Y-FF-21101 per animal. Tumor uptake in the mouse xenograft model and estimated absorbed radiation doses in the spleen of monkeys decreased with increasing antibody doses of 111 In-FF-21101. Conversely, the estimated absorbed radiation dose in the red marrow increased with increasing antibody dose. An antibody dose of 4.8 mg/m 2 was considered appropriate for humans, on the basis of efficacy and safety. The maximum tolerated administered activity of 90 Y-FF-21101 was estimated to be 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.

the journal of nuclear medicine

Preclinical Characterization of the Radioimmunoconjugate <sup>111</sup>In or <sup>90</sup>Y-FF-21101 Against a P-Cadherin–Expressing Tumor in a Mouse Xenograft Model and a Nonhuman Primate

Preclinical Characterization of the Radioimmunoconjugate 111In or 90Y-FF-21101 Against a P-Cadherin–Expressing Tumor in a Mouse Xenograft Model and a Nonhuman Primate

Preclinical Characterization of the Radioimmunoconjugate ¹¹¹In or ⁹⁰Y-FF-21101 Against a P-Cadherin–Expressing Tumor in a Mouse Xenograft Model and a Nonhuman Primate