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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 - PubMed

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

Yuichi Funase et al. J Nucl Med. 2021 Feb.

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 111In- or 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 or 90Y-labeled FF-21101 were evaluated. The pharmacokinetics of 111In or 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), or no (A549) P-cadherin expression. The tumor suppression effect after 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 absorbed radiation dose in humans after injection of 90Y-FF-21101 was estimated using γ-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 constants 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 the intensity of P-cadherin expression in the cells. 90Y-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 90Y-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 111In-FF-21101. Conversely, the estimated absorbed radiation dose in the red marrow increased with increasing antibody dose. An antibody dose of 4.8 mg/m2 was considered appropriate for humans, on the basis of efficacy and safety. The maximum tolerated administered activity of 90Y-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.

Keywords: CDH3; antibody, dosimetry; targeted radionuclide therapy; theranostics.

© 2021 by the Society of Nuclear Medicine and Molecular Imaging.

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Figures

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Graphical abstract
FIGURE 1.
FIGURE 1.

Binding activity of radiolabeled FF-21101 to sCDH3C: saturation binding curve of 111In-FF-21101 (A), Scatchard plot of 111In-FF-21101 (B), saturation binding curve of 90Y-FF-21101 (C), and Scatchard plot of 90Y-FF-21101 (D). Bound refers to amount of radiolabeled FF-21101 bound to sCDH3C. Free refers to concentration of free radiolabeled FF-21101. Bmax = maximum binding.

FIGURE 2.
FIGURE 2.

Time–activity (%ID/g) curves for 90Y-FF-21101 and 111In-FF-21101 in each organ of normal mice. Error bars represent SD (n = 3 per time point).

FIGURE 3.
FIGURE 3.

Time–activity (%ID/g) curves for uptake of 111In-FF-21101 and 111In-hIgG in tumor (A) and blood (B) in high (H1373), moderate (EBC-1), or negative (A549) P-cadherin–expressing models. Error bars represent SD (n = 3 per time point).

FIGURE 4.
FIGURE 4.

Tumor suppression in NCI-H1373 (A) and EBC-1 (B) mouse xenograft models. Tumor growth curves show mean tumor volumes ± SD (n = 6). Curves are plotted until first tumor per group reached 10% of total body weight. *P < 0.05.

FIGURE 5.
FIGURE 5.

Radiation dose dependency of 90Y-FF-21101 in EBC1 mouse xenograft model. (A) Tumor growth curve. (B) Relative body weight. Curves show mean ± SD (n = 6) and are plotted until first tumor per group reached 10% of total body weight.

FIGURE 6.
FIGURE 6.

Effect of antibody dose on tumor accumulation and biodistribution. (A) Tumor accumulation for different antibody doses (3.73, 30, 112, and 373 μg/animal) of 111In-FF-21101 in NCI-H1373 mouse xenograft model. Results are presented as %ID/g of tumor at each time point. Error bars represent SD (n = 3 per time point). (B) Whole-body planar imaging of cynomolgus monkeys 48 h after 111In-FF-21101 administration. Locations of heart (H), liver (L), and spleen (S) are indicated by arrows. Full-field-of-view images are shown in Supplemental Figures 3–5.

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