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.
Highlights
The cell-to-cell adhesion molecule known as P-cadherin is overexpressed in several tumors, including breast, colon, lung, and pancreas [1,2,3], and is implicated in tumor cell motility, migration, and invasiveness [4]
To enhance the pharmacologic activity, we investigated 90Y-conjugated anti–P-cadherin monoclonal antibody, considering the successful therapeutic efficacy of 90Y-ibritumomab tiuxetan, a 90Y-labeled anti-CD20 antibody, against non-Hodgkin lymphoma [14]
Tumor uptake of 111In-FF-21101 in NCI-H1373–inoculated mice decreased with increases in antibody dose, and the trend persisted at each time point (Fig. 6A)
Summary
The cell-to-cell adhesion molecule known as P-cadherin is overexpressed in several tumors, including breast, colon, lung, and pancreas [1,2,3], and is implicated in tumor cell motility, migration, and invasiveness [4]. P-cadherin is considered to be an attractive target for solid-tumor treatment. PF-03732010 is a humanized anti–P-cadherin monoclonal antibody that exhibited high therapeutic efficacy in preclinical studies [12]. PF-03732010 failed to exert therapeutic efficacy in the phase 1 trial (NCT00557505) [13], suggesting insufficient pharmacologic activity for solid tumor treatment. To enhance the pharmacologic activity, we investigated 90Y-conjugated anti–P-cadherin monoclonal antibody, considering the successful therapeutic efficacy of 90Y-ibritumomab tiuxetan, a 90Y-labeled anti-CD20 antibody, against non-Hodgkin lymphoma [14]. Since P-cadherin expression is high in tumors and low in normal tissues, it can facilitate a biodistribution appropriate for achieving high efficacy with radioimmunotherapy. FF-21101, a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)–conjugated chimeric human/mouse monoclonal antibody of IgG1 (PPMX2032), targets human P-cadherin. 90Y-FF-21101 constitutes an armed antibody strategy for solid tumor treatment and may be more effective than anti–P-cadherin therapy alone. We evaluated the tumor-suppressive effects of 90Y-FF-21101, FF-21101, and 90Ylabeled P-cadherin nonspecific antibody in a mouse xenograft model and estimated the clinical safety of 90Y-FF-21101 in humans by evaluating biodistribution in nonhuman primates and extrapolating those results to patients
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