RESUMEN
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.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Cadherinas/inmunología , Cadherinas/metabolismo , Regulación Neoplásica de la Expresión Génica/inmunología , Inmunoconjugados/inmunología , Radioisótopos de Indio/química , Radioisótopos de Itrio/química , Animales , Línea Celular Tumoral , Transformación Celular Neoplásica , Inmunoconjugados/química , Marcaje Isotópico , Macaca fascicularis , Masculino , Ratones , Radioinmunoterapia , Distribución TisularRESUMEN
PURPOSE: 90Y-FF-21101 is an Yttrium-90-conjugated, chimeric mAb that is highly specific for binding to human placental (P)-cadherin, a cell-to-cell adhesion molecule overexpressed and associated with cancer invasion and metastatic dissemination in many cancer types. We report the clinical activity of 90Y-FF-21101 in a first-in-human phase I study in patients with advanced solid tumors. PATIENTS AND METHODS: The safety and efficacy of 90Y-FF-21101 were evaluated in a phase I 3+3 dose-escalation study in patients with advanced solid tumors (n = 15) over a dose range of 5-25 mCi/m2. Dosimetry using 111In-FF-21101 was performed 1 week prior to assess radiation doses to critical organs. Patients who demonstrated clinical benefit received repeated 90Y-FF-21101 administration every 4 months. RESULTS: 111In-FF-21101 uptake was observed primarily in the spleen, kidneys, testes, lungs, and liver, with tumor uptake observed in the majority of patients. Organ dose estimates for all patients were below applicable limits. P-cadherin expression H-scores ranged from 0 to 242 with 40% of samples exhibiting scores ≥100. FF-21101 protein pharmacokinetics were linear with increasing antibody dose, and the mean half-life was 69.7 (±12.1) hours. Radioactivity clearance paralleled antibody clearance. A complete clinical response was observed in a patient with clear cell ovarian carcinoma, correlating with a high tumor P-cadherin expression. Stable disease was observed in a variety of other tumor types, without dose-limiting toxicity. CONCLUSIONS: The favorable safety profile and initial antitumor activity observed for 90Y-FF-21101 warrant further evaluation of this radioimmunotherapeutic (RIT) approach and provide initial clinical data supporting P-cadherin as a potential target for cancer treatment.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Cadherinas/antagonistas & inhibidores , Neoplasias/radioterapia , Radioinmunoterapia , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/inmunología , Cadherinas/genética , Cadherinas/inmunología , Antígeno Carcinoembrionario/genética , Adhesión Celular/efectos de los fármacos , Fraccionamiento de la Dosis de Radiación , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inmunoglobulinas/inmunología , Radioisótopos de Indio/administración & dosificación , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Pulmón/efectos de los fármacos , Masculino , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/patología , Bazo/efectos de los fármacos , Testículo/efectos de los fármacos , Radioisótopos de Itrio/administración & dosificaciónRESUMEN
The human glycine-N-acyltransferase (hGLYAT) gene and two related-genes (GLYATL1 and GLYATL2) were isolated. Human GLYAT, GLYATL1, and GLYATL2 cDNAs were isolated and shown to encode polypeptides of 295, 302, and 294 amino acids, respectively. GLYAT catalyzes glycine-N-acyltransfer reaction with benzoyl-CoA acting as a typical aralkyl transferase, while GLYATL1 catalyzed glutamine-N-acyltransfer reaction with phenylacetyl-CoA as an arylacetyl transferase. GLYAT was shown to be expressed specifically in the liver and kidney, and the cellular localization of GLYAT protein was restricted to the mitochondria. Interestingly, labeling using highly affinity purified anti-GLYAT antibody revealed that GLYAT expression was suppressed in all hepatocellular carcinomas, but not in other liver diseases. hGLYAT repression in cancerous cells in the liver was controlled at the transcriptional level. hGLYAT is a good candidate as a novel marker of hepatocellular carcinoma and may be a key molecule in the transition between differentiation and carcinogenesis of liver cells.