RESUMO
This study aimed to evaluate the safety, pharmacokinetics, and pharmacodynamics of PPMX-T003, a novel human monoclonal antibody for transferrin receptor 1 (TFR1), in healthy individuals. Forty participants were enrolled and randomized to PPMX-T003 dose groups (n = 6/group) and the placebo group (n = 10). The safety and pharmacokinetics profiles were assessed according to the sequential, ascending single-dose intravenous infusions of PPMX-T003 from 0.008 mg/kg to 0.25 mg/kg. Adverse events (AEs) after PPMX-T003 administration occurred in 16 of 30 participants. Any severe AE and AE incidence were not reported, but they tended to increase depending on the dose. Laboratory tests, vital signs, and standard 12-lead electrocardiogram showed no clinically relevant changes. Five participants experienced an infusion-related reaction but recovered on days 5-10. Regarding pharmacokinetics, PPMX-T003 has a nonlinear elimination pattern. PPMX-T003 in the 0.25 mg/kg group showed apparent (>50%) decreased serum levels of reticulocytes from day 3 and sustained moderate (<10%) fall of hematocrit and hemoglobin counts from day 7. In conclusion, the antibody-mediated blockade of TFR1 elicited the expected fall in blood cell levels and showed an acceptable safety profile, supporting the continuing development of PPMX-T003 as a new candidate for polycythemia vera treatment.
Assuntos
Anticorpos Monoclonais , Antígenos CD , Humanos , Infusões Intravenosas , Método Duplo-Cego , Receptores da TransferrinaRESUMO
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.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Caderinas/antagonistas & inibidores , Neoplasias/radioterapia , Radioimunoterapia , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Caderinas/genética , Caderinas/imunologia , Antígeno Carcinoembrionário/genética , Adesão Celular/efeitos dos fármacos , Fracionamento da Dose de Radiação , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunoglobulinas/imunologia , Radioisótopos de Índio/administração & dosagem , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Masculino , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Baço/efeitos dos fármacos , Testículo/efeitos dos fármacos , Radioisótopos de Ítrio/administração & dosagemRESUMO
Transferrin receptor (TfR) is an attractive molecule for targeted therapy of cancer. Various TfR-targeted therapeutic agents such as anti-TfR antibodies conjugated with anticancer agents have been developed. An antibody that recognizes both human and murine TfR is needed to predict the toxicity of antibody-based agents before clinical trials, there is no such antibody to date. In this study, a new fully human monoclonal antibody TSP-A18 that recognizes both human and murine TfR was developed and the correlation analysis of the radiolabeled antibody uptake and TfR expression in two murine strains was conducted. TSP-A18 was selected using extracellular portions of human and murine TfR from a human antibody library. The cross-reactivity of TSP-A18 with human and murine cells was confirmed by flow cytometry. Cell binding and competitive inhibition assays with [111In]TSP-A18 showed that TSP-A18 bound highly to TfR-expressing MIAPaCa-2 cells with high affinity. Biodistribution studies of [111In]TSP-A18 and [67Ga]citrate (a transferrin-mediated imaging probe) were conducted in C57BL/6J and BALB/c-nu/nu mice. [111In]TSP-A18 was accumulated highly in the spleen and bone containing marrow component of both strains, whereas high [67Ga]citrate uptake was only observed in bone containing marrow component and not in the spleen. Western blotting indicated the spleen showed the strongest TfR expression compared with other organs in both strains. There was significant correlation between [111In]TSP-A18 uptake and TfR protein expression in both strains, whereas there was significant correlation of [67Ga]citrate uptake with TfR expression only in C57BL/6J. These findings suggest that the difference in TfR expression between murine strains should be carefully considered when testing for the toxicity of anti-TfR antibody in mice and the uptake of anti-TfR antibody could reflect tissue TfR expression more accurately compared with that of transferrin-mediated imaging probe such as [67Ga]citrate.