RESUMO
PURPOSE: The IGF-1R signaling pathway has been implicated in multiple cancers as important for cell survival, proliferation, invasion and metastasis. BIIB022 is a non-glycosylated human IgG4 monoclonal antibody (mAb) with specificity for IGF-1R. Unlike other anti-IGF1R antibodies, BIIB022 has no effector functions. Additionally, inhibition is via an allosteric rather than competitive mechanism, which further differentiates this antibody from others. We sought to determine the safety and tolerability of BIIB022 and determine the pharmacokinetic (PK) and pharmacodynamic (PD) profile of this antibody. METHODS: A multi-institutional phase I study evaluated the safety of escalating doses of BIIB022 given IV q3wk until progression or unacceptable toxicity in patients with advanced solid tumors. Five sequential BIIB022 dose cohorts were evaluated using a standard 3 + 3 dose-escalation design (1.5, 5. 10, 20, 30 mg/kg); 10 additional patients were treated at the recommended phase 2 dose. RESULTS: 34 patients were treated. Toxicities were manageable and mostly low grade; grade 3-4 hyperglycemia was not observed. No RECIST responses were observed, although three patients had metabolic responses associated with prolonged stable disease. The PK of BIIB022 was nearly linear in the dose range from 10 to 30 mg/kg, with some nonlinearity at lower doses (1.5-5.0 mg/kg), likely due to target-mediated drug disposition of BIIB022 at low serum concentrations. PD analyses showed decrease in IGF-1R levels on leucocytes, with stable serum values of IGF-1 and IGF-2. CONCLUSIONS: BIIB022 can be safely given at 30 mg/kg IV every 3 weeks with preliminary evidence of biological activity in selected patients.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias/tratamento farmacológico , Receptor IGF Tipo 1/antagonistas & inibidores , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias/sangue , Receptor IGF Tipo 1/sangue , Receptor IGF Tipo 1/imunologiaRESUMO
The concluding session of this workshop focused on barriers that might be impeding the successful transition of radiopharmaceuticals from research tools to diagnostics and therapeutics that reach commercial success. Some lessons can be learned by reviewing the technology adoption life cycle as described by Geoffrey A. Moore (Moore, GA. Crossing the chasm. New York: HarperCollins, 2002). Additionally, a review of highly successful radiopharmaceuticals suggests that achieving commercial success may require advocacy by other interested groups.
Assuntos
Indústria Farmacêutica/tendências , Marketing/tendências , Compostos Radiofarmacêuticos/uso terapêutico , Transferência de Tecnologia , Comércio , Indústria Farmacêutica/economia , Marketing/economia , Compostos Radiofarmacêuticos/economiaRESUMO
UNLABELLED: AMG 110, a bispecific T cell engager (BiTE) antibody construct, induces T cell-mediated cancer cell death by cross-linking epithelial cell adhesion molecule (EpCAM) on tumor cells with a cluster of differentiation 3 ε (CD3ε) on T cells. We labeled AMG 110 with (89)Zr or near-infrared fluorescent dye (IRDye) 800CW to study its tumor targeting and tissue distribution. METHODS: Biodistribution and tumor uptake of (89)Zr-AMG 110 was studied up to 6 d after intravenous administration to nude BALB/c mice bearing high EpCAM-expressing HT-29 colorectal cancer xenografts. Tumor uptake of (89)Zr-AMG 110 was compared with uptake in head and neck squamous cell cancer FaDu (intermediate EpCAM) and promyelocytic leukemia HL60 (EpCAM-negative) xenografts. Intratumoral distribution in HT-29 tumors was studied using 800CW-AMG 110. RESULTS: Tumor uptake of (89)Zr-AMG 110 can be clearly visualized using small-animal PET imaging up to 72 h after injection. The highest tumor uptake of (89)Zr-AMG 110 at the 40-µg dose level was observed at 6 and 24 h (respectively, 5.35 ± 0.22 and 5.30 ± 0.20 percentage injected dose per gram; n = 3 and 4). Tumor uptake of (89)Zr-AMG 110 was EpCAM-specific and correlated with EpCAM expression. 800CW-AMG 110 accumulated at the tumor cell surface in viable EpCAM-expressing tumor tissue. CONCLUSION: PET and fluorescent imaging provided real-time information about AMG 110 distribution and tumor uptake in vivo. Our data support using (89)Zr and IRDye 800CW to evaluate tumor and tissue uptake kinetics of bispecific T cell engager antibody constructs in preclinical and clinical settings.
Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Molécula de Adesão da Célula Epitelial/imunologia , Tomografia por Emissão de Pósitrons/métodos , Radioisótopos , Linfócitos T/imunologia , Zircônio , Animais , Células HL-60 , Células HT29 , Humanos , Marcação por Isótopo , Masculino , Camundongos , Distribuição TecidualRESUMO
UNLABELLED: The ibritumomab tiuxetan therapeutic regimen consists of a dose of rituximab, 250 mg/m(2), followed by (111)In-ibritumomab tiuxetan, for imaging, on day 1 and a dose of rituximab followed by (90)Y-ibritumomab tiuxetan, for therapy, on day 7, 8, or 9. Treatment with the Food and Drug Administration-approved regimen also requires that scans be performed at 2-24 h and at 48-72 h after the (111)In-ibritumomab tiuxetan, with an optional third scan at 90-120 h, to confirm appropriate biodistribution. In the clinical trials before the approval of the regimen, only 1 patient (of approximately 400) was not treated with (90)Y-ibritumomab tiuxetan after imaging with (111)In-ibritumomab tiuxetan, because of altered biodistribution. The Zevalin Imaging Registry was established by Biogen Idec Inc. to identify cases of potential altered biodistribution and to collect clinical information in cases in which the regimen was not completed after imaging. METHODS: The registry surveyed treating physicians to verify completion of treatment with the ibritumomab tiuxetan therapeutic regimen in patients treated with (111)In-ibritumomab tiuxetan between March 27, 2002, and March 31, 2003. RESULTS: Survey data were collected on 953 of an estimated 1,144-1,192 patients in whom ibritumomab tiuxetan therapy was initiated (case capture rate of 80%-83%). Thirty-eight cases were reported in which a decision not to treat was made after imaging with (111)In-ibritumomab tiuxetan (4.0% of all cases captured); 16 of these were for imaging reasons, and 22 were for medical reasons. Twelve of the 16 imaging cases met the criteria for altered biodistribution (1.3%). Of these 12 cases, 6 (0.6%) were suspected to be true altered biodistribution and 6 appeared to be due to the use of a procedure for radiolabeling (111)In-ibritumomab tiuxetan that differed from that in the prescribing information. All cases of altered biodistribution were seen on the first image (2-24 h) after the administration of (111)In-ibritumomab tiuxetan. The 22 cases in which decisions not to treat were made for medical reasons accounted for 2.3% of the cases. The majority of these cases (19/22) were in patients who had an expected biodistribution but had a rapid change in their clinical condition that precluded treatment. CONCLUSION: The rate of true altered biodistribution was 0.6% in the Zevalin Imaging Registry, which collected treatment decisions based on data from approximately 80% of all patients treated commercially in the first year after drug approval. All cases of altered biodistribution were apparent on the first image, obtained at 2-24 h after the administration of (111)In-ibritumomab tiuxetan.
Assuntos
Anticorpos Monoclonais/farmacocinética , Radioisótopos de Índio , Linfoma não Hodgkin/diagnóstico por imagem , Linfoma não Hodgkin/metabolismo , Sistema de Registros , Medição de Risco/métodos , Anticorpos Monoclonais/uso terapêutico , Humanos , Linfoma não Hodgkin/radioterapia , Especificidade de Órgãos , Cintilografia , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/uso terapêutico , Reprodutibilidade dos Testes , Fatores de Risco , Sensibilidade e Especificidade , Distribuição Tecidual , Estados Unidos , Imagem Corporal Total , Contagem Corporal Total , Radioisótopos de Ítrio/uso terapêuticoRESUMO
Yttrium 90-labeled ibritumomab tiuxetan is approved for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma (NHL). To date, the efficacy of repeated courses of radioimmunoconjugate treatment in patients whose disease has progressed has not been studied as a formal endpoint in a clinical trial setting. However, several clinical studies have been conducted in patients with progressive NHL who had previously received 90Y ibritumomab tiuxetan. A retrospective review of these studies has shown that clinical responses have been achieved with all types of subsequent treatment with no apparent impact on their efficacy. In addition, no significant differences in toxicities with subsequent therapies have been observed between patients who had previously received 90Y ibritumomab tiuxetan therapy and those who had not. These findings suggest that patients previously treated with 90Y ibritumomab tiuxetan can feasibly undergo other forms of treatment for progressive NHL, and that a clinical response to further treatment options is not precluded by administration of 90Y ibritumomab tiuxetan.