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1.
Front Immunol ; 12: 728322, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34512662

RESUMO

Novel molecules that directly target the neonatal Fc receptor (FcRn) and/or Fc gamma receptors (FcγRs) are emerging as promising treatments for immunoglobulin G (IgG)-dependent autoimmune pathologies. Mutated Fc regions and monoclonal antibodies that target FcRn are currently in clinical development and hold promise for reducing the levels of circulating IgG. Additionally, engineered structures containing multimeric Fc regions allow the dual targeting of FcRn and FcγRs; however, their tolerance needs to first be validated in phase I clinical studies. Here, for the first time, we have developed a modified monomeric recombinant Fc optimized for binding to all FcRns and FcγRs without the drawback of possible tolerance associated with FcγR cross-linking. A rational approach using Fc engineering allowed the selection of LFBD192, an Fc with a combination of six mutations that exhibits improved binding to human FcRn and FcγR as well as mouse FcRn and FcγRIV. The potency of LFBD192 was compared with that of intravenous immunoglobulin (IVIg), an FcRn blocker (Fc-MST-HN), and a trimeric Fc that blocks FcRn and/or immune complex-mediated cell activation through FcγR without triggering an immune reaction in several in vitro tests and validated in three mouse models of autoimmune disease.


Assuntos
Antirreumáticos/farmacologia , Artrite Experimental/prevenção & controle , Autoimunidade/efeitos dos fármacos , Fragmentos Fc das Imunoglobulinas/farmacologia , Receptores Fc/antagonistas & inibidores , Receptores de IgG/antagonistas & inibidores , Animais , Antirreumáticos/metabolismo , Artrite Experimental/genética , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Ligação Competitiva , Complemento C5a/metabolismo , Feminino , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Fragmentos Fc das Imunoglobulinas/imunologia , Fragmentos Fc das Imunoglobulinas/metabolismo , Interleucina-2/metabolismo , Células Jurkat , Cinética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Fagocitose/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Ligação Proteica , Engenharia de Proteínas , Receptores Fc/genética , Receptores Fc/imunologia , Receptores Fc/metabolismo , Receptores de IgG/genética , Receptores de IgG/imunologia , Receptores de IgG/metabolismo , Via Secretória , Transdução de Sinais , Células THP-1
2.
Br J Clin Pharmacol ; 86(2): 329-337, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31658379

RESUMO

AIMS: The pharmacokinetics (PK) of a triple-secured fibrinogen concentrate (FC) was assessed in patients ≥40 kg by noncompartmental analysis over a period of 14 days with multiple blood samples. Limited PK time point assessments in children lead to consideration of using Bayesian estimation for paediatric data. The objectives were (i) to define the population PK of FC in patients with afibrinogenaemia; (ii) to detect age- and body weight-related differences and consequences for dose adjustment. METHODS: A population PK model was built using plasma fibrinogen activity data collected in 31 patients aged 1 to 48 years who had participated in a single-dose PK study with FC 0.06 g kg-1 . RESULTS: A 1-compartment model with allometric scaling accounting for body weight was found to best describe the kinetics of FC. Addition of age and sex as covariates did not improve the model. Incremental in vivo recovery assessed at the end of infusion with the predicted maximal concentrations was lower, weight-adjusted clearance was higher, and fibrinogen elimination half-life was shorter in patients <40 kg than patients ≥40 kg. Interpatient variability was similar in both groups. CONCLUSION: Dosing in patients ≥40 kg based on the previous empirical finding using noncompartmental analysis where FC 1 g kg-1 raises the plasma fibrinogen activity by 23 g L-1 was confirmed. In patients <40 kg, (covering the age range from birth up to about 12 years old) FC 1 g kg-1 raises the plasma fibrinogen by 19 g L-1 . Dosing should be adapted accordingly unless therapy is individualized.


Assuntos
Afibrinogenemia , Afibrinogenemia/tratamento farmacológico , Fatores Etários , Teorema de Bayes , Peso Corporal , Criança , Fibrinogênio , Humanos
3.
Eur J Nucl Med Mol Imaging ; 35(4): 756-65, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18157530

RESUMO

PURPOSE: (153)Sm-ethylenediaminetetramethylenephosphonic acid (EDTMP; Quadramet) is indicated for the treatment of painful bone metastases, whereas zoledronic acid (Zometa) is indicated for the prevention of skeletal complications. Because of the different therapeutic effects, combining the treatments may be beneficial. Both, however, accumulate in areas with increased osteoblastic activity. Possible drug interactions were investigated. METHODS: Patients with hormone-refractory prostate cancer were treated with 18.5 MBq/kg (153)Sm-EDTMP in weeks 1 and 3 and with 37 MBq/kg in week 15. Treatment with 4 mg zoledronic acid began in week 3 and continued every 4 weeks through week 23. In weeks 3 and 15, zoledronic acid was administered 2 days before (153)Sm-EDTMP treatment. Urine was collected 48 h after injection of (153)Sm-EDTMP, and whole-body images were obtained 6, 24 and 48 h post-injection. The effect of zoledronic acid on total bone uptake of (153)Sm-EDTMP was measured indirectly by the cumulative activity excreted in the urine in weeks 1, 3 and 15. Biodistribution, safety, tolerability and effect on prostate-specific antigen level were also studied. RESULTS: The urinary excretion in week 3 divided by the urinary excretion in week 1 (baseline) times 100% was mean 98.4 +/- 11.6% (median 96.2%). From week 1 to 15, after four zoledronic acid treatments, the mean ratio was 101.9 +/- 10.7% (median 101.8%). Bioequivalence could be concluded by using a two-sample t test for both per-protocol (n = 13) and full-analysis sets (n = 18). Toxicity was comparable to of monotherapy with (153)Sm-EDTMP. CONCLUSION: Zoledronic acid treatment does not influence (153)Sm-EDTMP skeletal uptake. Combined treatment is feasible and safe.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Difosfonatos/uso terapêutico , Imidazóis/uso terapêutico , Compostos Organometálicos/uso terapêutico , Compostos Organofosforados/uso terapêutico , Neoplasias da Próstata/radioterapia , Radioisótopos/uso terapêutico , Samário/uso terapêutico , Conservadores da Densidade Óssea/efeitos adversos , Neoplasias Ósseas/radioterapia , Terapia Combinada , Difosfonatos/efeitos adversos , Humanos , Imidazóis/efeitos adversos , Injeções Intravenosas , Masculino , Taxa de Depuração Metabólica , Metástase Neoplásica , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/efeitos adversos , Compostos Organometálicos/farmacocinética , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/efeitos adversos , Compostos Organofosforados/farmacocinética , Neoplasias da Próstata/patologia , Radioisótopos/administração & dosagem , Radioisótopos/efeitos adversos , Radioisótopos/farmacocinética , Samário/administração & dosagem , Samário/efeitos adversos , Samário/farmacocinética , Ácido Zoledrônico
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