RESUMO
BACKGROUND: Vatreptacog alfa, a recombinant human factor VIIa (rFVIIa) analog developed to improve the treatment of bleeds in hemophilia patients with inhibitors, differs from native FVIIa by three amino acid substitutions. In a randomized, double-blind, crossover, confirmatory phase III trial (adept(™) 2), 8/72 (11%) hemophilia A or B patients with inhibitors treated for acute bleeds developed anti-drug antibodies (ADAs) to vatreptacog alfa. OBJECTIVES: To characterize the formation of anti-vatreptacog alfa ADAs in hemophilia patients with inhibitors. METHODS/PATIENTS: This was a post hoc analysis of adept(™) 2. Immunoglobulin isotype determination, specificity analysis of rFVIIa cross-reactive antibodies, epitope mapping of rFVIIa single mutant analogs and pharmacokinetic (PK) profiling were performed to characterize the ADAs. RESULTS: Immunoglobulin isotyping indicated that the ADAs were of the immunoglobulin G subtype. In epitope mapping, none of the rFVIIa single mutant analogs (V158D, E296V or M298Q) contained the complete antibody epitope, confirming that the antibodies were specific for vatreptacog alfa. In two patients, for whom PK profiling was performed both before and after the development of ADAs, vatreptacog alfa showed a prolonged elimination phase following ADA development. During the follow-up evaluation, the rFVIIa cross-reactivity disappeared after the last vatreptacog alfa exposure, despite continued exposure to rFVIIa as part of standard care. CONCLUSIONS: Results from the vatreptacog alfa phase III trial demonstrate that the specific changes made, albeit relatively small, to the FVIIa molecule alter its clinical immunogenicity.
Assuntos
Substituição de Aminoácidos , Fator VIIa/imunologia , Isoanticorpos/biossíntese , Sequência de Aminoácidos , Especificidade de Anticorpos , Reações Antígeno-Anticorpo , Reações Cruzadas , Epitopos/química , Epitopos/imunologia , Fator VIIa/química , Fator VIIa/genética , Fator VIIa/farmacocinética , Antígenos HLA-D/análise , Antígenos HLA-D/genética , Hemofilia A/sangue , Hemorragia/tratamento farmacológico , Hemorragia/etiologia , Humanos , Imunoglobulina G/biossíntese , Imunoglobulina G/imunologia , Isoanticorpos/imunologia , Testes de Neutralização , Estrutura Terciária de Proteína/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacocinética , Relação Estrutura-AtividadeAssuntos
Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Anticorpos Monoclonais Humanizados , Proteínas do Sistema Complemento/biossíntese , Proteínas do Sistema Complemento/genética , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Niacinamida/administração & dosagem , Rituximab , SorafenibeAssuntos
Citocinas/metabolismo , Síndrome POEMS/metabolismo , Animais , Osso e Ossos/metabolismo , Fatores de Crescimento Endotelial/metabolismo , Hematopoese , Humanos , Interleucina-6/metabolismo , Linfocinas/metabolismo , Sistema Nervoso/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Fatores de Crescimento/metabolismo , Receptores de Interleucina-6/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularAssuntos
Citocinas/metabolismo , Síndrome POEMS/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Humanos , Interleucina-1/metabolismo , Neoplasias/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Fator de Crescimento Transformador beta1 , Fator de Necrose Tumoral alfa/metabolismoRESUMO
This article summarizes the clinical, radiological and laboratory features of syndrome, which is known by the acronym "POEMS". POEMS syndrome is a rare multisystemic syndrome with plasma cell dyscrasia. POEMS is characterized by the combination of polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes. Other signs are frequently observed in affected patients, such as peripheral edema, arteriopathy, nephropathy, thrombocytosis and osteosclerotic lesions. The plasma cell dyscrasia in POEMS syndrome differs from the dyscrasia found in multiple myeloma. It has been suggested that pleiotropic cytokines which act in synergy on immune, nervous, endocrine and vascular systems could play a pathogenic role in POEMS syndrome.
