ABSTRACT
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.
Subject(s)
Amino Acid Substitution , Factor VIIa/immunology , Isoantibodies/biosynthesis , Amino Acid Sequence , Antibody Specificity , Antigen-Antibody Reactions , Cross Reactions , Epitopes/chemistry , Epitopes/immunology , Factor VIIa/chemistry , Factor VIIa/genetics , Factor VIIa/pharmacokinetics , HLA-D Antigens/analysis , HLA-D Antigens/genetics , Hemophilia A/blood , Hemorrhage/drug therapy , Hemorrhage/etiology , Humans , Immunoglobulin G/biosynthesis , Immunoglobulin G/immunology , Isoantibodies/immunology , Neutralization Tests , Protein Structure, Tertiary/genetics , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/immunology , Recombinant Proteins/pharmacokinetics , Structure-Activity RelationshipSubject(s)
Antibodies, Monoclonal, Murine-Derived/administration & dosage , Antibodies, Monoclonal/administration & dosage , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Niacinamide/analogs & derivatives , Phenylurea Compounds/administration & dosage , Antibodies, Monoclonal, Humanized , Complement System Proteins/biosynthesis , Complement System Proteins/genetics , Gene Expression Regulation, Leukemic/drug effects , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Niacinamide/administration & dosage , Rituximab , SorafenibSubject(s)
Cytokines/metabolism , POEMS Syndrome/metabolism , Animals , Bone and Bones/metabolism , Endothelial Growth Factors/metabolism , Hematopoiesis , Humans , Interleukin-6/metabolism , Lymphokines/metabolism , Nervous System/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Receptors, Growth Factor/metabolism , Receptors, Interleukin-6/metabolism , Receptors, Vascular Endothelial Growth Factor , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth FactorsABSTRACT
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.
