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1.
Recent Pat Drug Deliv Formul ; 12(3): 212-222, 2018.
Article in English | MEDLINE | ID: mdl-30019653

ABSTRACT

BACKGROUND: While protein therapeutics are invaluable in managing numerous diseases, many require frequent injections to maintain therapeutically effective concentrations, due to their short half-life in circulation. PolyXen™, a platform and patented technology employing biodegradable, non-immunogenic and hydrophilic Polysialic Acids (PSA) for drug delivery, is being utilized to overcome such limitations, thereby potentially enabling the clinical utility of a broad range of protein therapeutics. Here, we report the recent progress on two development candidates, polysialylated deoxyribonuclease I (PSA-DNase) and polysialylated erythropoietin (PSA-EPO). METHODS AND RESULTS: Chemical polysialylation of DNase I (DNase) using PSA with different chain length at various conjugation sites led to improved stability against proteases and thermal stress, and slightly reduced enzymatic activity. Polysialylation of EPO resulted in retention of protein structure and PSA-EPO remained biologically active. PSA-EPO had a significantly prolonged circulating half-life (e.g. t1/2 of PSA-EPO = ~400 h in patients after subcutaneous administration, aimed for once monthly administration, vs. t1/2 of EPO = ~22 h; administered twice or thrice weekly), and retained in vivo efficacy. CONCLUSION: This approach has been clinically validated in phase I (in healthy volunteers) and II studies of PSA-EPO [for managing anemia in patients with chronic kidney disease (CKD)].


Subject(s)
Anemia/prevention & control , Deoxyribonuclease I/pharmacology , Drug Delivery Systems/methods , Erythropoietin/pharmacology , Erythropoietin/pharmacokinetics , Sialic Acids/pharmacokinetics , Animals , Deoxyribonuclease I/adverse effects , Deoxyribonuclease I/chemistry , Drug Stability , Erythropoietin/administration & dosage , Erythropoietin/chemistry , Female , Half-Life , Humans , Injections, Subcutaneous , Patents as Topic , Rats , Sialic Acids/chemistry
2.
Neurotherapeutics ; 13(4): 895-904, 2016 10.
Article in English | MEDLINE | ID: mdl-27324388

ABSTRACT

Previously, we showed that CD206-targeted liposomal delivery of co-encapsulated immunodominant myelin basic protein (MBP) sequences MBP46-62, MBP124-139 and MBP147-170 (Xemys) suppressed experimental autoimmune encephalomyelitis in dark Agouti rats. The objective of this study was to assess the safety of Xemys in the treatment of patients with relapsing-remitting multiple sclerosis (MS) and secondary progressive MS, who failed to achieve a sustained response to first-line disease-modifying therapies. In this phase I, open-label, dose-escalating, proof-of-concept study, 20 patients with relapsing-remitting or secondary progressive MS received weekly subcutaneously injections with ascending doses of Xemys up to a total dose of 2.675 mg. Clinical examinations, including Expanded Disability Status Scale score, magnetic resonance imaging results, and serum cytokine concentrations, were assessed before the first injection and for up to 17 weeks after the final injection. Xemys was safe and well tolerated when administered for 6 weeks to a maximum single dose of 900 µg. Expanded Disability Status Scale scores and numbers of T2-weighted and new gadolinium-enhancing lesions on magnetic resonance imaging were statistically unchanged at study exit compared with baseline; nonetheless, the increase of number of active gadolinium-enhancing lesions on weeks 7 and 10 in comparison with baseline was statistically significant. During treatment, the serum concentrations of the cytokines monocyte chemoattractant protein-1, macrophage inflammatory protein-1ß, and interleukin-7 decreased, whereas the level of tumor necrosis factor-α increased. These results provide evidence for the further development of Xemys as an antigen-specific, disease-modifying therapy for patients with MS.


Subject(s)
Antigens, CD/metabolism , Lectins, C-Type/metabolism , Mannose-Binding Lectins/metabolism , Multiple Sclerosis/drug therapy , Myelin Basic Protein/chemistry , Myelin Basic Protein/therapeutic use , Peptide Fragments/therapeutic use , Adult , Cytokines/blood , Disability Evaluation , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Multiple Sclerosis/blood , Multiple Sclerosis/diagnostic imaging , Phospholipids/therapeutic use , Statistics, Nonparametric , Treatment Outcome , Young Adult
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