Enhanced in vivo efficacy of a long-life type I Interferon superagonist in a mouse model of multiple sclerosis

Harari, Daniel; Kallweit, Nadine; Abramovich, Renne; Sasson, Keren; Zozulya, Alla L.; Smith, Paul A.; Schlapschy, Martin; Aharoni, Rina; Köster, Mario; Eliam, Raya; Skerra, Arne; Schreiber, Gideon

doi:10.1016/j.jneuroim.2014.08.588

Cited by 7 publications

(11 citation statements)

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“…25,26 The high in vitro and in vivo stabilizing effects obtained with the short PAS sequences (i.e., 40 and 75 residues long, respectively) used in this work may be ascribed to the peculiar multivalency of HFt, which is formed by 24 subunits auto-assembled in a spherical cage. The long plasma half-lives of our HFt-PAS-DOXO complexes are likely to facilitate timedependent large drug accumulation in tumors, with a significant improvement also in the therapeutic efficacy.…”

Section: ■ Results and Discussionmentioning

confidence: 91%

“…This behavior is in agreement with previous reports on PASylated proteins and has been ascribed to their reduced binding of SDS, whose negatively charged sulfate headgroup normally provides the electrophoretic driving force. 25,26 The calculated masses for HFt-based proteins were then verified by mass spectrometry MALDI-TOF experiments (Supporting Figure 1).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…In fact, the use of natively disordered PAS polypeptides had been reported to eliminate the disadvantages associated with protein-PEGylation for the development and production of a number of biopharmaceuticals. 25,26 As an example, after synthetic conjugation of PEG molecules with recombinant proteins, additional in vitro processing and purification steps have to be performed to obtain PEG derivatives with suitably high purity (GMP-grade); this results in both lower yields and increased manufacturing costs. Conversely, genetic constructs containing PAS polypeptides are uniquely homogeneous, stable in blood plasma, and degradable by kidney enzymes, thus evading organ accumulation while lacking toxicity and immunogenicity in animals.…”

Section: ■ Introductionmentioning

confidence: 99%

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Improved Doxorubicin Encapsulation and Pharmacokinetics of Ferritin–Fusion Protein Nanocarriers Bearing Proline, Serine, and Alanine Elements

Tremante²,

et al. 2015

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A novel human ferritin-based nanocarrier, composed of 24 modified monomers able to auto-assemble into a modified protein cage, was produced and used as selective carrier of anti-tumor payloads. Each modified monomer derives from the genetic fusion of two distinct modules, namely the heavy chain of human ferritin (HFt) and a stabilizing/protective PAS polypeptide sequence rich in proline (P), serine (S), and alanine (A) residues. Two genetically fused protein constructs containing PAS polymers with 40- and 75-residue lengths, respectively, were compared. They were produced and purified as recombinant proteins in Escherichia coli at high yields. Both preparations were highly soluble and stable in vitro as well as in mouse plasma. Size-exclusion chromatography, dynamic light scattering, and transmission electron microscopy results indicated that PASylated ferritins are fully assembled and highly monodispersed. In addition, yields and stability of encapsulated doxorubicin were significantly better for both HFt-PAS proteins than for wild-type HFt. Importantly, PAS sequences considerably prolonged the half-life of HFt in the mouse bloodstream. Finally, our doxorubicin-loaded nanocages preserved the pharmacological activity of the drug. Taken together, these results indicate that both of the developed HFt-PAS fusion proteins are promising nanocarriers for future applications in cancer therapy.

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Section: ■ Results and Discussionmentioning

confidence: 91%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Improved Doxorubicin Encapsulation and Pharmacokinetics of Ferritin–Fusion Protein Nanocarriers Bearing Proline, Serine, and Alanine Elements

Tremante²,

et al. 2015

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“…PASylation has allowed the design of biopharmaceuticals with tailored pharmacological properties to improve animal studies, as well as therapies and diagnosis of various diseases [13,23,24]. Here, we explored the efficacy of a new long-acting leptin version prepared via PASylation in a CLA-induced lipodystrophic (LD) mouse model.…”

Section: Discussionmentioning

confidence: 99%

Treatment of diet-induced lipodystrophic C57BL/6J mice with long-acting PASylated leptin normalises insulin sensitivity and hepatic steatosis by promoting lipid utilisation

et al. 2016

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Aims/hypothesis Recombinant leptin offers a viable treatment for lipodystrophy (LD) syndromes. However, due to its short plasma half-life, leptin replacement therapy requires at least daily subcutaneous (s.c.) injections. Here, we optimised this treatment strategy in LD mice by using a novel leptin version with extended plasma half-life using PASylation technology. Methods A long-acting leptin version was prepared by genetic fusion with a 600 residue polypeptide made of Pro, Ala and Ser (PASylation), which enlarges the hydrodynamic volume and, thus, retards renal filtration, allowing less frequent injection. LD was induced in C57BL/6J mice by feeding a diet supplemented with conjugated linoleic acid (CLA). Chronic and acute effects of leptin treatment were assessed by evaluating plasma insulin levels, insulin tolerance, histological liver sections, energy expenditure, energy intake and body composition.Results In a cohort of female mice, 4 nmol PAS-leptin (applied via four s.c. injections every 3 days) successfully alleviated the CLA-induced LD phenotype, which was characterised by hyperinsulinaemia, insulin intolerance and hepatosteatosis. The same injection regimen had no measurable effect when unmodified recombinant leptin was administered at an equivalent dose. In a cohort of LD males, a single s.c. injection of PAS-leptin did not affect energy expenditure but inhibited food intake and promoted a shift in fuel selection towards preferential fat oxidation, which mechanistically substantiates the metabolic improvements. Conclusions/interpretation The excellent pharmacological properties render PASylated leptin an agent of choice for refining both animal studies and therapeutic strategies in the context of LD syndromes and beyond.

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“…140 IFN-β is most widely used in MS treatment and has been shown in vivo to act through the upregulation of PD-L1, which results in a decrease in neuroinflammation and a therapeutic effect for patients with MS. 140,141 A previous study illustrated that PD-L1 expression inversely correlates with strong CNS inflammation in MS plaques, further suggesting that PD-L1 acts in a protective manner, downregulating the inflammation associated with T-cell extension into the CNS. 142 Several studies have shown a correlation between the upregulated expression of PD-1/PD-L1 and the associated MS stage using the EAE mouse model.…”

Section: Pd-1/pd-l1 Association With Msmentioning

confidence: 97%

Involvement of Immune Regulation in Multiple Sclerosis

Spagnuolo

Piavis

Williams

2017

Immunol Immunogenet Insights

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Multiple sclerosis (MS) is a neurodegenerative disease characterized by neuroinflammation and demyelination that results in axon loss. Multiple sclerosis has been shown to be the result of an autoimmune response caused by a mixture of genetic and environmental factors. Dendritic cells are prominent antigen-presenting cells that interact with various molecules to regulate the immune system. The dysfunction of various features of immune regulation, including interleukins (ILs), CD4 + T cells, and suppressor of cytokine signaling (SOCS1), has been implicated in the pathogenesis of MS. T cells, particularly through the malfunction of B7-costimulatory pathways, have been shown to affect the progression of the disease. SOCS1 is important in regulating the function of T cells through its interactions with other nearby genes, especially CLEC16A, with abnormal decreases in SOCS1 expression leading to the exhibition of MS symptoms. The activation of IL-23 receptors on CD4 + T cells is pivotal to their differentiation into pathogenic T H 17 cells. Several promising compounds that downregulate gene expression of IL-23 and IL-23R have been discovered but require further investigation for efficacy and safety. Given their role in the severity and progression of MS, therapies that decrease these dysregulations may ultimately decrease symptoms and in turn improve patients' quality of life.

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Enhanced in vivo efficacy of a long-life type I Interferon superagonist in a mouse model of multiple sclerosis

Cited by 7 publications

References 0 publications

Improved Doxorubicin Encapsulation and Pharmacokinetics of Ferritin–Fusion Protein Nanocarriers Bearing Proline, Serine, and Alanine Elements

Improved Doxorubicin Encapsulation and Pharmacokinetics of Ferritin–Fusion Protein Nanocarriers Bearing Proline, Serine, and Alanine Elements

Treatment of diet-induced lipodystrophic C57BL/6J mice with long-acting PASylated leptin normalises insulin sensitivity and hepatic steatosis by promoting lipid utilisation

Involvement of Immune Regulation in Multiple Sclerosis

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