A glycosylated recombinant human granulocyte colony stimulating factor produced in a novel protein production system (AVI-014) in healthy subjects: a first-in human, single dose, controlled study

BACKGROUND: AVI-014 is an egg white-derived, recombinant, human granulocyte colony-stimulating factor (G-CSF). This healthy volunteer study is the first human investigation of AVI-014. METHODS: 24 male and female subjects received a single subcutaneous injection of AVI-014 at 4 or 8 mcg/kg. 16 control subjects received 4 or 8 mcg/kg of filgrastim (Neupogen, Amgen) in a partially blinded, parallel fashion. RESULTS: The Geometric Mean Ratio (GMR) (90% CI) of 4 mcg/kg AVI-014/filgrastim AUC(0-72 hr) was 1.00 (0.76, 1.31) and Cmax was 0.86 (0.66, 1.13). At the 8 mcg/kg dose, the AUC(0-72) GMR was 0.89 (0.69, 1.14) and Cmax was 0.76 (0.58, 0.98). A priori pharmacokinetic bioequivalence was defined as the 90% CI of the GMR bounded by 0.8-1.25. Both the white blood cell and absolute neutrophil count area under the % increase curve AUC(0-9 days) and Cmax (maximal % increase from baseline)GMR at 4 and 8 mcg/kg fell within the 0.5-2.0 a priori bound set for pharmacodynamic bioequivalence. The CD 34+ % increase curve AUC(0-9 days) and Cmax GMR for both doses was approximately 1, but 90% confidence intervals were large due to inherent variance, and this measure did not meet pharmacodynamic bioequivalence. AVI-014 demonstrated a side effect profile similar to that of filgrastim. CONCLUSION: AVI-014 has safety, pharmacokinetic, and pharmacodynamic properties comparable to filgrastim at an equal dose in healthy volunteers. These findings support further investigation in AVI-014

Vitamin D in autoimmunity: Molecular mechanisms and therapeutic potential

Over the last three decades, it has become clear that the role of vitamin D goes beyond the regulation of calcium homeostasis and bone health. An important extraskeletal effect of vitamin D is the modulation of the immune system. In the context of autoimmune diseases, this is illustrated by correlations of vitamin D status and genetic polymorphisms in the vitamin D receptor with the incidence and severity of the disease. These correlations warrant investigation into the potential use of vitamin D in the treatment of patients with autoimmune diseases. In recent years, several clinical trials have been performed to investigate the therapeutic value of vitamin D in multiple sclerosis, rheumatoid arthritis, Crohn's disease, type I diabetes, and systemic lupus erythematosus. Additionally, a second angle of investigation has focused on unraveling the molecular pathways used by vitamin D in order to find new potential therapeutic targets. This review will not only provide an overview of the clinical trials that have been performed but also discuss the current knowledge about the molecular mechanisms underlying the immunomodulatory effects of vitamin D and how these advances can be used in the treatment of autoimmune diseases

Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion

Interferon-gamma (IFN-¿) is a pleiotropic molecule with associated antiproliferative, pro-apoptotic and antitumor mechanisms. This effector cytokine, often considered as a major effector of immunity, has been used in the treatment of several diseases, despite its adverse effects. Although broad evidence implicating IFN-¿ in tumor immune surveillance, IFN-¿-based therapies undergoing clinical trials have been of limited success. In fact, recent reports suggested that it may also play a protumorigenic role, namely, through IFN-¿ signaling insensitivity, downregulation of major histocompatibility complexes, and upregulation of indoleamine 2,3-dioxygenase and of checkpoint inhibitors, as programmed cell-death ligand 1. However, the IFN-¿-mediated responses are still positively associated with patient's survival in several cancers. Consequently, major research efforts are required to understand the immune contexture in which IFN-¿ induces its intricate and highly regulated effects in the tumor microenvironment. This review discusses the current knowledge on the pro- and antitumorigenic effects of IFN-¿ as part of the complex immune response to cancer, highlighting the relevance to identify IFN-¿ responsive patients for the improvement of therapies that exploit associated signaling pathways.This article is a result of the project NORTE-01-0145-FEDER- 000012, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Part-nership Agreement, through the European Regional Development Fund (ERDF) and through the FCT PhD Programmes by Human Capital Operational Programme (POCH), specifically by the BiotechHealth Programme. FC and RG, KS, and MO also acknowledge FCT for PhD grant (PD/BD/114013/2015) and for the FCT Investigator Grants (IF/00638/2014, IF/00004/2014 and IF/01066/2012), respectively. AC has a postdoctoral fellowship (POCI-01-0145-FEDER-016390). KS received an iMM Laço- 2016 research grant