Targeting the Human β Receptor Inhibits Contact Dermatitis in a Transgenic Mouse Model.

Allergic contact dermatitis (ACD) is a prevalent and poorly controlled inflammatory disease caused by skin infiltration of T cells and granulocytes. The beta common (β) cytokines GM-CSF, IL-3, and IL-5 are powerful regulators of granulocyte function that signal through their common receptor subunit β, a property that has made β an attractive target to simultaneously inhibit these cytokines. However, the species specificity of β has precluded testing of inhibitors of human β in mouse models.

Increased potency of recombinant VWF D'D3 albumin fusion proteins engineered for enhanced affinity for coagulation factor VIII.

Background: We have recently reported on a recombinant von Willebrand factor (VWF) D'D3 albumin fusion protein (rD'D3-FP) developed to extend the half-life of coagulation factor VIII (FVIII) for the treatment of hemophilia A. Based on predictive modelling presented in this study, we hypothesized that modifying rD'D3-FP to improve FVIII interaction would reduce exchange with endogenous VWF and provide additional FVIII half-life benefit.

Objectives: The aim of this study was to identify novel rD'D3-FP variants with enhanced therapeutic efficacy in extending FVIII half-life.

Identification of a modified coagulation factor X with enhanced activation properties as potential hemostatic agent.

Hemophilia A and hemophilia B are X-linked inherited bleeding disorders caused by a deficiency of coagulation factor VIII and IX, respectively. Standard of care is prophylactic factor replacement therapy; however, the development of neutralizing antibodies against these factors represents serious complications underlining the need for alternative treatment approaches. Human coagulation factor X has a central role within the blood coagulation system making it an attractive target for the development of alternative treatment strategies for patients with hemophilia.

FVIII half-life extension by coadministration of a D'D3 albumin fusion protein in mice, rabbits, rats, and monkeys.

A novel mechanism for extending the circulatory half-life of coagulation factor VIII (FVIII) has been established and evaluated preclinically. The FVIII binding domain of von Willebrand factor (D'D3) fused to human albumin (rD'D3-FP) dose dependently improved pharmacokinetics parameters of coadministered FVIII in all animal species tested, from mouse to cynomolgus monkey, after IV injection. At higher doses, the half-life of recombinant FVIII (rVIII-SingleChain) was calculated to be increased 2.

Utility of a high VWF: FVIII ratio in preventing FVIII accumulation: a study in VWF-deficient mice.

Treatment of von Willebrand disease typically requires multiple infusions of von Willebrand factor (VWF)/factor VIII (FVIII) concentrate. Accumulation of FVIII is a clinical concern due to potential risk for thromboembolism. This study sought to determine whether VWF/FVIII concentrate of high VWF:FVIII ratio can prevent FVIII accumulation.