Tividenofusp alfa

Tividenofusp alfa utilizes a "Transport Vehicle" (TV) technology to address the metabolic defect of Hunter syndrome at the molecular level. Hunter syndrome is caused by mutations in the IDS gene encoding iduronate-2-sulfatase: This enzyme deficiency leads to perturbed lysosomal degradation. Tividenofusp alfa consists of a functional recombinant human iduronate-2-sulfatase (IDS) enzyme fused to a transport moiety—a modified Fc domain of an antibody that binds with high affinity to the human insulin receptor (HIR).

Following intravenous administration, the transport moiety binds to insulin receptors expressed on the surface of brain endothelial cells that form the blood-brain barrier. This binding triggers the transport of the entire fusion protein across the BBB and into the brain parenchyma. Once inside the CNS (and in systemic tissues), the IDS portion of the molecule binds to mannose-6-phosphate (M6P) receptors on the surface of target cells, leading to internalization into the cell. The protein is trafficked to the lysosomes, where the IDS enzyme becomes active. It catalyzes the hydrolysis of the 2-sulfate groups of the L-iduronate-2-sulfate units of heparan sulfate and dermatan sulfate. By breaking down these accumulated GAGs, tividenofusp alfa prevents further cellular damage and reverses the lysosomal storage pathology that drives the neurologic and systemic manifestations of the disease.