What is the mechanism of Pabinafusp Alfa?

Pabinafusp Alfa, also known as JR-141, is an innovative therapeutic agent designed to address the challenges posed by certain lysosomal storage disorders, particularly Hunter syndrome or Mucopolysaccharidosis II (MPS II). Hunter syndrome primarily results from a deficiency of the enzyme iduronate-2-sulfatase (IDS), which leads to the accumulation of glycosaminoglycans (GAGs) in various tissues, contributing to a range of severe physical and neurological symptoms. The development of Pabinafusp Alfa represents a significant advancement in the treatment of these disorders, particularly in overcoming the limitations of traditional enzyme replacement therapies (ERT).

The primary mechanism of action of Pabinafusp Alfa hinges on its bifunctional structure, which integrates both the therapeutic enzyme and a proprietary delivery system to enhance its efficacy. The compound consists of a genetically engineered fusion protein that combines the human IDS enzyme with an anti-transferrin receptor antibody. This design is crucial for several reasons.

First, the anti-transferrin receptor antibody component of Pabinafusp Alfa is key to its ability to cross the blood-brain barrier (BBB). The BBB is a highly selective permeability barrier that shields the brain from potentially harmful substances in the bloodstream but also poses a significant obstacle to the delivery of therapeutic agents for central nervous system (CNS) disorders. By targeting the transferrin receptor, which is abundantly expressed on the endothelial cells of the BBB, Pabinafusp Alfa leverages receptor-mediated transcytosis to facilitate the transport of the therapeutic enzyme across the BBB. This targeted approach ensures that the IDS enzyme can reach the CNS, a critical aspect given that neurological manifestations are a significant burden in Hunter syndrome.

Once across the BBB, the IDS enzyme component of Pabinafusp Alfa becomes active in degrading accumulated GAGs in the lysosomes of CNS cells. This enzymatic activity is essential for mitigating the pathological accumulation of these substrates, thereby alleviating neurological symptoms and potentially improving cognitive function and quality of life for patients.

Beyond its CNS effects, Pabinafusp Alfa is also effective in peripheral tissues. The fusion protein can be taken up by cells throughout the body via mannose-6-phosphate receptors, a common pathway for lysosomal enzymes. This dual-targeting capability ensures comprehensive treatment of both central and peripheral symptoms of Hunter syndrome.

Clinical studies have demonstrated the efficacy of Pabinafusp Alfa in reducing GAG levels in both the CNS and peripheral tissues, confirming its potential as a transformative therapy for MPS II patients. Moreover, the ability of Pabinafusp Alfa to address neurological symptoms is particularly noteworthy, as traditional ERTs without BBB-crossing capabilities fail to impact these critical aspects of the disease.

In summary, Pabinafusp Alfa's mechanism of action is fundamentally based on its unique bifunctional structure that combines the therapeutic enzyme IDS with an anti-transferrin receptor antibody. This design enables effective delivery of the enzyme across the BBB and into the CNS, addressing a significant unmet need in the treatment of Hunter syndrome. By targeting both central and peripheral manifestations of the disease, Pabinafusp Alfa offers a promising therapeutic option that can significantly improve the overall management and quality of life for patients suffering from this debilitating disorder.