ASGR2

Asialoglycoprotein receptor 2 (ASGR2), a member of the asialoglycoprotein receptor family, is a key component of the hepatic glycoprotein clearance system. By recognizing desialylated glycoproteins, ASGR2 facilitates their endocytosis and lysosomal degradation. This receptor has attracted considerable attention as a drug target due to its liver-specific expression, high endocytic capacity and involvement in numerous physiological and pathological processes. Therapeutic applications targeting ASGR2 have shown promise, particularly in the treatment of hemophilia through the delivery of recombinant therapeutic proteins such as recombinant human factor VIII (F8), moroctocog alfa and lonoctocog alfa.

NCBI Gene ID: 433

UniProtKB ID: P07307

Structure of ASGR2

ASGR2 is a key component of the asialoglycoprotein receptor (ASGPR) complex, primarily expressed on hepatocytes. This receptor system is essential for the clearance of desialylated glycoproteins from the bloodstream. Structural Features of ASGR2:

• Type II Transmembrane Protein: ASGR2 is characterized by a short N-terminal cytoplasmic domain, a single transmembrane segment, and a substantial C-terminal extracellular region.
• Extracellular Domain: The extracellular portion contains a C-type lectin domain responsible for calcium-dependent carbohydrate recognition, specifically binding to terminal galactose and N-acetylgalactosamine residues.
• Quaternary Structure: Functionally, ASGR2 associates with ASGR1 to form hetero-oligomeric complexes, typically comprising two ASGR1 subunits and one ASGR2 subunit.

Figure 1. Schematic representation of ASGP-R, illustrating the hetero-oligomer composed of two H1 and one H2 subunit, each of them containing four domains. (Das et al., 2019)

Mechanism of Action of ASGR2

ASGR2 is a C-type lectin receptor that binds ligands with high specificity and affinity. The carbohydrate recognition domain of the receptor interacts with galactose or N-acetylgalactosamine on glycoproteins, triggering receptor-mediated endocytosis. Once internalized, the ligand-receptor complex is trafficked to early endosomes where the acidic environment promotes ligand dissociation. The receptor is recycled back to the plasma membrane, while the ligands are targeted to lysosomes for degradation. This recycling efficiency underscores ASGR2's capacity as a drug delivery receptor, allowing for repeated use without receptor saturation.

Figure 2. Molecular interaction between (a) D-galactose and (b) acetyl-galactosamine at the active binding site (CRD) of ASGP-R. (Das et al., 2019)

Physiological Roles of ASGR2

• Serum Glycoprotein Clearance: ASGR2, as part of the ASGPR complex, binds to desialylated glycoproteins—those lacking terminal sialic acid residues—facilitating their removal from the circulation. This process is critical for regulating the half-life of circulating glycoproteins and preventing the accumulation of potentially harmful desialylated proteins.
• Hepatic Endocytosis: The receptor mediates the internalization of bound glycoproteins via receptor-mediated endocytosis. Once internalized, these glycoproteins are directed to lysosomes for degradation, thereby contributing to the recycling of glycoprotein components and maintaining cellular homeostasis.

Pathological Roles of ASGR2

• Viral Infections: ASGR2 has been implicated in facilitating hepatic infections by certain viruses. For example, the asialoglycoprotein receptor may facilitate hepatic infection by multiple viruses, including hepatitis B.
• Autoimmunity: Autoantibodies against ASGPR, which includes ASGR2, have been detected in patients with autoimmune liver diseases such as autoimmune hepatitis. The presence of these autoantibodies suggests a potential role for ASGR2 in the pathogenesis of these diseases, possibly by disrupting normal receptor function or by serving as an autoimmune target.

Asialoglycoprotein Receptor Mediated Hepatocyte Targeting

ASGPR has a high affinity for glycoproteins that expose terminal galactose or N-acetylgalactosamine residues. By conjugating therapeutic agents to ligands containing these sugar moieties, it is possible to target drugs specifically to hepatocytes. Upon binding to ASGPR, the receptor-ligand complex undergoes endocytosis, delivering the therapeutic payload directly into the liver cells.

Figure 3. Graphic abstract of asialoglycoprotein receptor mediated hepatocyte targeting. (D'Souza and Devarajan, 2015)

Applications in Drug Delivery

• Ligand-Drug Conjugates: Therapeutic molecules can be directly linked to galactose or N-acetylgalactosamine residues, facilitating receptor-mediated uptake by hepatocytes.
• Nanocarrier Systems: Nanoparticles functionalized with ASGPR-recognized ligands can encapsulate drugs, enhancing delivery efficiency and specificity to liver cells.

Clinical Implications

ASGPR-mediated targeting holds great promise for the treatment of liver-specific diseases, including viral hepatitis, liver fibrosis and hepatocellular carcinoma. By ensuring precise delivery of therapeutics to hepatocytes, this strategy aims to maximize therapeutic efficacy while minimizing off-target effects.

ASGR2 as a Therapeutic Target in Hemophilia A

Hemophilia A, characterized by a deficiency in coagulation factor VIII, is managed through replacement therapy using recombinant factor VIII (rFVIII). ASGR2 plays a critical role in the hepatic uptake and clearance of rFVIII, influencing its half-life and therapeutic efficacy. Recent advancements in rFVIII design have optimized ASGR2 interactions to improve stability and bioavailability.

• Recombinant Human F8/Antihemophilic Factor: This therapeutic mimics endogenous Factor VIII and interacts with ASGR2 for hepatic clearance. Receptor-mediated uptake of recombinant F8 ensures a controlled degradation process, reducing systemic side effects.
• Moroctocog Alfa (BDDrFVIII): This B-domain deleted rFVIII variant shows improved stability and reduced immunogenicity. By retaining the ASGR2 binding domains, moroctocog alfa achieves effective hepatic targeting, extending its circulation time and therapeutic window.
• Lonoctocog Alfa (Recombinant Factor VIII): Lonoctocog alfa is an extended half-life rFVIII product designed with ASGR2 specificity in mind. Modifications in its glycosylation profile reduce its clearance rate while maintaining receptor-mediated hepatic uptake.

Advantages of ASGR2-Targeted Therapies

The liver-specific expression of ASGR2 minimizes off-target effects, making it an ideal receptor for targeted drug delivery. In addition, its high endocytic capacity allows for efficient drug internalization, enhancing therapeutic protein uptake and reducing systemic exposure. In hemophilia A, ASGR2 targeting has improved the pharmacokinetics of rFVIII, resulting in reduced dosing frequency and improved patient compliance.

As a top supplier of therapeutic proteins, Creative BioMart offers recombinant human F8/Antihemophilic Factor, moroctocog alfa (BDDrFVIII) and lonoctocog alfa (recombinant Factor VIII) targeting ASGR2 for the treatment of hemophilia A. Contact us for more information!

References

1. D'Souza AA, Devarajan PV. Asialoglycoprotein receptor mediated hepatocyte targeting — Strategies and applications. Journal of Controlled Release. 2015;203:126-139. doi:10.1016/j.jconrel.2015.02.022
2. Das S, Kudale P, Dandekar P, Devarajan PV. Asialoglycoprotein receptor and targeting strategies. In: Devarajan PV, Dandekar P, D'Souza AA, eds. Targeted Intracellular Drug Delivery by Receptor Mediated Endocytosis. Vol 39. Springer International Publishing; 2019:353-381. doi:10.1007/978-3-030-29168-6_12