An internalizing antibody specific for the human asialoglycoprotein receptor

Area of Science:

• Hepatology
• Immunology
• Molecular Biology

Background:

• The liver is a prime target for gene and drug delivery due to its unique characteristics.
• The asialoglycoprotein receptor (ASGPR) is a liver-specific lectin crucial for endocytosis, making it an ideal target for liver-directed therapies.
• Current strategies for ASGPR targeting include using asialoglycoprotein-coupled, galactosylated molecules, or anti-ASGPR antibodies.

Purpose of the Study:

• To isolate and characterize a novel single-chain antibody fragment (scFv) targeting the ASGPR.
• To evaluate the efficacy of the developed scFv as a targeting moiety for liver-specific drug delivery.
• To demonstrate the potential of the scFv in mediating ASGPR-specific cellular internalization and subsequent cell death.

Main Methods:

• Isolation of a novel anti-ASGPR scFv (B11) from the synthetic human "Ronit-1" antibody phage display library.
• Characterization of B11 binding to both recombinant and native forms of ASGPR.
• Assessment of B11's ability to facilitate ASGPR-specific internalization of an immunotoxin (B11-PE38KDEL) and induce cell death.

Main Results:

• A novel anti-ASGPR scFv, designated B11, was successfully isolated.
• B11 demonstrated specific binding to both recombinant and native ASGPR.
• The B11-PE38KDEL immunotoxin mediated ASGPR-specific internalization and induced significant cell death, confirming B11's targeting capability.

Conclusions:

• The newly isolated anti-ASGPR scFv (B11) is a potent targeting moiety for ASGPR-directed drug delivery.
• This antibody fragment shows promise for developing targeted liver therapies.
• B11 facilitates receptor-mediated endocytosis and subsequent cell death, highlighting its therapeutic potential.