Rapid depletion of "catch-and-release" anti-ASGR1 antibody in vivo

MAbs. 2024 Jan-Dec;16(1):2383013. doi: 10.1080/19420862.2024.2383013. Epub 2024 Jul 25.

Abstract

Targeting antigens with antibodies exhibiting pH/Ca2+-dependent binding against an antigen is an attractive strategy to mitigate target-mediated disposition and antigen buffering. Studies have reported improved serum exposure of antibodies exhibiting pH/Ca2+-binding against membrane-bound receptors. Asialoglycoprotein receptor 1 (ASGR1) is a membrane-bound receptor primarily localized in hepatocytes. With a high expression level of approximately one million receptors per cell, high turnover, and rapid recycling, targeting this receptor with a conventional antibody is a challenge. In this study, we identified an antibody exhibiting pH/Ca2+-dependent binding to ASGR1 and generated antibody variants with increased binding to neonatal crystallizable fragment receptor (FcRn). Serum exposures of the generated anti-ASGR1 antibodies were analyzed in transgenic mice expressing human FcRn. Contrary to published reports of increased serum exposure of pH/Ca2+-dependent antibodies, the pH/Ca2+-dependent anti-ASGR1 antibody had rapid serum clearance in comparison to a conventional anti-ASGR1 antibody. We conducted sub-cellular trafficking studies of the anti-ASGR1 antibodies along with receptor quantification analysis for mechanistic understanding of the rapid serum clearance of pH/Ca2+-dependent anti-ASGR1 antibody. The findings from our study provide valuable insights in identifying the antigens, especially membrane bound, that may benefit from targeting with pH/Ca2+-dependent antibodies to obtain increased serum exposure.

Keywords: Antigen-antibody trafficking; TMDD; fluorescence microscopy; pH/Ca2+-dependent antibodies; pharmacokinetics.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Asialoglycoprotein Receptor* / immunology
  • Asialoglycoprotein Receptor* / metabolism
  • Calcium / metabolism
  • Histocompatibility Antigens Class I* / genetics
  • Histocompatibility Antigens Class I* / immunology
  • Humans
  • Hydrogen-Ion Concentration
  • Mice
  • Mice, Transgenic*
  • Receptors, Fc* / genetics
  • Receptors, Fc* / immunology
  • Receptors, Fc* / metabolism

Substances

  • Asialoglycoprotein Receptor
  • Receptors, Fc
  • Fc receptor, neonatal
  • Histocompatibility Antigens Class I
  • ASGR1 protein, human
  • Antibodies, Monoclonal
  • Calcium

Grants and funding

The author(s) reported there is no funding associated with the work featured in this article.