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

• Published in: mAbs Vol. 16; no. 1; p. 2383013
• Main Authors: Devanaboyina, Siva Charan, Li, Peng, LaGory, Edward L, Poon-Andersen, Carrie, Cook, Kevin D, Soto, Marcus, Wang, Zhe, Dang, Khue, Uyeda, Craig, Case, Ryan B, Thomas, Veena A, Primack, Ronya, Ponce, Manuel, Di, Mei, Ouyang, Brian, Kaner, Joelle, Lam, Sheung Kwan, Mostafavi, Mina
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis Group 31.12.2024
• Subjects: Animals; Antibodies, Monoclonal - immunology; Antigen-antibody trafficking; Asialoglycoprotein Receptor - immunology; Asialoglycoprotein Receptor - metabolism; Calcium - metabolism; fluorescence microscopy; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - immunology; Humans; Hydrogen-Ion Concentration; Mice; Mice, Transgenic; pH/Ca2+-dependent antibodies; pharmacokinetics; Receptors, Fc - genetics; Receptors, Fc - immunology; Receptors, Fc - metabolism; TMDD; pharmacokinetics; pH/Ca2+-dependent antibodies; Antigen-antibody trafficking; fluorescence microscopy; TMDD
• ISSN: 1942-0862; 1942-0870; 1942-0870
• DOI: 10.1080/19420862.2024.2383013

Targeting antigens with antibodies exhibiting pH/Ca -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/Ca -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/Ca -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/Ca -dependent antibodies, the pH/Ca -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/Ca -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/Ca -dependent antibodies to obtain increased serum exposure.