Rapid depletion of “catch-and-release” anti-ASGR1 antibody in vivo
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....
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2024.2383013 |
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| author | Siva Charan Devanaboyina Peng Li Edward L. LaGory Carrie Poon-Andersen Kevin D. Cook Marcus Soto Zhe Wang Khue Dang Craig Uyeda Ryan B. Case Veena A. Thomas Ronya Primack Manuel Ponce Mei Di Brian Ouyang Joelle Kaner Sheung Kwan Lam Mina Mostafavi |
| author_facet | Siva Charan Devanaboyina Peng Li Edward L. LaGory Carrie Poon-Andersen Kevin D. Cook Marcus Soto Zhe Wang Khue Dang Craig Uyeda Ryan B. Case Veena A. Thomas Ronya Primack Manuel Ponce Mei Di Brian Ouyang Joelle Kaner Sheung Kwan Lam Mina Mostafavi |
| author_sort | Siva Charan Devanaboyina |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e01cdf9351b64b009ab7296a2022f247 |
| institution | Kabale University |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-e01cdf9351b64b009ab7296a2022f2472025-01-31T04:19:38ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2024.2383013Rapid depletion of “catch-and-release” anti-ASGR1 antibody in vivoSiva Charan Devanaboyina0Peng Li1Edward L. LaGory2Carrie Poon-Andersen3Kevin D. Cook4Marcus Soto5Zhe Wang6Khue Dang7Craig Uyeda8Ryan B. Case9Veena A. Thomas10Ronya Primack11Manuel Ponce12Mei Di13Brian Ouyang14Joelle Kaner15Sheung Kwan Lam16Mina Mostafavi17Department of Pharmacokinetics and Drug Metabolism, Amgen Research, Amgen Inc, South San Francisco, CA, USADepartment of Biologics, Amgen Research, Amgen Inc, South San Francisco, CA, USADepartment of Pharmacokinetics and Drug Metabolism, Amgen Research, Amgen Inc, South San Francisco, CA, USADepartment of Pharmacokinetics and Drug Metabolism, Amgen Research, Amgen Inc, South San Francisco, CA, USADepartment of Pharmacokinetics and Drug Metabolism, Amgen Research, Amgen Inc, South San Francisco, CA, USADepartment of Pharmacokinetics and Drug Metabolism, Amgen Research, Amgen Inc, Thousand Oaks, CA, USADepartment of Pharmacokinetics and Drug Metabolism, Amgen Research, Amgen Inc, South San Francisco, CA, USADepartment of Biologics, Amgen Research, Amgen Inc, South San Francisco, CA, USADepartment of Pharmacokinetics and Drug Metabolism, Amgen Research, Amgen Inc, South San Francisco, CA, USADepartment of Lead Discovery and Characterization, Amgen Research, Amgen Inc, South San Francisco, CA, USADepartment of Pharmacokinetics and Drug Metabolism, Amgen Research, Amgen Inc, South San Francisco, CA, USADepartment of Pharmacokinetics and Drug Metabolism, Amgen Research, Amgen Inc, Thousand Oaks, CA, USADepartment of Pharmacokinetics and Drug Metabolism, Amgen Research, Amgen Inc, Thousand Oaks, CA, USADepartment of Cardiometabolic disorders, Amgen Research, Amgen Inc, South San Francisco, CA, USADepartment of Biologics, Amgen Research, Amgen Inc, South San Francisco, CA, USADepartment of Biologics, Amgen Research, Amgen Inc, South San Francisco, CA, USADepartment of Biologics, Amgen Research, Amgen Inc, South San Francisco, CA, USADepartment of Biologics, Amgen Research, Amgen Inc, South San Francisco, CA, USATargeting 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.https://www.tandfonline.com/doi/10.1080/19420862.2024.2383013Antigen-antibody traffickingfluorescence microscopypH/Ca2+-dependent antibodiespharmacokineticsTMDD |
| spellingShingle | Siva Charan Devanaboyina Peng Li Edward L. LaGory Carrie Poon-Andersen Kevin D. Cook Marcus Soto Zhe Wang Khue Dang Craig Uyeda Ryan B. Case Veena A. Thomas Ronya Primack Manuel Ponce Mei Di Brian Ouyang Joelle Kaner Sheung Kwan Lam Mina Mostafavi Rapid depletion of “catch-and-release” anti-ASGR1 antibody in vivo mAbs Antigen-antibody trafficking fluorescence microscopy pH/Ca2+-dependent antibodies pharmacokinetics TMDD |
| title | Rapid depletion of “catch-and-release” anti-ASGR1 antibody in vivo |
| title_full | Rapid depletion of “catch-and-release” anti-ASGR1 antibody in vivo |
| title_fullStr | Rapid depletion of “catch-and-release” anti-ASGR1 antibody in vivo |
| title_full_unstemmed | Rapid depletion of “catch-and-release” anti-ASGR1 antibody in vivo |
| title_short | Rapid depletion of “catch-and-release” anti-ASGR1 antibody in vivo |
| title_sort | rapid depletion of catch and release anti asgr1 antibody in vivo |
| topic | Antigen-antibody trafficking fluorescence microscopy pH/Ca2+-dependent antibodies pharmacokinetics TMDD |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2383013 |
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