Effect of variable domain charge on in vitro and in vivo disposition of monoclonal antibodies
A growing body of evidence supports the important role of molecular charge on antibody pharmacokinetics (PK), yet a quantitative description of the effect of charge on systemic and tissue disposition of antibodies is still lacking. Consequently, we have systematically engineered complementarity-dete...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2021-01-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2021.1993769 |
| _version_ | 1828292621292797952 |
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| author | Shufang Liu Ashwni Verma Hubert Kettenberger Wolfgang F. Richter Dhaval K. Shah |
| author_facet | Shufang Liu Ashwni Verma Hubert Kettenberger Wolfgang F. Richter Dhaval K. Shah |
| author_sort | Shufang Liu |
| collection | DOAJ |
| description | A growing body of evidence supports the important role of molecular charge on antibody pharmacokinetics (PK), yet a quantitative description of the effect of charge on systemic and tissue disposition of antibodies is still lacking. Consequently, we have systematically engineered complementarity-determining regions (CDRs) of trastuzumab to create a series of variants with an isoelectric point (pI) range of 6.3–8.9 and a variable region (Fv) charge range of −8.9 to +10.9 (at pH 5.5), and have investigated in vitro and in vivo disposition of these molecules. These monoclonal antibodies (mAbs) exhibited incrementally enhanced binding to cell surfaces and cellular uptake with increased positive charge in antigen-negative cells. After single intravenous dosing in mice, a bell-shaped relationship between systemic exposure and Fv charge was observed, with both extended negative and positive charge patches leading to more rapid nonspecific clearance. Whole-body PK experiments revealed that, although overall exposures of most variants in the tissues were very similar, positive charge of mAbs led to significantly enhanced tissue:plasma concentration ratios for most tissues. In well-perfused organs such as liver, spleen, and kidney, the positive charge variants show superior accumulation. In tissues with continuous capillaries such as fat, muscle, skin, and bone, plasma concentrations governed tissue exposures. The in vitro and in vivo disposition data presented here facilitate better understanding of the impact of charge modifications on antibody PK, and suggest that alteration in the charge may help to improve tissue:plasma concentration ratios for mAbs in certain tissues. The data presented here also paves the way for the development of physiologically based pharmacokinetic models of mAbs that incorporate charge variations. |
| first_indexed | 2024-04-13T11:11:36Z |
| format | Article |
| id | doaj.art-e73ce0565b654394aa4bd90e5fc450a1 |
| institution | Directory Open Access Journal |
| issn | 1942-0862 1942-0870 |
| language | English |
| last_indexed | 2024-04-13T11:11:36Z |
| publishDate | 2021-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj.art-e73ce0565b654394aa4bd90e5fc450a12022-12-22T02:49:06ZengTaylor & Francis GroupmAbs1942-08621942-08702021-01-0113110.1080/19420862.2021.1993769Effect of variable domain charge on in vitro and in vivo disposition of monoclonal antibodiesShufang Liu0Ashwni Verma1Hubert Kettenberger2Wolfgang F. Richter3Dhaval K. Shah4Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, the State University of New York at Buffalo, Buffalo, USADepartment of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, the State University of New York at Buffalo, Buffalo, USARoche Pharma Research and Early Development (Pred), Large Molecule Research (Lmr), Roche Innovation Center Munich, Penzberg, GermanyRoche Pharma Research and Early Development (Pred), Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, SwitzerlandDepartment of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, the State University of New York at Buffalo, Buffalo, USAA growing body of evidence supports the important role of molecular charge on antibody pharmacokinetics (PK), yet a quantitative description of the effect of charge on systemic and tissue disposition of antibodies is still lacking. Consequently, we have systematically engineered complementarity-determining regions (CDRs) of trastuzumab to create a series of variants with an isoelectric point (pI) range of 6.3–8.9 and a variable region (Fv) charge range of −8.9 to +10.9 (at pH 5.5), and have investigated in vitro and in vivo disposition of these molecules. These monoclonal antibodies (mAbs) exhibited incrementally enhanced binding to cell surfaces and cellular uptake with increased positive charge in antigen-negative cells. After single intravenous dosing in mice, a bell-shaped relationship between systemic exposure and Fv charge was observed, with both extended negative and positive charge patches leading to more rapid nonspecific clearance. Whole-body PK experiments revealed that, although overall exposures of most variants in the tissues were very similar, positive charge of mAbs led to significantly enhanced tissue:plasma concentration ratios for most tissues. In well-perfused organs such as liver, spleen, and kidney, the positive charge variants show superior accumulation. In tissues with continuous capillaries such as fat, muscle, skin, and bone, plasma concentrations governed tissue exposures. The in vitro and in vivo disposition data presented here facilitate better understanding of the impact of charge modifications on antibody PK, and suggest that alteration in the charge may help to improve tissue:plasma concentration ratios for mAbs in certain tissues. The data presented here also paves the way for the development of physiologically based pharmacokinetic models of mAbs that incorporate charge variations.https://www.tandfonline.com/doi/10.1080/19420862.2021.1993769Antibody pharmacokineticscharge modificationtissue distribution |
| spellingShingle | Shufang Liu Ashwni Verma Hubert Kettenberger Wolfgang F. Richter Dhaval K. Shah Effect of variable domain charge on in vitro and in vivo disposition of monoclonal antibodies mAbs Antibody pharmacokinetics charge modification tissue distribution |
| title | Effect of variable domain charge on in vitro and in vivo disposition of monoclonal antibodies |
| title_full | Effect of variable domain charge on in vitro and in vivo disposition of monoclonal antibodies |
| title_fullStr | Effect of variable domain charge on in vitro and in vivo disposition of monoclonal antibodies |
| title_full_unstemmed | Effect of variable domain charge on in vitro and in vivo disposition of monoclonal antibodies |
| title_short | Effect of variable domain charge on in vitro and in vivo disposition of monoclonal antibodies |
| title_sort | effect of variable domain charge on in vitro and in vivo disposition of monoclonal antibodies |
| topic | Antibody pharmacokinetics charge modification tissue distribution |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2021.1993769 |
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