Improved pharmacokinetics of HIV-neutralizing VRC01-class antibodies achieved by reduction of net positive charge on variable domain
ABSTRACTThe amino-acid composition of the immunoglobulin variable region has been observed to impact antibody pharmacokinetics (PK). Here, we sought to improve the PK of the broad HIV−1-neutralizing VRC01-class antibodies, VRC07-523LS and N6LS, by reducing the net positive charge in their variable d...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2023-12-01
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| Series: | mAbs |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2023.2223350 |
| _version_ | 1797356260336599040 |
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| author | Young D. Kwon Amarendra Pegu Eun Sung Yang Baoshan Zhang Michael F. Bender Mangaiarkarasi Asokan Qingbo Liu Krisha McKee Bob C. Lin Tracy Liu Mark K. Louder Reda Rawi Mateo Reveiz Andrew J. Schaub Chen-Hsiang Shen Nicole A. Doria-Rose Paolo Lusso John R. Mascola Peter D. Kwong |
| author_facet | Young D. Kwon Amarendra Pegu Eun Sung Yang Baoshan Zhang Michael F. Bender Mangaiarkarasi Asokan Qingbo Liu Krisha McKee Bob C. Lin Tracy Liu Mark K. Louder Reda Rawi Mateo Reveiz Andrew J. Schaub Chen-Hsiang Shen Nicole A. Doria-Rose Paolo Lusso John R. Mascola Peter D. Kwong |
| author_sort | Young D. Kwon |
| collection | DOAJ |
| description | ABSTRACTThe amino-acid composition of the immunoglobulin variable region has been observed to impact antibody pharmacokinetics (PK). Here, we sought to improve the PK of the broad HIV−1-neutralizing VRC01-class antibodies, VRC07-523LS and N6LS, by reducing the net positive charge in their variable domains. We used a structure-guided approach to generate a panel of antibody variants incorporating select Arg or Lys substituted to Asp, Gln, Glu, or Ser. The engineered variants exhibited reduced affinity to heparin, reduced polyreactivity, and improved PK in human FcRn-transgenic mice. One variant, VRC07-523LS.v34, with three charge substitutions, had an observed in vivo half-life and an estimated human half-life of 10.8 and 60 days, respectively (versus 5.4 and 38 days for VRC07-523LS) and retained functionality, neutralizing 92% of a 208-strain panel at a geometric mean IC80 <1 µg/mL. Another variant, N6LS.C49, with two charge substitutions, had an observed in vivo half-life and an estimated human half-life of 14.5 and 80 days (versus 9.0 and 44 days for N6LS) and neutralized ~80% of 208 strains at a geometric mean IC80 <1 µg/mL. Since Arg and Lys residues are prevalent in human antibodies, we propose substitution of select Arg or Lys with Asp, Gln, Glu, or Ser in the framework region as a general means to improve PK of therapeutic antibodies. |
| first_indexed | 2024-03-08T14:24:02Z |
| format | Article |
| id | doaj.art-404c6bcba63e47658183c99f62376df3 |
| institution | Directory Open Access Journal |
| issn | 1942-0862 1942-0870 |
| language | English |
| last_indexed | 2024-03-08T14:24:02Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj.art-404c6bcba63e47658183c99f62376df32024-01-13T11:27:51ZengTaylor & Francis GroupmAbs1942-08621942-08702023-12-0115110.1080/19420862.2023.2223350Improved pharmacokinetics of HIV-neutralizing VRC01-class antibodies achieved by reduction of net positive charge on variable domainYoung D. Kwon0Amarendra Pegu1Eun Sung Yang2Baoshan Zhang3Michael F. Bender4Mangaiarkarasi Asokan5Qingbo Liu6Krisha McKee7Bob C. Lin8Tracy Liu9Mark K. Louder10Reda Rawi11Mateo Reveiz12Andrew J. Schaub13Chen-Hsiang Shen14Nicole A. Doria-Rose15Paolo Lusso16John R. Mascola17Peter D. Kwong18Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USALaboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USALaboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USAABSTRACTThe amino-acid composition of the immunoglobulin variable region has been observed to impact antibody pharmacokinetics (PK). Here, we sought to improve the PK of the broad HIV−1-neutralizing VRC01-class antibodies, VRC07-523LS and N6LS, by reducing the net positive charge in their variable domains. We used a structure-guided approach to generate a panel of antibody variants incorporating select Arg or Lys substituted to Asp, Gln, Glu, or Ser. The engineered variants exhibited reduced affinity to heparin, reduced polyreactivity, and improved PK in human FcRn-transgenic mice. One variant, VRC07-523LS.v34, with three charge substitutions, had an observed in vivo half-life and an estimated human half-life of 10.8 and 60 days, respectively (versus 5.4 and 38 days for VRC07-523LS) and retained functionality, neutralizing 92% of a 208-strain panel at a geometric mean IC80 <1 µg/mL. Another variant, N6LS.C49, with two charge substitutions, had an observed in vivo half-life and an estimated human half-life of 14.5 and 80 days (versus 9.0 and 44 days for N6LS) and neutralized ~80% of 208 strains at a geometric mean IC80 <1 µg/mL. Since Arg and Lys residues are prevalent in human antibodies, we propose substitution of select Arg or Lys with Asp, Gln, Glu, or Ser in the framework region as a general means to improve PK of therapeutic antibodies.https://www.tandfonline.com/doi/10.1080/19420862.2023.2223350Antibody-mediated preventionnet positive charge reductionpharmacokineticsserum half-lifesurface chargevariable region |
| spellingShingle | Young D. Kwon Amarendra Pegu Eun Sung Yang Baoshan Zhang Michael F. Bender Mangaiarkarasi Asokan Qingbo Liu Krisha McKee Bob C. Lin Tracy Liu Mark K. Louder Reda Rawi Mateo Reveiz Andrew J. Schaub Chen-Hsiang Shen Nicole A. Doria-Rose Paolo Lusso John R. Mascola Peter D. Kwong Improved pharmacokinetics of HIV-neutralizing VRC01-class antibodies achieved by reduction of net positive charge on variable domain mAbs Antibody-mediated prevention net positive charge reduction pharmacokinetics serum half-life surface charge variable region |
| title | Improved pharmacokinetics of HIV-neutralizing VRC01-class antibodies achieved by reduction of net positive charge on variable domain |
| title_full | Improved pharmacokinetics of HIV-neutralizing VRC01-class antibodies achieved by reduction of net positive charge on variable domain |
| title_fullStr | Improved pharmacokinetics of HIV-neutralizing VRC01-class antibodies achieved by reduction of net positive charge on variable domain |
| title_full_unstemmed | Improved pharmacokinetics of HIV-neutralizing VRC01-class antibodies achieved by reduction of net positive charge on variable domain |
| title_short | Improved pharmacokinetics of HIV-neutralizing VRC01-class antibodies achieved by reduction of net positive charge on variable domain |
| title_sort | improved pharmacokinetics of hiv neutralizing vrc01 class antibodies achieved by reduction of net positive charge on variable domain |
| topic | Antibody-mediated prevention net positive charge reduction pharmacokinetics serum half-life surface charge variable region |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2023.2223350 |
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