A matrix of structure-based designs yields improved VRC01-class antibodies for HIV-1 therapy and prevention
Passive transfer of broadly neutralizing antibodies is showing promise in the treatment and prevention of HIV-1. One class of antibodies, the VRC01 class, appears especially promising. To improve VRC01-class antibodies, we combined structure-based design with a matrix-based approach to generate VRC0...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2021-01-01
|
| Series: | mAbs |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2021.1946918 |
| _version_ | 1818489389852917760 |
|---|---|
| author | Young D. Kwon Mangaiarkarasi Asokan Jason Gorman Baoshan Zhang Qingbo Liu Mark K. Louder Bob C. Lin Krisha McKee Amarendra Pegu Raffaello Verardi Eun Sung Yang VRC Production Program Kevin Carlton Nicole A. Doria-Rose Paolo Lusso John R. Mascola Peter D. Kwong |
| author_facet | Young D. Kwon Mangaiarkarasi Asokan Jason Gorman Baoshan Zhang Qingbo Liu Mark K. Louder Bob C. Lin Krisha McKee Amarendra Pegu Raffaello Verardi Eun Sung Yang VRC Production Program Kevin Carlton Nicole A. Doria-Rose Paolo Lusso John R. Mascola Peter D. Kwong |
| author_sort | Young D. Kwon |
| collection | DOAJ |
| description | Passive transfer of broadly neutralizing antibodies is showing promise in the treatment and prevention of HIV-1. One class of antibodies, the VRC01 class, appears especially promising. To improve VRC01-class antibodies, we combined structure-based design with a matrix-based approach to generate VRC01-class variants that filled an interfacial cavity, used diverse third-complementarity-determining regions, reduced potential steric clashes, or exploited extended contacts to a neighboring protomer within the envelope trimer. On a 208-strain panel, variant VRC01.23LS neutralized 90% of the panel at a geometric mean IC80 less than 1 μg/ml, and in transgenic mice with human neonatal-Fc receptor, the serum half-life of VRC01.23LS was indistinguishable from that of the parent VRC01LS, which has a half-life of 71 d in humans. A cryo-electron microscopy structure of VRC01.23 Fab in complex with BG505 DS-SOSIP.664 Env trimer determined at 3.4-Å resolution confirmed the structural basis for its ~10-fold improved potency relative to VRC01. Another variant, VRC07-523-F54-LS.v3, neutralized 95% of the 208-isolated panel at a geometric mean IC80 of less than 1 μg/ml, with a half-life comparable to that of the parental VRC07-523LS. Our matrix-based structural approach thus enables the engineering of VRC01 variants for HIV-1 therapy and prevention with improved potency, breadth, and pharmacokinetics. |
| first_indexed | 2024-12-10T17:03:17Z |
| format | Article |
| id | doaj.art-fd7ff32ab1e546deaa0798bcdf196936 |
| institution | Directory Open Access Journal |
| issn | 1942-0862 1942-0870 |
| language | English |
| last_indexed | 2024-12-10T17:03:17Z |
| publishDate | 2021-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj.art-fd7ff32ab1e546deaa0798bcdf1969362022-12-22T01:40:32ZengTaylor & Francis GroupmAbs1942-08621942-08702021-01-0113110.1080/19420862.2021.1946918A matrix of structure-based designs yields improved VRC01-class antibodies for HIV-1 therapy and preventionYoung D. Kwon0Mangaiarkarasi Asokan1Jason Gorman2Baoshan Zhang3Qingbo Liu4Mark K. Louder5Bob C. Lin6Krisha McKee7Amarendra Pegu8Raffaello Verardi9Eun Sung Yang10VRC Production Program11Kevin Carlton12Nicole A. Doria-Rose13Paolo Lusso14John R. Mascola15Peter D. Kwong16Vaccine 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, 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, 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, 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, USAPassive transfer of broadly neutralizing antibodies is showing promise in the treatment and prevention of HIV-1. One class of antibodies, the VRC01 class, appears especially promising. To improve VRC01-class antibodies, we combined structure-based design with a matrix-based approach to generate VRC01-class variants that filled an interfacial cavity, used diverse third-complementarity-determining regions, reduced potential steric clashes, or exploited extended contacts to a neighboring protomer within the envelope trimer. On a 208-strain panel, variant VRC01.23LS neutralized 90% of the panel at a geometric mean IC80 less than 1 μg/ml, and in transgenic mice with human neonatal-Fc receptor, the serum half-life of VRC01.23LS was indistinguishable from that of the parent VRC01LS, which has a half-life of 71 d in humans. A cryo-electron microscopy structure of VRC01.23 Fab in complex with BG505 DS-SOSIP.664 Env trimer determined at 3.4-Å resolution confirmed the structural basis for its ~10-fold improved potency relative to VRC01. Another variant, VRC07-523-F54-LS.v3, neutralized 95% of the 208-isolated panel at a geometric mean IC80 of less than 1 μg/ml, with a half-life comparable to that of the parental VRC07-523LS. Our matrix-based structural approach thus enables the engineering of VRC01 variants for HIV-1 therapy and prevention with improved potency, breadth, and pharmacokinetics.https://www.tandfonline.com/doi/10.1080/19420862.2021.1946918Antibody VRC01broadly neutralizing antibodyHIV-1 envelope trimermatrix-based designpolyreactivityprophylaxis |
| spellingShingle | Young D. Kwon Mangaiarkarasi Asokan Jason Gorman Baoshan Zhang Qingbo Liu Mark K. Louder Bob C. Lin Krisha McKee Amarendra Pegu Raffaello Verardi Eun Sung Yang VRC Production Program Kevin Carlton Nicole A. Doria-Rose Paolo Lusso John R. Mascola Peter D. Kwong A matrix of structure-based designs yields improved VRC01-class antibodies for HIV-1 therapy and prevention mAbs Antibody VRC01 broadly neutralizing antibody HIV-1 envelope trimer matrix-based design polyreactivity prophylaxis |
| title | A matrix of structure-based designs yields improved VRC01-class antibodies for HIV-1 therapy and prevention |
| title_full | A matrix of structure-based designs yields improved VRC01-class antibodies for HIV-1 therapy and prevention |
| title_fullStr | A matrix of structure-based designs yields improved VRC01-class antibodies for HIV-1 therapy and prevention |
| title_full_unstemmed | A matrix of structure-based designs yields improved VRC01-class antibodies for HIV-1 therapy and prevention |
| title_short | A matrix of structure-based designs yields improved VRC01-class antibodies for HIV-1 therapy and prevention |
| title_sort | matrix of structure based designs yields improved vrc01 class antibodies for hiv 1 therapy and prevention |
| topic | Antibody VRC01 broadly neutralizing antibody HIV-1 envelope trimer matrix-based design polyreactivity prophylaxis |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2021.1946918 |
| work_keys_str_mv | AT youngdkwon amatrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT mangaiarkarasiasokan amatrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT jasongorman amatrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT baoshanzhang amatrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT qingboliu amatrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT markklouder amatrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT bobclin amatrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT krishamckee amatrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT amarendrapegu amatrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT raffaelloverardi amatrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT eunsungyang amatrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT vrcproductionprogram amatrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT kevincarlton amatrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT nicoleadoriarose amatrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT paololusso amatrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT johnrmascola amatrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT peterdkwong amatrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT youngdkwon matrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT mangaiarkarasiasokan matrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT jasongorman matrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT baoshanzhang matrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT qingboliu matrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT markklouder matrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT bobclin matrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT krishamckee matrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT amarendrapegu matrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT raffaelloverardi matrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT eunsungyang matrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT vrcproductionprogram matrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT kevincarlton matrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT nicoleadoriarose matrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT paololusso matrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT johnrmascola matrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention AT peterdkwong matrixofstructurebaseddesignsyieldsimprovedvrc01classantibodiesforhiv1therapyandprevention |