Bispecific antibody CAP256.J3LS targets V2-apex and CD4-binding sites with high breadth and potency
Antibody CAP256-VRC26.25 targets the second hypervariable region (V2) at the apex of the HIV envelope (Env) trimer with extraordinary neutralization potency, although less than optimal breadth. To improve breadth, we linked the light chain of CAP256V2LS, an optimized version of CAP256-VRC26.25 curre...
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Taylor & Francis Group
2023-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2023.2165390 |
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| author | Baoshan Zhang Jason Gorman Young D. Kwon Amarendra Pegu Cara W. Chao Tracy Liu Mangaiarkarasi Asokan Michael F. Bender Tatsiana Bylund Leland Damron Deepika Gollapudi Paula Lei Yile Li Cuiping Liu Mark K. Louder Krisha McKee Adam S. Olia Reda Rawi Arne Schön Shuishu Wang Eun Sung Yang Yongping Yang Kevin Carlton Nicole A. Doria-Rose Lawrence Shapiro Michael S. Seaman John R. Mascola Peter D. Kwong |
| author_facet | Baoshan Zhang Jason Gorman Young D. Kwon Amarendra Pegu Cara W. Chao Tracy Liu Mangaiarkarasi Asokan Michael F. Bender Tatsiana Bylund Leland Damron Deepika Gollapudi Paula Lei Yile Li Cuiping Liu Mark K. Louder Krisha McKee Adam S. Olia Reda Rawi Arne Schön Shuishu Wang Eun Sung Yang Yongping Yang Kevin Carlton Nicole A. Doria-Rose Lawrence Shapiro Michael S. Seaman John R. Mascola Peter D. Kwong |
| author_sort | Baoshan Zhang |
| collection | DOAJ |
| description | Antibody CAP256-VRC26.25 targets the second hypervariable region (V2) at the apex of the HIV envelope (Env) trimer with extraordinary neutralization potency, although less than optimal breadth. To improve breadth, we linked the light chain of CAP256V2LS, an optimized version of CAP256-VRC26.25 currently under clinical evaluation, to the llama nanobody J3, which has broad CD4-binding site-directed neutralization. The J3-linked bispecific antibody exhibited improved breadth and potency over both J3 and CAP256V2LS, indicative of synergistic neutralization. The cryo-EM structure of the bispecific antibody in complex with a prefusion-closed Env trimer revealed simultaneous binding of J3 and CAP256V2LS. We further optimized the pharmacokinetics of the bispecific antibody by reducing the net positive charge of J3. The optimized bispecific antibody, which we named CAP256.J3LS, had a half-life similar to CAP256V2LS in human FcRn knock-in mice and exhibited suitable auto-reactivity, manufacturability, and biophysical risk. CAP256.J3LS neutralized over 97% of a multiclade 208-strain panel (geometric mean concentration for 80% inhibition (IC80) 0.079 μg/ml) and 100% of a 100-virus clade C panel (geometric mean IC80 of 0.05 μg/ml), suggesting its anti-HIV utility especially in regions where clade C dominates. |
| format | Article |
| id | doaj-art-bddbe9ec6f5b4b779bcbe4b49830cab8 |
| institution | DOAJ |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-bddbe9ec6f5b4b779bcbe4b49830cab82025-08-20T03:15:09ZengTaylor & Francis GroupmAbs1942-08621942-08702023-12-0115110.1080/19420862.2023.2165390Bispecific antibody CAP256.J3LS targets V2-apex and CD4-binding sites with high breadth and potencyBaoshan Zhang0Jason Gorman1Young D. Kwon2Amarendra Pegu3Cara W. Chao4Tracy Liu5Mangaiarkarasi Asokan6Michael F. Bender7Tatsiana Bylund8Leland Damron9Deepika Gollapudi10Paula Lei11Yile Li12Cuiping Liu13Mark K. Louder14Krisha McKee15Adam S. Olia16Reda Rawi17Arne Schön18Shuishu Wang19Eun Sung Yang20Yongping Yang21Kevin Carlton22Nicole A. Doria-Rose23Lawrence Shapiro24Michael S. Seaman25John R. Mascola26Peter D. Kwong27Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USADepartment of Biology, Johns Hopkins University, Baltimore, MD, USAVaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USADepartment of Biochemistry, Columbia University, New York, NY, USABeth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USAVaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USAVaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USAAntibody CAP256-VRC26.25 targets the second hypervariable region (V2) at the apex of the HIV envelope (Env) trimer with extraordinary neutralization potency, although less than optimal breadth. To improve breadth, we linked the light chain of CAP256V2LS, an optimized version of CAP256-VRC26.25 currently under clinical evaluation, to the llama nanobody J3, which has broad CD4-binding site-directed neutralization. The J3-linked bispecific antibody exhibited improved breadth and potency over both J3 and CAP256V2LS, indicative of synergistic neutralization. The cryo-EM structure of the bispecific antibody in complex with a prefusion-closed Env trimer revealed simultaneous binding of J3 and CAP256V2LS. We further optimized the pharmacokinetics of the bispecific antibody by reducing the net positive charge of J3. The optimized bispecific antibody, which we named CAP256.J3LS, had a half-life similar to CAP256V2LS in human FcRn knock-in mice and exhibited suitable auto-reactivity, manufacturability, and biophysical risk. CAP256.J3LS neutralized over 97% of a multiclade 208-strain panel (geometric mean concentration for 80% inhibition (IC80) 0.079 μg/ml) and 100% of a 100-virus clade C panel (geometric mean IC80 of 0.05 μg/ml), suggesting its anti-HIV utility especially in regions where clade C dominates.https://www.tandfonline.com/doi/10.1080/19420862.2023.2165390Antibody half-lifeantibody improvementbispecific antibodyCAP256-VRC26.25CD4-binding sitecryo-electron microscopy |
| spellingShingle | Baoshan Zhang Jason Gorman Young D. Kwon Amarendra Pegu Cara W. Chao Tracy Liu Mangaiarkarasi Asokan Michael F. Bender Tatsiana Bylund Leland Damron Deepika Gollapudi Paula Lei Yile Li Cuiping Liu Mark K. Louder Krisha McKee Adam S. Olia Reda Rawi Arne Schön Shuishu Wang Eun Sung Yang Yongping Yang Kevin Carlton Nicole A. Doria-Rose Lawrence Shapiro Michael S. Seaman John R. Mascola Peter D. Kwong Bispecific antibody CAP256.J3LS targets V2-apex and CD4-binding sites with high breadth and potency mAbs Antibody half-life antibody improvement bispecific antibody CAP256-VRC26.25 CD4-binding site cryo-electron microscopy |
| title | Bispecific antibody CAP256.J3LS targets V2-apex and CD4-binding sites with high breadth and potency |
| title_full | Bispecific antibody CAP256.J3LS targets V2-apex and CD4-binding sites with high breadth and potency |
| title_fullStr | Bispecific antibody CAP256.J3LS targets V2-apex and CD4-binding sites with high breadth and potency |
| title_full_unstemmed | Bispecific antibody CAP256.J3LS targets V2-apex and CD4-binding sites with high breadth and potency |
| title_short | Bispecific antibody CAP256.J3LS targets V2-apex and CD4-binding sites with high breadth and potency |
| title_sort | bispecific antibody cap256 j3ls targets v2 apex and cd4 binding sites with high breadth and potency |
| topic | Antibody half-life antibody improvement bispecific antibody CAP256-VRC26.25 CD4-binding site cryo-electron microscopy |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2023.2165390 |
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