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Ultrapotent Broadly Neutralizing Human-llama Bispecific Antibodies against HIV-1

  1. Author:
    Xu, Jianliang [ORCID]
    Zhou, Tongqing [ORCID]
    McKee, Krisha
    Zhang, Baoshan
    Liu, Cuiping
    Nazzari, Alexandra F
    Pegu, Amarendra
    Shen, Chen-Hsiang
    Becker, Jordan E
    Bender, Michael F
    Chan, Payton
    Changela, Anita
    Chaudhary, Ridhi
    Chen, Xuejun
    Einav, Tal
    Kwon, Young Do
    Lin, Bob C
    Louder, Mark K
    Merriam, Jonah S
    Morano, Nicholas C
    O'Dell, Sijy
    Olia, Adam S
    Rawi, Reda
    Roark, Ryan S
    Stephens,Tyler
    Teng, I-Ting
    Tourtellott-Fogt, Emily
    Wang, Shuishu
    Yang, Eun Sung
    Shapiro, Lawrence
    Tsybovsky,Yaroslav
    Doria-Rose, Nicole A
    Casellas, Rafael
    Kwong, Peter D [ORCID]

  2. Author Address

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA., Laboratory of Lymphocyte Nuclear Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, 20892, USA., Department of Biology, Georgia State University, Atlanta, GA, 30303, USA., Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, 10027, USA., Department of Biochemistry and Molecular Biophysics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, 10032, USA., Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA., Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA., Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, 10032, USA., Hematopoietic Biology and Malignancy, MD Anderson Cancer Center, Houston, TX, 77054, USA.,
    1. Year: 2024
    2. Date: May 05
    3. Epub Date: 2024 05 05
  2. Journal: Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
    1. Pages: e2309268
  4. Type of Article: Article
  5. Article Number: e2309268
  1. Abstract:

    Broadly neutralizing antibodies are proposed as therapeutic and prophylactic agents against HIV-1, but their potency and breadth are less than optimal. This study describes the immunization of a llama with the prefusion-stabilized HIV-1 envelope (Env) trimer, BG505 DS-SOSIP, and the identification and improvement of potent neutralizing nanobodies recognizing the CD4-binding site (CD4bs) of vulnerability. Two of the vaccine-elicited CD4bs-targeting nanobodies, G36 and R27, when engineered into a triple tandem format with llama IgG2a-hinge region and human IgG1-constant region (G36×3-IgG2a and R27×3-IgG2a), neutralized 96% of a multiclade 208-strain panel at geometric mean IC80s of 0.314 and 0.033 µg mL-1, respectively. Cryo-EM structures of these nanobodies in complex with Env trimer revealed the two nanobodies to neutralize HIV-1 by mimicking the recognition of the CD4 receptor. To enhance their neutralizing potency and breadth, nanobodies are linked to the light chain of the V2-apex-targeting broadly neutralizing antibody, CAP256V2LS. The resultant human-llama bispecific antibody CAP256L-R27×3LS exhibited ultrapotent neutralization and breadth exceeding other published HIV-1 broadly neutralizing antibodies, with pharmacokinetics determined in FcRn-Fc mice similar to the parent CAP256V2LS. Vaccine-elicited llama nanobodies, when combined with V2-apex broadly neutralizing antibodies, may therefore be able to fulfill anti-HIV-1 therapeutic and prophylactic clinical goals. © 2024 The Authors. Advanced Science published by Wiley-VCH GmbH. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

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External Sources

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  2. DOI: 10.1002/advs.202309268
  3. PMID: 38704686

Library Notes

  1. Fiscal Year: FY2023-2024
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