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

SUBMITTER: Xu J 

PROVIDER: S-EPMC11234422 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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

Xu Jianliang J   Zhou Tongqing T   McKee Krisha K   Zhang Baoshan B   Liu Cuiping C   Nazzari Alexandra F AF   Pegu Amarendra A   Shen Chen-Hsiang CH   Becker Jordan E JE   Bender Michael F MF   Chan Payton P   Changela Anita A   Chaudhary Ridhi R   Chen Xuejun X   Einav Tal T   Kwon Young Do YD   Lin Bob C BC   Louder Mark K MK   Merriam Jonah S JS   Morano Nicholas C NC   O'Dell Sijy S   Olia Adam S AS   Rawi Reda R   Roark Ryan S RS   Stephens Tyler T   Teng I-Ting IT   Tourtellott-Fogt Emily E   Wang Shuishu S   Yang Eun Sung ES   Shapiro Lawrence L   Tsybovsky Yaroslav Y   Doria-Rose Nicole A NA   Casellas Rafael R   Kwong Peter D PD  

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20240505 26


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  ...[more]

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