Details

Autor(en) / Beteiligte

• Xu, Jianliang
• Zhou, Tongqing
• 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

Titel

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

Ist Teil von

• Advanced science, 2024-05, p.e2309268-e2309268

Ort / Verlag

Germany

Erscheinungsjahr

2024

Link zum Volltext

Quelle

Wiley Online Library All Journals

Beschreibungen/Notizen

• 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 IC s of 0.314 and 0.033 µg mL , 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.