{Reference Type}: Journal Article
{Title}: Ultrapotent Broadly Neutralizing Human-llama Bispecific Antibodies against HIV-1.
{Author}: Xu J;Zhou T;McKee K;Zhang B;Liu C;Nazzari AF;Pegu A;Shen CH;Becker JE;Bender MF;Chan P;Changela A;Chaudhary R;Chen X;Einav T;Kwon YD;Lin BC;Louder MK;Merriam JS;Morano NC;O'Dell S;Olia AS;Rawi R;Roark RS;Stephens T;Teng IT;Tourtellott-Fogt E;Wang S;Yang ES;Shapiro L;Tsybovsky Y;Doria-Rose NA;Casellas R;Kwong PD;
{Journal}: Adv Sci (Weinh)
{Volume}: 11
{Issue}: 26
{Year}: 2024 Jul 5
{Factor}: 17.521
{DOI}: 10.1002/advs.202309268
{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.