Exceptionally broad HIV-1 neutralization via bispecific antibody–mediated
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Posted On: 10/04/2025 11:10:29 PM
Exceptionally broad HIV-1 neutralization via bispecific antibody–mediated prepositioning
September 30, 2025
https://www.pnas.org/doi/full/10.1073/pnas.2517311122
...To generate a bsAb that prepositions an NHR-targeting antibody, we created hybrids between D5_AR and P140 (also known as PRO140 or leronlimab), which competes with gp120 for CCR5 binding (14, 15) (Fig. 2A). While P140 has previously been incorporated into bsAbs (16–18), our study pairs P140 with D5_AR, an antibody that selectively binds the highly conserved NHR, which is specifically and transiently exposed only during the PHI stage of the fusion process...
...However, since the TZM-bl cells express CCR5, D5_AR/P140 bsAb potently neutralized both pseudoviruses, with IC80 values of 0.075 μg/mL for HXB2 and 0.15 μg/mL for WEAUd15.410.5017, indicating that prepositioning of D5_AR via P140 is critical to maximizing its activity...
...Compared to iMab/D5_AR, which achieved a median IC80 value of 0.52 μg/mL, D5_AR/P140 was 6.4 fold more potent, achieving neutralization with a median IC80 value of 0.082 μg/mL.. Based on this scoring framework, D5_AR/P140 achieves exceptionally broad neutralization with predicted clinical prevention efficacies that exceed those of previously characterized bnAbs...
...Overall, our findings demonstrate that targeting the PHI with the engineered bsAb D5_AR/P140 results in potent and exceptionally broad neutralization. These results further support the NHR as a viable therapeutic target and define a new class of engineered bnAbs against HIV-1.
September 30, 2025
https://www.pnas.org/doi/full/10.1073/pnas.2517311122
...To generate a bsAb that prepositions an NHR-targeting antibody, we created hybrids between D5_AR and P140 (also known as PRO140 or leronlimab), which competes with gp120 for CCR5 binding (14, 15) (Fig. 2A). While P140 has previously been incorporated into bsAbs (16–18), our study pairs P140 with D5_AR, an antibody that selectively binds the highly conserved NHR, which is specifically and transiently exposed only during the PHI stage of the fusion process...
...However, since the TZM-bl cells express CCR5, D5_AR/P140 bsAb potently neutralized both pseudoviruses, with IC80 values of 0.075 μg/mL for HXB2 and 0.15 μg/mL for WEAUd15.410.5017, indicating that prepositioning of D5_AR via P140 is critical to maximizing its activity...
...Compared to iMab/D5_AR, which achieved a median IC80 value of 0.52 μg/mL, D5_AR/P140 was 6.4 fold more potent, achieving neutralization with a median IC80 value of 0.082 μg/mL.. Based on this scoring framework, D5_AR/P140 achieves exceptionally broad neutralization with predicted clinical prevention efficacies that exceed those of previously characterized bnAbs...
...Overall, our findings demonstrate that targeting the PHI with the engineered bsAb D5_AR/P140 results in potent and exceptionally broad neutralization. These results further support the NHR as a viable therapeutic target and define a new class of engineered bnAbs against HIV-1.
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