Recombinant Human Anti-HIV-1 gp120 Antibody (PGT121)

The arrow indicates the day of PGT121 infusion, the gray line equals median value and the dotted line indicates the lower limit of quantification for HIV-1 RNA levels (40 copies (cp) ml^-1). Asterisks indicate the time point at which ART was started, and dots indicate when samples were collected for sequencing.

Stephenson, K. E., Julg, B., Tan, C. S., Zash, R., Walsh, S. R., Rolle, C. P., ... & Barouch, D. H. (2021). Safety, pharmacokinetics and antiviral activity of PGT121, a broadly neutralizing monoclonal antibody against HIV-1: a randomized, placebo-controlled, phase 1 clinical trial. Nature medicine, 27(10), 1718-1724.

IC50 neutralization scores (µg ml^-1), indicating sensitivity or resistance to PGT121 among isolated viruses, are shown for each participant, before and after PGT121 administration.

Stephenson, K. E., Julg, B., Tan, C. S., Zash, R., Walsh, S. R., Rolle, C. P., ... & Barouch, D. H. (2021). Safety, pharmacokinetics and antiviral activity of PGT121, a broadly neutralizing monoclonal antibody against HIV-1: a randomized, placebo-controlled, phase 1 clinical trial. Nature medicine, 27(10), 1718-1724.

Open circles indicate that either HIV-1 RNA (black) or PGT121 level (red) was below the limit of detection.

Stephenson, K. E., Julg, B., Tan, C. S., Zash, R., Walsh, S. R., Rolle, C. P., ... & Barouch, D. H. (2021). Safety, pharmacokinetics and antiviral activity of PGT121, a broadly neutralizing monoclonal antibody against HIV-1: a randomized, placebo-controlled, phase 1 clinical trial. Nature medicine, 27(10), 1718-1724.

The percentages of Env-, Gag- and Pol-specific CD8+ T cells secreting IFN-γ and TNF-α Env are shown for participants 6113 and 1536 at day 0 (D0) and day 84 (D84).

Stephenson, K. E., Julg, B., Tan, C. S., Zash, R., Walsh, S. R., Rolle, C. P., ... & Barouch, D. H. (2021). Safety, pharmacokinetics and antiviral activity of PGT121, a broadly neutralizing monoclonal antibody against HIV-1: a randomized, placebo-controlled, phase 1 clinical trial. Nature medicine, 27(10), 1718-1724.

The magnitude of Gag- and Pol-specific IFN-γ-secreting cellular immune responses (spot-forming units (SFU) 10-6 PBMCs) is plotted by peptide subpool for participants 6113 and 1536 at D0 and D84.

Stephenson, K. E., Julg, B., Tan, C. S., Zash, R., Walsh, S. R., Rolle, C. P., ... & Barouch, D. H. (2021). Safety, pharmacokinetics and antiviral activity of PGT121, a broadly neutralizing monoclonal antibody against HIV-1: a randomized, placebo-controlled, phase 1 clinical trial. Nature medicine, 27(10), 1718-1724.

The order from left to right is as on the inset legend from top to bottom. Negative values indicate a decrease in binding affinity of sCD4 or PGV04 in the presence of PGT121 antibodies, positive values represent an increase in binding affinity and a value of ∼1 represents no effective change in binding affinity. Sequential ITC binding experiments show that sCD4 has over 100 to 650 fold decrease in binding affinity to gp120 when antibodies of the PGT121 family are pre-complexed with gp120. On the other hand, pre-complexing PGT121 antibodies with gp120 does not lead to a change in binding affinity for PGV04 to gp120.

Julien, J. P., Sok, D., Khayat, R., Lee, J. H., Doores, K. J., Walker, L. M., ... & Wilson, I. A. (2013). Broadly neutralizing antibody PGT121 allosterically modulates CD4 binding via recognition of the HIV-1 gp120 V3 base and multiple surrounding glycans. PLoS pathogens, 9(5), e1003342.

17b+gp120 (black) and 2G12+gp120 (orange) complexes bound well to CD4+ TZM-bl cells. On the other hand, a PGT123+gp120 complex (red) was not able to engage CD4+ TZM-bl cells. Lack of binding of the PGT123+gp120 complex to CD4+ TZM-bl cells is comparable to similar lack of binding of gp120 in complex with the CD4-binding site antibody PGV04 (blue).

Julien, J. P., Sok, D., Khayat, R., Lee, J. H., Doores, K. J., Walker, L. M., ... & Wilson, I. A. (2013). Broadly neutralizing antibody PGT121 allosterically modulates CD4 binding via recognition of the HIV-1 gp120 V3 base and multiple surrounding glycans. PLoS pathogens, 9(5), e1003342.

PGT123 Fab (pink), b12 Fab (yellow) and 17b Fab (green) were pre-incubated with the cells in titrating amounts at 37°C before being exposed to a constant amount of sCD4.

Julien, J. P., Sok, D., Khayat, R., Lee, J. H., Doores, K. J., Walker, L. M., ... & Wilson, I. A. (2013). Broadly neutralizing antibody PGT121 allosterically modulates CD4 binding via recognition of the HIV-1 gp120 V3 base and multiple surrounding glycans. PLoS pathogens, 9(5), e1003342.

PGT123 Fab (pink), b12 Fab (yellow) and 17b Fab (green) were pre-incubated with the cells in titrating amounts at 37°C before being exposed to a constant amount of PGV04.

Julien, J. P., Sok, D., Khayat, R., Lee, J. H., Doores, K. J., Walker, L. M., ... & Wilson, I. A. (2013). Broadly neutralizing antibody PGT121 allosterically modulates CD4 binding via recognition of the HIV-1 gp120 V3 base and multiple surrounding glycans. PLoS pathogens, 9(5), e1003342.

Top panel. Scatter plots of IC50 values for clones reported in the CATNAP database were grouped as 1990-2000, 2001-2010 and 2011-2016 for viruses from India along with those reported in the present study (indicated by larger dots). Bottom panel. Scatter plots of IC50 values for Env-pseudotyped viruses reported in the CATNAP database were grouped as 1990-2000, 2001-2005 and 2006-2010 for envs from Pan-Africa. Data points were color-coded based on the disease stage at sampling of the respective viruses. IC50 value of 5 µg/mL was considered as a threshold of neutralization sensitivity. Statistical assessment of increase in the IC50 values was performed with Jonckheere-Terpstra test (JTT)

Mullick, R., Sutar, J., Hingankar, N., Deshpande, S., Thakar, M., Sahay, S., ... & Bhattacharya, J. (2021). Neutralization diversity of HIV-1 Indian subtype C envelopes obtained from cross sectional and followed up individuals against broadly neutralizing monoclonal antibodies having distinct gp120 specificities. Retrovirology, 18(1), 1-13.

Mean IC50 values against bnAbs VRC01, CAP256-VRC26.25, PGDM1400 and PGT121 were plotted for viral clones prepared from longitudinally collected samples from three HIV-1 subtype C infected individuals (NARI IVC-2, NARI IVC-3 and NARI IVC-11). IC50 value of 5 µg/ml were considered as a threshold of neutralization sensitivity.

Mullick, R., Sutar, J., Hingankar, N., Deshpande, S., Thakar, M., Sahay, S., ... & Bhattacharya, J. (2021). Neutralization diversity of HIV-1 Indian subtype C envelopes obtained from cross sectional and followed up individuals against broadly neutralizing monoclonal antibodies having distinct gp120 specificities. Retrovirology, 18(1), 1-13.

a. Cumulative coverage of the virus panel (a fraction between 0 & 1) of 98 clones reported in the present study and CATNAP database from India at various IC50 values for single mAbs and/or mAb combinations with a target Ab concentration of 5 µg/ml. Dashed curve in each of the plots indicates four bnAb combinations. All other combinations are depicted according to the given color codes. Vertical dashed lines in each plot indicate the expected final Ab concentration of four bnAb combination (pink line) and combination under assessment (black line). b. Predicted geometric IC50 values against each bnAb/combination based on experimental IC50 values for viruses from India (N-98, left boxplot in each group) vs Viruses from Africa retrieved from CATNAP (N = 250, right boxplot in each group). Black lines in each plot indicate Median IC50 values. Statistical comparison within each group was performed with Mann-Whitney test

Mullick, R., Sutar, J., Hingankar, N., Deshpande, S., Thakar, M., Sahay, S., ... & Bhattacharya, J. (2021). Neutralization diversity of HIV-1 Indian subtype C envelopes obtained from cross sectional and followed up individuals against broadly neutralizing monoclonal antibodies having distinct gp120 specificities. Retrovirology, 18(1), 1-13.