Recombinant Human Antibody (PGT121) is capable of binding to HIV-1 gp120, expressed in HEK 293 cells. Expressed as the combination of a heavy chain (HC) containing VH from anti-HIV-1 gp120 mAb and CH1-3 region of human IgG and a light chain (LC) encoding VL from anti-HIV-1 gp120 proteins mAb and CL of human kappa light chain. Exists as a disulfide linked dimer of the HC and LC hetero-dimer under non-reducing condition. Although PGT121 binds complex-type N-glycans, PGT121 recognized high-mannose-only HIV envelopes in isolation and on virions.
Figure 1 Plasma HIV-1 RNA levels are shown following PGT121 infusion in HIV-infected viremic participants not on ART.
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.
Figure 2 IC50 neutralization
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.
Figure 3 HIV-1 viral load and PGT121 serum levels are shown for participants 6113 and 1536 following PGT121 infusion.
Open circles indicate that either HIV-1 RNA (black) or PGT121 level (red) was below the limit of detection.
Figure 4 Immunologic responses following PGT121 infusion in two long-term suppressors.
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).
Figure 5 Immunologic responses following PGT121 infusion in two long-term suppressors.
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.
Figure 6 Fold change in binding affinity (Kd) for sCD4 and PGV04 interactions with gp120 when antibodies of the PGT121 family are first pre-complexed with gp120.
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.
Figure 7 SEC-purified complexes of gp120 with various Fabs were tested for their ability to bind CD4+ TZM-bl cells by FACS.
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).
Figure 8 sCD4 binding to cells expressing JRFL Env on their surface as observed by flow cytometry.
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.
Figure 9 PGV04 binding to cells expressing JRFL Env on their surface as observed by flow cytometry.
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.
Figure 10 Comparison of trend in bnAb sensitivity across time against VRC01, CAP256-VRC26.25, PGDM1400 and PGT121.
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)
Figure 11 Progression of bnAb responses of pseudoviruses expressing envs obtained from longitudinally followed up individuals.
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.
Figure 12 Predictive analysis of effect of bnAb combinations on neutralization breadth and potency of HIV-1 Indian clade C.
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
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