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. 2016 Dec 1;73(4):365-373.
doi: 10.1097/QAI.0000000000001119.

Distinct HIV-1 Neutralization Potency Profiles of Ibalizumab-Based Bispecific Antibodies

Ruijiang Song  1 , Craig Pace, Michael S Seaman, Qing Fang, Ming Sun, Chasity D Andrews, Amos Wu, Neal N Padte, David D Ho
Affiliations

Distinct HIV-1 Neutralization Potency Profiles of Ibalizumab-Based Bispecific Antibodies

Ruijiang Song et al. J Acquir Immune Defic Syndr. .

Abstract

Background: Preexposure prophylaxis using antiretroviral agents has been shown to effectively prevent human immunodeficiency virus type 1 (HIV-1) acquisition in high-risk populations. However, the efficacy of these regimens is highly variable, which is thought to be largely due to the varying degrees of adherence to a daily intervention in the populations. Passive immunization using broadly neutralizing antibodies (bNAbs) against HIV-1, with their relatively long half-life and favorable safety profile, could provide an alternative to daily preexposure prophylaxis. However, most bNAbs have a limited breadth, only neutralizing 70%-90% of all HIV-1 strains.

Methods: To overcome the problem of limited antiviral breadth, we proposed that targeting human CD4 and HIV-1 envelope proteins simultaneously may improve virus-neutralization breadth and potency. Therefore, we constructed bispecific antibodies (biAbs) using single-chain variable fragments of anti-gp120 bNAbs fused to ibalizumab (iMab), a humanized monoclonal antibody that binds human CD4, the primary receptor for HIV-1.

Results: Some of our biAbs neutralized 100% of HIV-1 strains tested in vitro at clinically achievable concentrations. Distinct neutralization patterns were observed in this panel of biAbs. Those biAbs with specificity for the CD4-binding site on gp120 demonstrated 100% breadth, as well as slightly improved potency compared with iMab. In contrast, biAbs with specificity for the V1-V2 apex epitope or the V3-glycan epitope on gp120 demonstrated dramatically improved potency; some showed limited gain in neutralization breadth, whereas others (eg, PGT128-LM52 and 123-iMab) improved to 100% breadth.

Conclusion: Our data suggest that this panel of iMab-based biAbs could be used to probe the parameters for potent HIV-1 neutralization. Moreover, a few of these biAbs warrant further studies and possibly clinical development.

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Figures

Figure 1
Figure 1
Ibalizumab (iMab)-based biAb construction and confirmation. (A) Schematic depicting the structure of an iMab-based biAb. The variable fragments (VH and VL) of VRC01, 3BNC60, NIH45-46G54W, PGT123, PGT128 or 10E8 were tethered by a flexible glycine-serine linker to create a single-chain Fv (scFv), which was fused to the N-terminus or C-terminus of the iMab heavy chain. (B) SDS-PAGE analysis of purified VRC01-ibalizumab (01-iMab) bispecific Abs: iMab-VRC01(VH-VL) (iMab-01(HL)), VRC01(VL-VH)-iMab (01(LH)-iMab), and VRC01(VH-VL)-iMab (01(HL)-iMab). (C) 3BNC60-iMab (60-iMab) biAb. (D) PGT128-iMab (128-iMab) biAb.
Figure 2
Figure 2
Neutralization data for iMab-based biAbs against HIV-1 env pseudoviruses in the TZM-bl assay. (A) Comparison of three forms of 01-iMab biAbs: iMab-01(HL), 01(HL)-iMab, and 01(LH)-iMab. (B) Enhanced neutralization activity of 01-iMab comparing with its two parental mAbs. (C) Enhanced neutralization activity of 60-iMab compared to iMab and 3BNC60. (D) The neutralization activity of 128-iMab compared to iMab and PGT128. (E) The neutralization activity of 128-LM52 in comparison with 128-iMab.
Figure 3
Figure 3
Neutralization data for iMab and iMab-based biAbs against a panel (or a part of the panel) of 118 tier-2 HIV-1 Env pseudoviruses in the TZM-bl assay. For each virus, grey bars indicate maximum percent inhibition (MPI, %) when tested up to 10 μg/ml and red bars indicate the antibody concentrations that confer 50% neutralization (IC50) values. Viruses are ordered by descending MPI. iMab and 01-iMab were tested against the entire panel of viruses, while 128-iMab, 123-iMab, 60-iMab, and 45-46-iMab were tested against 65, 71, 75, and 75 viruses in the same virus panel, respectively. The data for iMab (26) were obtained from the literature.
Figure 4
Figure 4
Neutralization data for 128-LM52 against HIV-1 env pseudoviruses in the TZM-bl assay. (A) Comparison of 128-LM52 to 128-iMab. (B) Neutralization activity of 128-LM52 against a panel of 118 tier-2 HIV-1 Env pseudoviruses in the TZM-bl assay. For each virus, grey bars indicate maximum percent inhibition (MPI, %) when tested up to 10 μg/ml and red bars indicate the antibody concentrations that confer 50% neutralization (IC50) values. Viruses are ordered by descending MPI.
Figure 5
Figure 5
Neutralization data for iMab and iMab-based biAbs against a panel (or panel subset) of 118 tier-2 HIV-1 Env pseudoviruses in the TZM-bl assay. The corresponding (A) IC50 (μg/ml) and (B) IC80 (μg/ml) against each virus are showed. Red lines indicate the geometric means with 95% confidence intervals. IMab, 01-iMab, and 128-LM52 were tested against the entire panel of viruses, while 128-iMab, 123-iMab, 60-iMab, and 45-46-iMab were tested against 65, 71, 75, and 75 viruses from the same virus panel, respectively. The data for iMab were obtained from the literature (26).
Figure 6
Figure 6
Percent viral coverage achieved by iMab-based biAbs versus those observed for mAbs. (A) Viral coverage curves achieved with iMab-based 123-iMab, 128-iMab, and 128-LM52. (B) Viral coverage curves achieved with 01-iMab, 60-iMab, and 45-46-iMab. (C) Viral coverage curves achieved with selected parental mAbs, including iMab, PGT128, and PGT123. (D) Viral coverage curves achieved with VRC01, 3BNC117, iMab, and NIH45-46G54W. 3BNC117 was showed instead of 3BNC60 because it demonstrated comparable anti-viral potency compared to 3BNC60 (9). IMab-based biAbs and iMab were tested up to 10 μg/ml, while the other mAbs were tested up to 50 μg/ml.
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