Clinical Trials of Broadly Neutralizing Monoclonal Antibodies for Human Immunodeficiency Virus Prevention: A Review

Mahomed, Saajida; Garrett, Nigel; Baxter, Cheryl; Karim, Quarraisha Abdool; Karim, Salim S. Abdool

doi:10.1093/infdis/jiaa377

Cited by 63 publications

(69 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This unique study design revealed that while infant T/Fs are more likely to be escape variants from maternal neutralization responses when compared with the non-transmitted maternal variants, the mother’s natural ability to neutralize her own circulating viruses does not define a mother’s MTCT risk. Concerningly, we identified that maternal transmission status was tied to Env amino acid signatures that confer resistance to bnAbs, including those being used in clinical trials for HIV-1 prevention and therapy [66, 67] (https://clinicaltrials.gov/ct2/show/NCT03571204). These results caution the use of passive or active vaccine strategies targeting plasma bnAb activity in pregnant women and indicate that more work will need to address the risks of bnAb escape variants that are fit for virus transmission.…”

Section: Discussionmentioning

confidence: 99%

Mutations that confer resistance to broadly-neutralizing antibodies define HIV-1 variants of transmitting mothers from that of non-transmitting mothers

Kumar

Giorgi

et al. 2021

Preprint

View full text Add to dashboard Cite

Despite considerable reduction of mother-to-child transmission (MTCT) of HIV through use of maternal and infant antiretroviral therapy (ART), over 150,000 infants continue to become infected with HIV annually, falling far short of the World Health Organization goal of reaching <20,000 annual pediatric HIV cases worldwide by 2020. Prior to the widespread use of ART in the setting of pregnancy, over half of infants born to HIV-infected mothers were protected against HIV acquisition. Yet, the role of maternal immune factors in this protection against vertical transmission is still unclear, hampering the development of synergistic strategies to further reduce MTCT. It has been established that infant transmitted/founder (T/F) viruses are often resistant to maternal plasma, yet it is unknown if the neutralization resistance profile of circulating viruses predicts the maternal risk of transmission to her infant. In this study, we amplified HIV-1 envelope genes (env) by single genome amplification and produced representative Env variants from plasma of 19 non-transmitting mothers from the U.S. Women Infant Transmission Study (WITS), enrolled in the pre-ART era. Maternal HIV Env variants from non-transmitting mothers had similar sensitivity to autologous plasma as observed for non-transmitting variants from transmitting mothers. In contrast, infant variants were on average 30% less sensitive to paired plasma neutralization compared to non-transmitted maternal variants from both transmitting and non-transmitting mothers (p=0.015). Importantly, a signature sequence analysis revealed that motifs enriched in env sequences from transmitting mothers were associated with broadly neutralizing antibody (bnAb) resistance. Altogether, our findings suggest that circulating maternal virus resistance to bnAb-mediated neutralization, but not autologous plasma neutralization, near the time of delivery, predicts increased MTCT risk. These results caution that enhancement of maternal plasma neutralization through passive or active vaccination during pregnancy could drive the evolution of variants fit for vertical transmission.Author SummaryDespite widespread, effective use of ART among HIV infected pregnant women, new pediatric HIV infections increase by about 150,000 every year. Thus, alternative strategies will be required to reduce MTCT and eliminate pediatric HIV infections. Interestingly, in the absence of ART, less than half of HIV-infected pregnant women will transmit HIV, suggesting natural immune protection of infants from virus acquisition. To understand the impact of maternal plasma autologous virus neutralization responses on MTCT, we compared the plasma and bnAb neutralization sensitivity of the circulating viral population present at the time of delivery in untreated, HIV-infected transmitting and non-transmitting mothers. While there was no significant difference in the ability of transmitting and non-transmitting women to neutralize their own circulating virus strains, specific genetic motifs enriched in variants from transmitting mothers were associated with resistance to bnAbs, suggesting that acquired bnAb resistance is a common feature of vertically-transmitted variants. This work suggests that enhancement of plasma neutralization responses in HIV-infected mothers through passive or active vaccination could further drive selection of variants that couldbe vertically transmitted, and cautions the use of passive bnAbs for HIV-1 prophylaxis or therapy during pregnancy.

show abstract

Section: Discussionmentioning

confidence: 99%

Mutations that confer resistance to broadly-neutralizing antibodies define HIV-1 variants of transmitting mothers from that of non-transmitting mothers

Kumar

Giorgi

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Convalescent plasma with high concentrations of virus-specific immunoglobulins or recombinant fully human antibodies were shown to decrease the viral loads and reduce the mortality in patients infected with the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) 8 , human immunodeficiency virus (HIV) 9 , Ebola virus (EBOV) 10 , and most recently SARS-CoV-2 11 , confirming the efficacy of nAbs as prophylactic and therapeutic agents against viral infection. To date, most of the SARS-CoV-2 nAbs identified were derived from peripheral blood mononuclear cells (PBMC)s of convalescent COVID-19 patients 12 , 13 , or transgenic mice 14 in the context of single B-cell sorting 12 , 14 .…”

Section: Introductionmentioning

confidence: 92%

Screening of potent neutralizing antibodies against SARS-CoV-2 using convalescent patients-derived phage-display libraries

Pan¹,

Du²,

Liu

et al. 2021

Cell Discov

View full text Add to dashboard Cite

As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to threaten public health worldwide, the development of effective interventions is urgently needed. Neutralizing antibodies (nAbs) have great potential for the prevention and treatment of SARS-CoV-2 infection. In this study, ten nAbs were isolated from two phage-display immune libraries constructed from the pooled PBMCs of eight COVID-19 convalescent patients. Eight of them, consisting of heavy chains encoded by the immunoglobulin heavy-chain gene-variable region (IGHV)3-66 or IGHV3-53 genes, recognized the same epitope on the receptor-binding domain (RBD), while the remaining two bound to different epitopes. Among the ten antibodies, 2B11 exhibited the highest affinity and neutralization potency against the original wild-type (WT) SARS-CoV-2 virus (KD = 4.76 nM for the S1 protein, IC50 = 6 ng/mL for pseudoviruses, and IC50 = 1 ng/mL for authentic viruses), and potent neutralizing ability against B.1.1.7 pseudoviruses. Furthermore, 1E10, targeting a distinct epitope on RBD, exhibited different neutralization efficiency against WT SARS-CoV-2 and its variants B.1.1.7, B.1.351, and P.1. The crystal structure of the 2B11–RBD complexes revealed that the epitope of 2B11 highly overlaps with the ACE2-binding site. The in vivo experiment of 2B11 using AdV5-hACE2-transduced mice showed encouraging therapeutic and prophylactic efficacy against SARS-CoV-2. Taken together, our results suggest that the highly potent SARS-CoV-2-neutralizing antibody, 2B11, could be used against the WT SARS-CoV-2 and B.1.1.7 variant, or in combination with a different epitope-targeted neutralizing antibody, such as 1E10, against SARS-CoV-2 variants.

show abstract

“…The discovery of broadly neutralising antibodies (bNAbs) in a small group of patients, so-called ‘elite controllers’ [ 17 , 18 ], took the prospect of using mAbs against HIV a major step closer. Several anti-HIV bNAbs are currently in clinical trials [ 19 ]. Current bNAbs are significantly more potent than the early neutralising mAbs.…”

Section: Introductionmentioning

confidence: 99%

Characterisation of a highly potent and near pan-neutralising anti-HIV monoclonal antibody expressed in tobacco plants

et al. 2021

View full text Add to dashboard Cite

Background HIV remains one of the most important health issues worldwide, with almost 40 million people living with HIV. Although patients develop antibodies against the virus, its high mutation rate allows evasion of immune responses. Some patients, however, produce antibodies that are able to bind to, and neutralise different strains of HIV. One such ‘broadly neutralising’ antibody is ‘N6’. Identified in 2016, N6 can neutralise 98% of HIV-1 isolates with a median IC50 of 0.066 µg/mL. This neutralisation breadth makes N6 a very promising therapeutic candidate. Results N6 was expressed in a glycoengineered line of N. benthamiana plants (pN6) and compared to the mammalian cell-expressed equivalent (mN6). Expression at 49 mg/kg (fresh leaf tissue) was achieved in plants, although extraction and purification are more challenging than for most plant-expressed antibodies. N-glycoanalysis demonstrated the absence of xylosylation and a reduction in α(1,3)-fucosylation that are typically found in plant glycoproteins. The N6 light chain contains a potential N-glycosylation site, which was modified and displayed more α(1,3)-fucose than the heavy chain. The binding kinetics of pN6 and mN6, measured by surface plasmon resonance, were similar for HIV gp120. pN6 had a tenfold higher affinity for FcγRIIIa, which was reflected in an antibody-dependent cellular cytotoxicity assay, where pN6 induced a more potent response from effector cells than that of mN6. pN6 demonstrated the same potency and breadth of neutralisation as mN6, against a panel of HIV strains. Conclusions The successful expression of N6 in tobacco supports the prospect of developing a low-cost, low-tech production platform for a monoclonal antibody cocktail to control HIV in low-to middle income countries. Graphic abstract

show abstract

Clinical Trials of Broadly Neutralizing Monoclonal Antibodies for Human Immunodeficiency Virus Prevention: A Review

Cited by 63 publications

References 46 publications

Mutations that confer resistance to broadly-neutralizing antibodies define HIV-1 variants of transmitting mothers from that of non-transmitting mothers

Mutations that confer resistance to broadly-neutralizing antibodies define HIV-1 variants of transmitting mothers from that of non-transmitting mothers

Screening of potent neutralizing antibodies against SARS-CoV-2 using convalescent patients-derived phage-display libraries

Characterisation of a highly potent and near pan-neutralising anti-HIV monoclonal antibody expressed in tobacco plants

Contact Info

Product

Resources

About