Bispecific Antibodies Against HIV

Montefiori, David C.

doi:10.1016/j.cell.2016.06.004

Cited by 15 publications

(12 citation statements)

References 10 publications

(14 reference statements)

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“…In this context, the potency and breadth of neutralization by 10E8 as well as its effectiveness at conferring cross-protection in vivo in primate models (8,(15)(16)(17) make it potentially useful for therapeutic developments. Two complementary strategies have been used to overcome potential limitations of 10E8 for pharmacological use, namely, (i) optimization of function and stability through mutagenesis (19) and (ii) promotion of polyvalence by antibody engineering (43). Following the latter strategy, recently reported works describe antibodies that simultaneously interact with two (bivalent) or three (trivalent) independent Env determinants, which contained the paratope of 10E8 as a basic component (18,20,44).…”

Section: Discussionmentioning

confidence: 99%

Functional Optimization of Broadly Neutralizing HIV-1 Antibody 10E8 by Promotion of Membrane Interactions

Rujas

Leaman

Insausti

et al. 2018

J Virol

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The 10E8 antibody targets a helical epitope in the membrane-proximal external region (MPER) and transmembrane domain (TMD) of the envelope glycoprotein (Env) subunit gp41 and is among the broadest known neutralizing antibodies against HIV-1. Accordingly, this antibody and its mechanism of action valuably inform the design of effective vaccines and immunotherapies. 10E8 exhibits unusual adaptations to attain specific, high-affinity binding to the MPER at the viral membrane interface. Reversing the charge of the basic paratope surface (from net positive to net negative) reportedly lowered its neutralization potency. Here, we hypothesized that by increasing the net positive charge in similar polar surface patches, the neutralization potency of the antibody may be enhanced. We found that an increased positive charge at this paratope surface strengthened an electrostatic interaction between the antibody and lipid bilayers, enabling 10E8 to interact spontaneously with membranes. Notably, the modified 10E8 antibody did not gain any apparent polyreactivity and neutralized virus with a significantly greater potency. Binding analyses indicated that the optimized 10E8 antibody bound with a higher affinity to the epitope peptide anchored in lipid bilayers and to Env spikes on virions. Overall, our data provide a proof of principle for the rational optimization of 10E8 via manipulation of its interaction with the membrane element of its epitope. However, the observation that a similar mutation strategy did not affect the potency of the first-generation anti-MPER antibody 4E10 shows possible limitations of this principle. Altogether, our results emphasize the crucial role played by the viral membrane in the antigenicity of the MPER-TMD of HIV-1. The broadly neutralizing antibody 10E8 blocks infection by nearly all HIV-1 isolates, a capacity which vaccine design seeks to reproduce. Engineered versions of this antibody also represent a promising treatment for HIV infection by passive immunization. Understanding its mechanism of action is therefore important to help in developing effective vaccines and biologics to combat HIV/AIDS. 10E8 engages its helical MPER epitope where the base of the envelope spike submerges into the viral membrane. To enable this interaction, this antibody evolved an unusual property: the ability to interact with the membrane surface. Here, we provide evidence that 10E8 can be made more effective by enhancing its interactions with membranes. Our findings strengthen the idea that to elicit antibodies similar to 10E8, vaccines must reproduce the membrane environment where these antibodies perform their function.

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Section: Discussionmentioning

confidence: 99%

Functional Optimization of Broadly Neutralizing HIV-1 Antibody 10E8 by Promotion of Membrane Interactions

Rujas

Leaman

Insausti

et al. 2018

J Virol

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“…Whilst ibalizumab targets the conformational epitope of the CD4 T-cell receptor, blocking cell entry by HIV-1, other candidates under development, either also target host antigens or alternatively directly bind HIV-1 antigens [46e48]. Research further includes the promise of bispecific and trispecific broadly neutralizing antibodies [31,49]. With regard to RSV, palivizumab interferes with virus attachment and fusion by binding RSV F protein [50].…”

Section: Viral Targetsmentioning

confidence: 99%

Monoclonal antibodies as anti-infective products: a promising future?

Pelfrene¹,

Mura²,

Sanches³

et al. 2019

Clinical Microbiology and Infection

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mAbs may represent important tools in treating or preventing infections occurring with reasonably sufficient prevalence to justify demand and for which existing alternatives are not deemed fully adequate. Future initiatives need to address the prohibitive costs encountered in the development process. The feasibility of more large-scale administration of alternative modalities merits further exploration. In order to ensure optimal prospect of regulatory success, an early dialogue with competent authorities is encouraged.

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“…Different approximations based on in vitro neutralization data allowed to determine the best combination of bNmAbs (up to four) considering their breadth, potency, complete neutralization, and instantaneous inhibitory potential and countering escape variant production (103, 104). Alternatively, engineered bivalent anti-Env antibodies showed an exquisite HIV-1 neutralization activity while preserving normal architecture of IgG (105, 106). Ravetch and colleagues combined Fabs from two different bNmAbs, one to the CD4bs (3BNC117) and another to V3-glycan epitope (PGT135) using a special hinge domain that increases flexibility and favors intra-trimeric, heterobivalent crosslinking of the two Fab arms (107).…”

Section: Current and Future Perspectives Of Hiv-1 Immunoprophylaxismentioning

confidence: 99%

Neutralizing Monoclonal Antibodies to Fight HIV-1: On the Threshold of Success

2017

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Anti-human immunodeficiency virus type-1 (anti-HIV-1) neutralizing monoclonal antibodies are broadening the spectrum of pre- and post-exposure treatment against HIV-1. A better understanding of how these antibodies develop and interact with particular regions of the viral envelope protein is guiding a more rational structure-based immunogen design. The aim of this article is to review the most recent advances in the field, from the development of these particular antibodies during natural HIV-1 infection, to their role preventing infection, boosting endogenous immune responses and clearing both free viral particles and persistently infected cells.

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Bispecific Antibodies Against HIV

Abstract: Synergistic bispecific antibodies against HIV exhibit extraordinary potency and breadth of neutralization as promising candidates for treatment and prevention.

Cited by 15 publications

References 10 publications

Functional Optimization of Broadly Neutralizing HIV-1 Antibody 10E8 by Promotion of Membrane Interactions

Functional Optimization of Broadly Neutralizing HIV-1 Antibody 10E8 by Promotion of Membrane Interactions

Monoclonal antibodies as anti-infective products: a promising future?

Neutralizing Monoclonal Antibodies to Fight HIV-1: On the Threshold of Success

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