Engineering and characterising a novel, highly potent bispecific antibody iMab-CAP256 that targets HIV-1

Moshoette, Tumelo; Ali, Stuart A.; Papathanasopoulos, Maria A.; Killick, Mark

doi:10.1186/s12977-019-0493-y

Cited by 13 publications

(21 citation statements)

References 80 publications

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“…The bsAb strategy is widely used in the treatment of cancer and inflammatory disorders 26,27 , and a limited number of cases have been reported for viral infection diseases [28][29][30] . Several studies have been proved that bsAbs exhibit enhanced breadth and potency than parental mAbs [31][32][33] . Therefore, bsAb is an effective strategy in drug development.…”

mentioning

confidence: 99%

An engineered bispecific human monoclonal antibody against SARS-CoV-2

Zhang

et al. 2022

Nat Immunol

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confidence: 99%

An engineered bispecific human monoclonal antibody against SARS-CoV-2

Zhang

et al. 2022

Nat Immunol

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“…Interestingly, the reduced susceptibility could be restored by adding a glycan molecule in the variable region of the antibody ( Song et al., 2013 ). Because dual targeting is thought to enhance biological efficacy, limit escape mechanisms, and increase target selectivity via a strong avidity effect mediated by concurrent binding, several iMab-based bispecific antibodies were created by genetically fusing iMab with broadly HIV-neutralizing antibodies (bNAbs), including anti-gp120 antibodies PG9 or PG16 ( Pace et al., 2013b ), m36.4 ( Sun et al., 2014 ), CAP256 ( Moshoette et al., 2019 ), and anti-gp41 antibody 10E8 ( Huang et al., 2016 ), which did show greatly improved activities to inhibit HIV-1 infection and overcome the resistance problem. For the first time, here, we generated an iMab-based bifunctional inhibitor by using a fusion inhibitor peptide as a partner.…”

Section: Discussionmentioning

confidence: 99%

“…Considering the high variability of HIV-1, bispecific or multi-specific antiviral inhibitors targeting different steps or epitopes of HIV-1 entry are extensively being exploited for broader coverage of the HIV-1 epidemic ( Padte et al., 2018 ; Steinhardt et al., 2018 ; Tuyishime and Ferrari, 2020 ). Notably, iMab-based bispecific antibodies possess significantly improved antiviral activity and genetic barrier to inducing HIV-1 resistance ( Pace et al., 2013b ; Sun et al., 2014 ; Huang et al., 2016 ; Song et al., 2016 ; Moshoette et al., 2019 ; Li et al., 2021 ). In this study, we designed and characterized a bispecific HIV inhibitor by fusing the fusion inhibitor 2P23 peptide with the single-chain variable fragment (scFv) of iMab, which had dramatically increased anti-HIV activities and breadth.…”

Section: Introductionmentioning

confidence: 99%

Design of a Bispecific HIV Entry Inhibitor Targeting the Cell Receptor CD4 and Viral Fusion Protein Gp41

Huang

Chen

et al. 2022

Front. Cell. Infect. Microbiol.

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Given the high variability and drug-resistance problem by human immunodeficiency virus type 1 (HIV-1), the development of bispecific or multi-specific inhibitors targeting different steps of HIV entry is highly appreciated. We previously generated a very potent short-peptide–based HIV fusion inhibitor 2P23. In this study, we designed and characterized a bifunctional inhibitor termed 2P23-iMab by genetically conjugating 2P23 to the single-chain variable fragment (scFv) of ibalizumab (iMab), a newly approved antibody drug targeting the cell receptor CD4. As anticipated, 2P23-iMab could bind to the cell membrane through CD4 anchoring and inhibit HIV-1 infection as well as viral Env-mediated cell–cell fusion efficiently. When tested against a large panel of HIV-1 pseudoviruses with different subtypes and phenotypes, 2P23-iMab exhibited dramatically improved inhibitory activity than the parental inhibitors; especially, it potently inhibited the viruses not being susceptible to iMab. Moreover, 2P23-iMab had a dramatically increased potency in inhibiting two panels of HIV-1 mutants that are resistant to T-20 or 2P23 and the infections of HIV-2 and simian immunodeficiency virus (SIV). In conclusion, our studies have provided new insights into the design of novel bispecific HIV entry inhibitors with highly potent and broad-spectrum antiviral activity.

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“…This effect is due to the localization of the anti-HIV antibody close to the host cell membrane through CCR5 or CD4 binding, for example, the 10E8-iMab, which targets the MPER region on the HIV virion and the CD4 receptor on the HIV target cell. This bispecific antibody has a geometric mean IC 50 potency of 0.002mg/mL compared to 0.4mg/mL for 10E8 and 0.05mg/mL for the iMab indicating a 25-fold improvement over the expected activity (27,31).…”

Section: Introductionmentioning

confidence: 95%

Combinations of Single Chain Variable Fragments From HIV Broadly Neutralizing Antibodies Demonstrate High Potency and Breadth

et al. 2021

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Broadly neutralizing antibodies (bNAbs) are currently being assessed in clinical trials for their ability to prevent HIV infection. Single chain variable fragments (scFv) of bNAbs have advantages over full antibodies as their smaller size permits improved diffusion into mucosal tissues and facilitates vector-driven gene expression. We have previously shown that scFv of bNAbs individually retain significant breadth and potency. Here we tested combinations of five scFv derived from bNAbs CAP256-VRC26.25 (V2-apex), PGT121 (N332-supersite), 3BNC117 (CD4bs), 8ANC195 (gp120-gp41 interface) and 10E8v4 (MPER). Either two or three scFv were combined in equimolar amounts and tested in the TZM-bl neutralization assay against a multiclade panel of 17 viruses. Experimental IC50 and IC80 data were compared to predicted neutralization titers based on single scFv titers using the Loewe additive and the Bliss-Hill model. Like full-sized antibodies, combinations of scFv showed significantly improved potency and breadth compared to single scFv. Combinations of two or three scFv generally followed an independent action model for breadth and potency with no significant synergy or antagonism observed overall although some exceptions were noted. The Loewe model underestimated potency for some dual and triple combinations while the Bliss-Hill model was better at predicting IC80 titers of triple combinations. Given this, we used the Bliss-Hill model to predict the coverage of scFv against a 45-virus panel at concentrations that correlated with protection in the AMP trials. Using IC80 titers and concentrations of 1μg/mL, there was 93% coverage for one dual scFv combination (3BNC117+10E8v4), and 96% coverage for two of the triple combinations (CAP256.25+3BNC117+10E8v4 and PGT121+3BNC117+10E8v4). Combinations of scFv, therefore, show significantly improved breadth and potency over individual scFv and given their size advantage, have potential for use in passive immunization.

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Engineering and characterising a novel, highly potent bispecific antibody iMab-CAP256 that targets HIV-1

Cited by 13 publications

References 80 publications

An engineered bispecific human monoclonal antibody against SARS-CoV-2

An engineered bispecific human monoclonal antibody against SARS-CoV-2

Design of a Bispecific HIV Entry Inhibitor Targeting the Cell Receptor CD4 and Viral Fusion Protein Gp41

Combinations of Single Chain Variable Fragments From HIV Broadly Neutralizing Antibodies Demonstrate High Potency and Breadth

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