Potent anti-viral activity of a trispecific HIV neutralizing antibody in SHIV-infected monkeys

Pegu, Amarendra; Xu, Li; DeMouth, Megan E.; Fabozzi, Giulia; March, Kylie; Almasri, Cassandra; Cully, Michelle D.; Wang, Keyun; Yang, Eun Sung; Dias, Joana; Fennessey, Christine M.; Hataye, Jason; Wei, Ronnie R.; Rao, Ercole; Casazza, Joseph P.; Promsote, Wanwisa; Asokan, Mangaiarkarasi; McKee, Krisha; Schmidt, Stephen D.; Chen, Xuejun; Liu, Cuiping; Shi, Wei; Geng, Hui; Foulds, Kathryn E.; Kao, Shu‐Fang; Noe, Amy T.; Li, Hui; Shaw, George M.; Zhou, Tongqing; Petrovas, Constantinos; Todd, John-Paul; Keele, Brandon F.; Lifson, Jeffrey D.; Doria‐Rose, Nicole A.; Koup, Richard A.; Yang, Zhiyong; Nabel, Gary J.; Mascola, John R.

doi:10.1016/j.celrep.2021.110199

Cited by 21 publications

(26 citation statements)

References 61 publications

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“…In a step further in the development of these molecules, a tri-specific antibody-like molecule was generated to include bNAbs with 3 HIV Env specificities, N6 (targeting the CD4bs), PGDM1400 (targeting the V2 glycan), and 10E8v4 (targeting the MPER). This tri-specific antibody-like molecule neutralized clade A SHIV BG505 more potently than any of the parental bNAbs (154), showing comparable potency but greater breadth than a previously developed tri-specific molecule including VRC01/ PGDM1400/10E8v4 specificities (153). The newly improved tri-specific antibody-like molecule (N6-CD4bs/PGDM1400-V2 glycan/10E8v4-MPER) was shown to reduce viremia from 100to 1000-fold in viremic SHIV-infected adult NHPs (154) although transient viral rebound was observed when ART was interrupted, likely due to decline of antibody-like molecule level.…”

Section: Engineered Antibody-like Moleculesmentioning

confidence: 88%

“…This tri-specific antibody-like molecule neutralized clade A SHIV BG505 more potently than any of the parental bNAbs (154), showing comparable potency but greater breadth than a previously developed tri-specific molecule including VRC01/ PGDM1400/10E8v4 specificities (153). The newly improved tri-specific antibody-like molecule (N6-CD4bs/PGDM1400-V2 glycan/10E8v4-MPER) was shown to reduce viremia from 100to 1000-fold in viremic SHIV-infected adult NHPs (154) although transient viral rebound was observed when ART was interrupted, likely due to decline of antibody-like molecule level. However, similar to prior observations with mono-and dual-bNAb therapy, rebound viremia was returned to low levels via CD8+ T cell mediated viral control (154).…”

Section: Engineered Antibody-like Moleculesmentioning

confidence: 88%

“…The newly improved tri-specific antibody-like molecule (N6-CD4bs/PGDM1400-V2 glycan/10E8v4-MPER) was shown to reduce viremia from 100- to 1000-fold in viremic SHIV-infected adult NHPs ( 154 ) although transient viral rebound was observed when ART was interrupted, likely due to decline of antibody-like molecule level. However, similar to prior observations with mono- and dual-bNAb therapy, rebound viremia was returned to low levels via CD8+ T cell mediated viral control ( 154 ).…”

Section: Passive Immunization Strategiesmentioning

confidence: 99%

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Challenges and Opportunities of Therapies Targeting Early Life Immunity for Pediatric HIV Cure

et al. 2022

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Early initiation of antiretroviral therapy (ART) significantly improves clinical outcomes and reduces mortality of infants/children living with HIV. However, the ability of infected cells to establish latent viral reservoirs shortly after infection and to persist during long-term ART remains a major barrier to cure. In addition, while early ART treatment of infants living with HIV can limit the size of the virus reservoir, it can also blunt HIV-specific immune responses and does not mediate clearance of latently infected viral reservoirs. Thus, adjunctive immune-based therapies that are geared towards limiting the establishment of the virus reservoir and/or mediating the clearance of persistent reservoirs are of interest for their potential to achieve viral remission in the setting of pediatric HIV. Because of the differences between the early life and adult immune systems, these interventions may need to be tailored to the pediatric settings. Understanding the attributes and specificities of the early life immune milieu that are likely to impact the virus reservoir is important to guide the development of pediatric-specific immune-based interventions towards viral remission and cure. In this review, we compare the immune profiles of pediatric and adult HIV elite controllers, discuss the characteristics of cellular and anatomic HIV reservoirs in pediatric populations, and highlight the potential values of current cure strategies using immune-based therapies for long-term viral remission in the absence of ART in children living with HIV.

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Section: Engineered Antibody-like Moleculesmentioning

confidence: 88%

Section: Engineered Antibody-like Moleculesmentioning

confidence: 88%

Section: Passive Immunization Strategiesmentioning

confidence: 99%

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Challenges and Opportunities of Therapies Targeting Early Life Immunity for Pediatric HIV Cure

et al. 2022

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“…A final practical issue that emerged was that enough synergy in the model made the bi-specific potent even at concentrations below current limits of detection. Though we modeled bi-specifics, recent work with tri-specific antibodies shows they can prevent SHIV infection [ 31 ], but may depend on their strongest component [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Optimizing clinical dosing of combination broadly neutralizing antibodies for HIV prevention

et al. 2022

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Broadly neutralizing antibodies (bNAbs) are promising agents to prevent HIV infection and achieve HIV remission without antiretroviral therapy (ART). As with ART, bNAb combinations are likely needed to cover HIV’s extensive diversity. Not all bNAbs are identical in terms of their breadth, potency, and in vivo longevity (half-life). Given these differences, it is important to optimally select the composition, or dose ratio, of combination bNAb therapies for future clinical studies. We developed a model that synthesizes 1) pharmacokinetics, 2) potency against a wide HIV diversity, 3) interaction models for how drugs work together, and 4) correlates that translate in vitro potency to clinical protection. We found optimization requires drug-specific balances between potency, longevity, and interaction type. As an example, tradeoffs between longevity and potency are shown by comparing a combination therapy to a bi-specific antibody (a single protein merging both bNAbs) that takes the better potency but the worse longevity of the two components. Then, we illustrate a realistic dose ratio optimization of a triple combination of VRC07, 3BNC117, and 10–1074 bNAbs. We apply protection estimates derived from both a non-human primate (NHP) challenge study meta-analysis and the human antibody mediated prevention (AMP) trials. In both cases, we find a 2:1:1 dose emphasizing VRC07 is nearly optimal. Our approach can be immediately applied to optimize the next generation of combination antibody prevention and cure studies.

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“…We previously identified three monoclonal antibodies (mAb), B1-182.1, A19-46.1 and A19-61.1 (hereafter termed 182.1, 46.1 and 61.1), that target distinct receptor binding domain (RBD) epitopes and retain high potency and breath against most VOCs (17,20): 182.1 displays subnanomolar potency against pre-Omicron VOCs (17,20), including Beta and Delta (Fig 1A ) and maintains potency to BA.1, BA.1.1, BA.2 and BA.2.12.1 that is similar to mAb S309 which showed clinical efficacy against BA.1 (21, 22); 61.1 has subnanomolar potency against Alpha, Beta and Delta variants but loses activity to Omicron BA.1 and BA.1.1, and then recovers neutralization activity against BA.2, BA.2.12.1 and BA.4/5 (17,20) We previously developed recombinant trispecific antibodies against HIV-1 by combining arms from selected broadly neutralizing antibodies into a single molecule that showed unprecedented potency and breadth (26). These antibodies broadly neutralized >98% of circulating virus strains (26) and exerted antiviral effects in non-human primates while also mitigating the generation of viral immune escape (27). We hypothesized that multispecific antibodies could be designed against SARS-CoV-2 that similarly improve breadth and neutralization reactivity to cover known and evolving antigenic variation.…”

Section: Main Textmentioning

confidence: 99%

A multispecific antibody prevents immune escape and confers pan-SARS-CoV-2 neutralization

Wei

Wang

Pegu

et al. 2022

Preprint

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Continued evolution of the SARS-CoV-2 spike poses a challenge to immune interventions. To develop antibodies that protect against evolving SARS-CoV-2 viruses, we combined antibodies that recognize different RBD sites to generate a trivalent antibody that potently neutralized all major variants, including the most recent Omicron lineages. Negative stain electron microscopy suggests that this multispecific achieves synergistic neutralization by engaging different epitopes in specific orientations that facilitate inter-spike binding. These interactions resulted in not only improved potency but also importantly prevented virus escape, a feature not seen with parental antibody cocktails or the most potent clinical mAb. Such multispecific antibodies simplify treatment, maximize coverage, decrease the likelihood of SARS-CoV-2 escape, and provide the basis for building universal SARS-CoV-2 antibody therapies that are more likely to maintain broad reactivity for future variants.

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Potent anti-viral activity of a trispecific HIV neutralizing antibody in SHIV-infected monkeys

Abstract: Highlights d Trispecific bNAbs reduce viremia 100-to 1000-fold in viremic SHIV-infected macaques d After treatment completion in these macaques, long-term viral control is CD8-mediated d Trispecific but not parental bNAbs suppress the emergence of resistant virus in culture

Cited by 21 publications

References 61 publications

Challenges and Opportunities of Therapies Targeting Early Life Immunity for Pediatric HIV Cure

Challenges and Opportunities of Therapies Targeting Early Life Immunity for Pediatric HIV Cure

Optimizing clinical dosing of combination broadly neutralizing antibodies for HIV prevention

A multispecific antibody prevents immune escape and confers pan-SARS-CoV-2 neutralization

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