A broadly protective therapeutic antibody against influenza B virus with two mechanisms of action

Chai, Ningli; Swem, Lee R.; Park, Summer; Nakamura, Gerald; Chiang, Nancy Y.; Estevez, Alberto; Fong, Rina; Kamen, Lynn; Kho, Elviza; Reichelt, Mike; Lin, Zhonghua; Chiu, Henry; Skippington, Elizabeth; Modrušan, Zora; Stinson, Jeremy; Xu, Min; Lupardus, P.J.; Ciferri, Claudio; Tan, Man‐Wah

doi:10.1038/ncomms14234

Cited by 56 publications

(57 citation statements)

References 57 publications

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“…The human efficacious dose of MHAB5553A is expected to be the same as that for MHAA4549A, a broadly neutralizing monoclonal IgG1 antibody that targets influenza A virus HA (25,26), based upon their similar mechanisms of action, comparable in vitro binding properties, comparable PK in mice and monkeys, and the same efficacious dose range in mouse influenza infection models (23,25,27,28). MHAA4549A also demonstrated strong antiviral activity at 3,600 mg in healthy volunteers challenged with influenza A virus (29).…”

Section: Discussionmentioning

confidence: 99%

“…In this phase 1 trial, MHAB5553A, a fully human, monoclonal IgG1 antibody that targets the esterase domain of the HA globular head of influenza B virus (23), was found to be generally well tolerated in healthy volunteers following a single i.v. administration ranging from 120 mg to 10,800 mg. Tissue cross-reactivity studies have shown that MHAB5553A does not cross-react with human epitopes (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…MHAB5553A also binds HA on the surface of influenza-infected cells; through its Fc domain, MHAB5553A induces Fc␥ receptor-bearing immune cells to kill infected cells via antibody-dependent cell-mediated cytotoxicity (ADCC) (23). In preclinical in vitro studies, MHAB5553A neutralized all tested influenza B virus strains from ancestral lineages, as well as the Victoria and Yamagata lineages.…”

mentioning

confidence: 95%

“…In preclinical in vitro studies, MHAB5553A neutralized all tested influenza B virus strains from ancestral lineages, as well as the Victoria and Yamagata lineages. In addition, in vivo efficacy studies in mouse models of influenza B have demonstrated that MHAB5553A has strong antiviral activity both as a single agent and in combination with oseltamivir (23). This paper reports results from the phase 1 entry-into-human study that assessed the safety, tolerability, and pharmacokinetics (PK) of MHAB5553A in healthy volunteers.…”

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confidence: 99%

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A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Study To Investigate the Safety, Tolerability, and Pharmacokinetics of an Anti-Influenza B Virus Monoclonal Antibody, MHAB5553A, in Healthy Volunteers

Lim¹,

Derby²,

Zhang³

et al. 2017

Antimicrob Agents Chemother

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Influenza B can cause significant morbidity and mortality. MHAB5553A, a human monoclonal immunoglobulin G1 (IgG1) antibody that binds to a highly conserved region of the hemagglutinin protein of influenza B virus, is being examined as a novel therapeutic for the treatment of influenza B patients with severe disease. This phase 1, randomized, double-blind, placebo-controlled, single-ascendingdose study was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of MHAB5553A. Twenty-six healthy male and female volunteers of Ͼ18 years of age were randomized into five cohorts receiving a single intravenous (i.v.) dose of 120, 1,200, 3,600, 8,400, or 10,800 mg MHAB5553A or placebo (four active:one placebo, except for the 120-mg cohort [4:2]). Subjects were followed for 120 days after dosing. No subject discontinued the study, no dose-limiting adverse events or serious adverse events were reported, and a maximum tolerated dose (MTD) was not defined. The most commonly reported adverse events were cold symptoms and headache; most were mild and occurred at a similar rate across all cohorts. MHAB5553A showed no relevant time-or dose-related changes in laboratory values or vital signs compared to the placebo. The observed serum PK was linear and generally dose proportional, and the observed nasal PK was nonlinear and generally non-dose proportional. MHAB5553A is generally well tolerated in healthy volunteers up to at least a single i.v. dose of 10,800 mg and demonstrated linear serum PK consistent with those of a human IgG1 antibody lacking known endogenous targets in humans. (This study has been registered at ClinicalTrials.gov under registration no. NCT02528903.)

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 95%

mentioning

confidence: 99%

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A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Study To Investigate the Safety, Tolerability, and Pharmacokinetics of an Anti-Influenza B Virus Monoclonal Antibody, MHAB5553A, in Healthy Volunteers

Lim¹,

Derby²,

Zhang³

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

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“…Apart from exceeding the efficacy window of oseltamivir of 48 hours post infection, treatment with 46B8 provided better protective outcomes as compared to a 5 day oseltamivir treatment regime in IBV challenged mice. Interestingly, combinational therapy of 46B8 and oseltamivir was able to reduce IBV titres in lungs of infected mice when compared to treatments of 46B8 or oseltamivir alone [31]. Another influenza B-specific mAb CR8071 also bound to VE and showed neutralising activities in vitro and in vivo [32].…”

Section: In Vivo Studies Of Ve Binding Mabsmentioning

confidence: 98%

The Vestigial Esterase Domain of Haemagglutinin of H5N1 Avian Influenza A Virus: Antigenicity and Contribution to Viral Pathogenesis

Zheng

Paul

et al. 2018

Preprint

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Initial attempts to develop monoclonal antibodies as therapeutics to resolve influenza infections focused mainly on searching for antibodies with the potential to neutralise the virus in vitro with classical haemagglutination inhibition and micro-neutralisation assays. This led to the identification of many antibodies that bind to the head domain of haemagglutinin (HA) which generally have potent neutralisation capabilities that block viral entry or viral membrane fusion. However, this class of antibodies has a narrow breadth of protection in that they are usually strain specific. This led to the emphasis on stalk targeting antibodies which are able to bind a broad range of viral targets that span across different influenza subtypes.Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted:

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Non‐Toxic Virucidal Macromolecules Show High Efficacy Against Influenza Virus Ex Vivo and In Vivo

et al. 2020

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Influenza is one of the most widespread viral infections worldwide and represents a major public health problem. The risk that one of the next pandemics is caused by an influenza strain is high. It is important to develop broad‐spectrum influenza antivirals to be ready for any possible vaccine shortcomings. Anti‐influenza drugs are available but they are far from ideal. Arguably, an ideal antiviral should target conserved viral domains and be virucidal, that is, irreversibly inhibit viral infectivity. Here, a new class of broad‐spectrum anti‐influenza macromolecules is described that meets these criteria and display exceedingly low toxicity. These compounds are based on a cyclodextrin core modified on its primary face with long hydrophobic linkers terminated either in 6'sialyl‐N‐acetyllactosamine (6’SLN) or in 3’SLN. SLN enables nanomolar inhibition of the viruses while the hydrophobic linkers confer irreversibility to the inhibition. The combination of these two properties allows for efficacy in vitro against several human or avian influenza strains, as well as against a 2009 pandemic influenza strain ex vivo. Importantly, it is shown that, in mice, one of the compounds provides therapeutic efficacy when administered 24 h post‐infection allowing 90% survival as opposed to no survival for the placebo and oseltamivir.

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A broadly protective therapeutic antibody against influenza B virus with two mechanisms of action

Cited by 56 publications

References 57 publications

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Study To Investigate the Safety, Tolerability, and Pharmacokinetics of an Anti-Influenza B Virus Monoclonal Antibody, MHAB5553A, in Healthy Volunteers

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Study To Investigate the Safety, Tolerability, and Pharmacokinetics of an Anti-Influenza B Virus Monoclonal Antibody, MHAB5553A, in Healthy Volunteers

The Vestigial Esterase Domain of Haemagglutinin of H5N1 Avian Influenza A Virus: Antigenicity and Contribution to Viral Pathogenesis

Non‐Toxic Virucidal Macromolecules Show High Efficacy Against Influenza Virus Ex Vivo and In Vivo

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