Nebulised ALX-0171 for respiratory syncytial virus lower respiratory tract infection in hospitalised children: a double-blind, randomised, placebo-controlled, phase 2b trial

Piedra, Pedro A.; Cunningham, Steve; Piedra, Pedra A; Verhulst, Stijn; Matthijs, Inge; Proesmans, Marijke; Goetghebuer, Tessa; Bosheva, Miroslava; Dosev, S; Nikolova, Olga; Chakarova, Petranka; Hupat, Elba Wu; Monsalve, Juan Mesa; Turkalj, Mirjana; Antoncic, Natasa Mesaric; Tešović, Goran; Sipl, Mirna; Bukvić, Blaženka Kljaić; Ivković‐Jureković, Irena; Čičak, Biserka; Skálová, Sylva; Horneff, Gerd; Vogelberg, Christian; Gács, E; Kalocsai, Krisztina; Madarasi, Anna; Kovács, Lajos; Novàk, Zoltán; Bene, Zsolt; Ashkenazi, Shai; Goldbart, Aviv; Bentur, Lea; Kolosa, Nadezda; Gardovska, Dace; Khaw, Poh Guan; Toh, Teck Hock; Bruyne, Jessie Anne de; Tan, Kah Kee; Alberto, Edison; Benjamin, Junior Sablan; Leon, Anjanette De; Szymański, Henryk; Repko, Miroslav; Kralinský, K.; Cueva, Ignacio Salamanca de la; Liria, C. Rodrigo Gonzalo de; Martinón-Torres, Federico; Romero, María Pilar; Montesinos, Emilio Monteagudo; Teeratakulpisarn, Jamaree; Puthanakit, Thanyawee; Oberdorfer, Peninnah; Warachit, Boonyarat; Brackeva, Benedicte; Dombrecht, Evelyne; Detalle, Laurent; Fleurinck, C.

doi:10.1016/s2213-2600(20)30320-9

Cited by 81 publications

(83 citation statements)

References 35 publications

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“…Direct administration to the airways is likely to provide faster and more robust antiviral activity in the respiratory tract, where the virus gains entry and replicate 16,32 , as intranasal delivery has been shown to result in fast and efficient drug delivery to the main site of SARS-CoV-2 infection, i.e., the upper and lower respiratory tract 32 . Indeed, the therapeutic effect of topical administration of ALX-0171 displayed promising results in reducing the RSV viral load 14,16 . To our best knowledge, the current study is the first to evaluate the in vivo efficacy of Nbs against SARS-CoV-2 infection via intranasal delivery.…”

Section: Discussionmentioning

confidence: 99%

“…This single variable domain, referred as a single-domain antibody, VHH, or Nanobody (Nb), has higher affinity, thermal stability and chemostability than most antibodies 8,9 and can easily be constructed into multivalent formats devoid of Fc, which will overcome potential deleterious antibody-dependent enhancement (ADE) of infection observed in some viral infections, including Dengue virus, HIV and SARS-CoV [10][11][12] . Their favorable biophysical properties have led to the development of several Nbs as therapeutics against viral infection, such as severe fever with thrombocytopenia syndrome virus (SFTSV) 13 and respiratory syncytial virus (RSV) [14][15][16] .…”

Section: Introductionmentioning

confidence: 99%

“…Nbs are delivered directly to the lungs via an inhaler given their small size, simple and robust structure, high thermal stability, and solubility. For instance, ALX-0171, a homotrimeric Nbs, is highly effective in reducing nasal and lung RSV titers via the pulmonary administration of inhalation 14,16 .…”

Section: Introductionmentioning

confidence: 99%

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A potent bispecific nanobody protects hACE2 mice against SARS-CoV-2 infection via intranasal administration

Cheng

et al. 2021

Preprint

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The dramatically expanding COVID-19 needs multiple effective countermeasures. Neutralizing antibodies are a potential therapeutic strategy for treating COVID-19. A number of neutralizing nanobodies (Nbs) were reported for their in vitro activities. However, in vivo protection of these nanobodies was not reported in animal models. In the current report, we characterized several RBD-specific Nbs isolated from a screen of an Nb library derived from an alpaca immunized with SARS-CoV-2 spike glycoprotein (S); among them, three Nbs exhibited picomolar potency against SARS-CoV-2 live virus, pseudotyped viruses, and 15 circulating SARS-CoV-2 variants. To improve the efficacy, various configurations of Nbs were engineered. Nb15-NbH-Nb15, a novel trimer constituted of three Nbs, was constructed to be bispecific for human serum albumin (HSA) and RBD of SARS-CoV-2. Nb15-NbH-Nb15 exhibited sub-ng/ml neutralization potency against the wild-type and currently circulating variants of SARS-CoV-2 with a long half-life in vivo. In addition, we showed that intranasal administration of Nb15-NbH-Nb15 provided 100% protection for both prophylactic and therapeutic purposes against SARS-CoV-2 infection in transgenic hACE2 mice. Nb15-NbH-Nb15 is a potential candidate for both prevention and treatment of SARS-CoV-2 through respiratory administration.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A potent bispecific nanobody protects hACE2 mice against SARS-CoV-2 infection via intranasal administration

Cheng

et al. 2021

Preprint

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“…The inherent stability of nanobodies enables aerosolized delivery directly to the nasal and lung epithelia (33). Indeed, aerosol delivery of a trimeric nanobody targeting respiratory syncytial virus (ALX-0171) was recently demonstrated to be effective in substantially decreasing measurable viral load in hospitalized infants (34). Finally, potential immunogenicity of camelid-derived nanobodies can be mitigated by established humanization strategies (35).…”

mentioning

confidence: 99%

An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike

Schoof

Faust

Saunders

et al. 2020

Science

363

443

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The SARS-CoV-2 virus enters host cells via an interaction between its Spike protein and the host cell receptor angiotensin converting enzyme 2 (ACE2). By screening a yeast surface-displayed library of synthetic nanobody sequences, we developed nanobodies that disrupt the interaction between Spike and ACE2. Cryogenic electron microscopy (cryo-EM) revealed that one nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains (RBDs) locked into their inaccessible down-state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains function after aerosolization, lyophilization, and heat treatment, which enables aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia.

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“…in similar proportions of drug-treated and placebo-treated patients [55, 56].Phase I and II studies of ALX-0171 (a trimeric antibody consisting of three identical anti-RSV humanized camelid V H Hs) administered in multiple doses by nebulization showed no evidence of treatment-emergent ADAs[57,58]. Phase I/II studies of ozoralizumab (ATN-…”

mentioning

confidence: 99%

Immunogenicity and humanization of single‐domain antibodies

et al. 2021

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Nebulised ALX-0171 for respiratory syncytial virus lower respiratory tract infection in hospitalised children: a double-blind, randomised, placebo-controlled, phase 2b trial

Cited by 81 publications

References 35 publications

A potent bispecific nanobody protects hACE2 mice against SARS-CoV-2 infection via intranasal administration

A potent bispecific nanobody protects hACE2 mice against SARS-CoV-2 infection via intranasal administration

An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike

Immunogenicity and humanization of single‐domain antibodies

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