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An oligoclonal combination of human monoclonal antibodies able to neutralize tetanus toxin in vivo

Published on Apr 1, 2019
· DOI :10.1016/j.toxcx.2019.100006
Eduardo Aliprandini1
Estimated H-index: 1
(USP: University of São Paulo),
Daniela Yumi Takata (USP: University of São Paulo)+ 3 AuthorsAna Maria Moro (NIST: National Institute of Standards and Technology)
Abstract The use of antibody-based therapy to treat a variety of diseases and conditions is well documented. The use of antibodies as an antidote to treat tetanus infections was one of the first examples of immunotherapy and remains the standard of care for cases involving potential infections. Plasma-derived immunoglobulins obtained from human or horse pose risks of infection from undetectable emergent viruses or may cause anaphylaxis. Further, there is a lack of consistency between lots. In the search for new formulations, we obtained a series of clonally related human monoclonal antibodies (mAbs) derived from B cells sorted from donors that presented anti-tetanus neutralizing titers. Donors were revaccinated prior to blood collection. Different strategies were used for single-cell sorting, since it was challenging to identify cells at a very low frequency: memory B cell sorting using fluorescent-labeled tetanus toxoid and toxin as baits, and plasmablast sorting done shortly after revaccination. Screening of the recombinant mAbs with the whole tetanus toxin allowed us to select candidates with therapeutic potential, since mAbs to different domains can contribute additively to the neutralizing effect. Because of selective binding to different domains, we tested mAbs individually, or in mixtures of two or three, in the neutralizing in vivo assay specified by Pharmacopeia for the determination of polyclonal hyperimmune sera potency. An oligoclonal mixture of three human mAbs completely neutralized the toxin injected in the animals, signaling an important step for clinical mAb development.
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Published on Jul 1, 2017in EBioMedicine
Angeline Rouers5
Estimated H-index: 5
(University of Paris),
Jéromine Klingler2
Estimated H-index: 2
(UDS: University of Strasbourg)
+ 15 AuthorsFaroudy Boufassa33
Estimated H-index: 33
(French Institute of Health and Medical Research)
Abstract HIV-specific broadly neutralizing antibodies (bnAbs) have been isolated from patients with high viremia but also from HIV controllers that repress HIV-1 replication. In these elite controllers (ECs), multiple parameters contribute to viral suppression, including genetic factors and immune responses. Defining the immune correlates associated with the generation of bnAbs may help in designing efficient immunotherapies. In this study, in ECs either positive or negative for the HLA-B*57 pro...
Published on Feb 16, 2017in Journal of Visualized Experiments 1.11
Mia J. Smith7
Estimated H-index: 7
(CSU: Colorado State University),
Thomas A. Packard7
Estimated H-index: 7
(University of Colorado Denver)
+ 4 AuthorsJohn C. Cambier18
Estimated H-index: 18
(University of Colorado Denver)
B cells reactive with a specific antigen usually occur at a frequency of <0.05% of lymphocytes. For decades researchers have sought methods to isolate and enrich these rare cells for studies of their phenotype and biology. Approaches are inevitably based on the principle that B cells recognize native antigen by virtue of cell surface receptors that are representative in specificity of antibodies that will eventually be secreted by their differentiated daughters. Perhaps the most obvious approach...
Published on Dec 1, 2016in Vaccine 3.27
Mark Doherty2
Estimated H-index: 2
Ruprecht Schmidt-Ott9
Estimated H-index: 9
+ 4 AuthorsAnthony L. Cunningham66
Estimated H-index: 66
Abstract One of the strategic objectives of the 2011–2020 Global Vaccine Action Plan is for the benefits of immunisation to be equitably extended to all people. This approach encompasses special groups at increased risk of vaccine-preventable diseases, such as preterm infants and pregnant women, as well as those with chronic and immune-compromising medical conditions or at increased risk of disease due to immunosenescence. Despite demonstrations of effectiveness and safety, vaccine uptake in the...
Published on Dec 1, 2014in Anaerobe 2.70
Richard Diego Gonzales y Tucker1
Estimated H-index: 1
(Alameda Health System),
Bradley W. Frazee17
Estimated H-index: 17
(UCSF: University of California, San Francisco)
Abstract Injection drug use (IDU), specifically non-intravenous “skin-popping” of heroin, seems to provide optimal conditions for Clostridial infection and toxin production. IDU is therefore a major risk factor for wound botulism and Clostridial necrotizing soft tissue infections (NSTI) and continues to be linked to cases of tetanus. Case clusters of all 3 diseases have occurred amo n g IDUs in Western U.S. and Europe. Medical personnel who care for the IDU population must be thoroughly familiar...
Published on Nov 28, 2014in Science 41.04
K Bercsenyi1
Estimated H-index: 1
(UCL: University College London),
Nathalie Schmieg4
Estimated H-index: 4
(UCL: University College London)
+ 7 AuthorsSchiavoGiampietro68
Estimated H-index: 68
(UCL: University College London)
Tetanus neurotoxin (TeNT) is among the most poisonous substances on Earth and a major cause of neonatal death in nonvaccinated areas. TeNT targets the neuromuscular junction (NMJ) with high affinity, yet the nature of the TeNT receptor complex remains unknown. Here, we show that the presence of nidogens (also known as entactins) at the NMJ is the main determinant for TeNT binding. Inhibition of the TeNT-nidogen interaction by using small nidogen-derived peptides or genetic ablation of nidogens p...
Published on Nov 1, 2014in Journal of Virology 4.32
Scott A. Smith22
Estimated H-index: 22
(VUMC: Vanderbilt University Medical Center),
A. Ruklanthi de Alwis2
Estimated H-index: 2
(UNC: University of North Carolina at Chapel Hill)
+ 3 AuthorsJames E. Crowe61
Estimated H-index: 61
(VUMC: Vanderbilt University Medical Center)
Natural dengue virus (DENV) infection in humans induces antibodies (Abs) that neutralize the serotype of infection in a potent and type-specific manner; however, most Abs generated in response to infection are serotype cross-reactive and poorly neutralizing. Such cross-reactive Abs may enhance disease during subsequent infection with a virus of a different DENV serotype. Previous screening assays for DENV-specific human B cells and antibodies, using viral and recombinant antigens, mainly led to ...
Published on Feb 1, 2014in Human Vaccines & Immunotherapeutics 2.59
Mehdi Yousefi19
Estimated H-index: 19
(Tabriz University of Medical Sciences),
Roya Khosravi-Eghbal2
Estimated H-index: 2
(Avicenna Research Institute)
+ 3 AuthorsFazel Shokri27
Estimated H-index: 27
(Tehran University of Medical Sciences)
Tetanus is caused by the tetanus neurotoxin (TeNT), a 150 kDa single polypeptide molecule which is cleaved into an active two-chain molecule composed of a 50 kDa N-terminal light (L) and a 100 kDa C-terminal heavy (H) chains. Recently, extensive effort has focused on characterization of TeNT binding receptors and toxin neutralization by monoclonal antibodies (mAbs). Toxin binding inhibition and neutralization is routinely assessed either in vitro by the ganglioside GT1b binding inhibition assay ...
Published on Jan 1, 2014in Critical Care 6.96
Chaturaka Rodrigo17
Estimated H-index: 17
(UoC: University of Colombo),
Deepika Fernando12
Estimated H-index: 12
(UoC: University of Colombo),
Senaka Rajapakse20
Estimated H-index: 20
(UoC: University of Colombo)
Tetanus is becoming rarer in both industrialized and developing nations due to an effective vaccination program. In 2010, the World Health Organization estimated there was a 93% reduction in newborns dying from tetanus worldwide, compared to the situation in the late 1980s. Due to its rarity, many diagnostic delays occur as physicians may not consider the diagnosis until the manifestations become overt. Without timely diagnosis and proper treatment, severe tetanus is fatal (mortality is also inf...
Published on Jan 1, 2013in Methods of Molecular Biology
Hedda Wardemann37
Estimated H-index: 37
(MPG: Max Planck Society),
Juliane Kofer4
Estimated H-index: 4
(MPG: Max Planck Society)
Published on Oct 1, 2012in Vaccine 3.27
Ping Luo13
Estimated H-index: 13
(Third Military Medical University),
Liyan Qin1
Estimated H-index: 1
(CQMU: Chongqing Medical University)
+ 7 AuthorsQuanming Zou27
Estimated H-index: 27
(Third Military Medical University)
Abstract Tetanus, a severe infectious disease, is caused by tetanus toxin (TT) from Clostridium tetani , which remains one of the most critical unsolved health problems despite preventive strategies. The carboxyl terminal of TT (TTC) is responsible for the binding of TT to neurons and for its toxicity and has been proven to be immunogenic and protective in various forms. It would therefore be extremely interesting to identify the epitope on TTC at a molecular level. In this study, we generated a...
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