Comparative<u>in vitro</u>and<u>in vivo</u>assessment of toxin neutralization by anti-tetanus toxin monoclonal antibodies

Yousefi, Mehdi; Khosravi-Eghbal, Roya; Mahmoudi, Ahmad; Jeddi-Tehrani, Mahmood; Rabbani, Hodjatallah; Shokri, Fazel

doi:10.4161/hv.26769

Cited by 24 publications

(20 citation statements)

References 29 publications

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“…[26] The exact role of the HC-N domain remains elusive. [28] Even though, monoclonal antibodies, capable of neutralizing the toxin in mice, were found to be binding to the C domain of the C-terminal part of the heavy chain (HC-C), [29,30] antibodies binding to the identified epitope might play a synergistic role in the neutralization process. Polysialogangliosides and integral membrane protein receptors have shown to be involved in the binding process.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Tetanus Toxin Specific Epitope in Single Amino Acid Resolution

Palermo

Weber

Rentschler

et al. 2017

Biotechnology Journal

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Vaccinations are among the most potent tools to fight infectious diseases. However, cross-reactions are an ongoing problem and there is an urgent need to fully understand the mechanisms of the immune response. For the development of a methodological workflow, the linear epitopes in the immune response to the tetanus toxin is investigated in sera of 19 vaccinated Europeans applying epitope mapping with peptide arrays. The most prominent epitope, appearing in nine different sera ( IHLVNNESSEVIVHK ), is investigated in a substitution analysis to identify the amino acids that are crucial for the binding of the corresponding antibody species - the antibody fingerprint. The antibody fingerprints of different individuals are compared and found to be strongly conserved ( ExxEVIVxK ), which is astonishing considering the randomness of their development. Additionally, the corresponding antibody species is isolated from one serum with batch chromatography using the amino acid sequence of the identified epitope and the tetanus specificity of the isolated antibody is verified by ELISA. Studying antibody fingerprints with peptide arrays should be transferable to any kind of humoral immune response toward protein antigens. Furthermore, antibody fingerprints have shown to be highly disease-specific and, therefore, can be employed as reliable biomarkers enabling the study of cross-reacting antigens.

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Section: Discussionmentioning

confidence: 99%

Identification of a Tetanus Toxin Specific Epitope in Single Amino Acid Resolution

Palermo

Weber

Rentschler

et al. 2017

Biotechnology Journal

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“…We have recently reported the dominance of the fragment C specific antibody response in mice following immunization with tetanus toxoid (Yousefi et al, 2013b). In the present study, 22 murine and 50 human anti-TeNT mAb were produced using hybridoma technology and EBV transformation methods, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…The ability of mAb to inhibit binding of TeNT to its receptor GT1b ganglioside was assessed in vitro by modification of a previously described procedure (Yousefi et al, 2013b). In brief, a concentration of TeNT that resulted in saturation of ganglioside GT1b binding was chosen (20 mg/ml) and mixed with different concentrations of the purified murine anti-TeNT mAb (1-10 mgr/ml) or 100 ml of undiluted LCL supernatants and the mixture then incubated for 2 h at room temperature (RT).…”

Section: Assessment Of Toxin Neutralizing Activity Of Monoclonal Antimentioning

confidence: 99%

Comparative human and mouse antibody responses against tetanus toxin at clonal level

Yousefi

Younesi

Bayat

et al. 2015

Journal of Immunotoxicology

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Tetanus is a highly fatal disease caused by tetanus neurotoxin (TeNT) and remains a major threat to human and animal health, despite preventive strategies. TeNT is composed of heavy and light chain linked by a disulfide bond. The antibody response to TeNT is polyclonal and directed to multiple epitopes within both the light and heavy chains, leading to toxin neutralization. This study was undertaken to localize and compare neutralizing epitopes recognized by human and mouse TeNT-specific antibodies at a clonal level. In the present study, 22 murine hybridoma clones and 50 human lymphoblastoid cell lines secreting monoclonal antibodies (mAb) were generated against TeNT. The specificity of these mAb was determined using different recombinant fragments of tetanus toxin. Moreover, this study investigated the in vitro toxin neutralizing activity of these mAb by a ganglioside GT1b assay. The results showed that tetanus toxoid immunization in humans and BALB/c mice induced a vigorous humoral immune response against different fragments of TeNT, particularly the carboxyl-terminal fragment of the heavy chain (known as fragment C). The fragment C-specific human and mouse mAb could largely neutralize TeNT. However, while all fragment C-specific human mAb reacted with the carboxyl-terminal part of this fragment (H CC ), the majority of the mouse mAb failed to recognize this region. These results suggested that fragment C is the major target for the TeNT neutralizing antibodies, although different epitopes seem to be targeted by human and mouse antibodies.

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“…In accordance with these findings, Yousefi et al detected synergistic neutralizing effects of one pair of MAbs, but not other pairs, that recognized two distinct but very close or overlapping epitopes within the GT1b-binding fragment of TeNT. This pair of MAbs displayed an in vivo potency several times higher than the commercial TIG antibody preparation [ 52 ]. The authors speculated that the observed cooperative binding effects were caused by conformational changes in the TeNT protein in which binding of the first antibody thermodynamically facilitated the binding of the second antibody.…”

Section: Synergistic Neutralization Of Mab Cocktailsmentioning

confidence: 99%

Monoclonal Antibody Combinations that Present Synergistic Neutralizing Activity: A Platform for Next-Generation Anti-Toxin Drugs

Diamant

Torgeman

Ozeri

et al. 2015

Toxins

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Monoclonal antibodies (MAbs) are among the fastest-growing therapeutics and are being developed for a broad range of indications, including the neutralization of toxins, bacteria and viruses. Nevertheless, MAbs potency is still relatively low when compared to conventional polyclonal Ab preparations. Moreover, the efficacy of an individual neutralizing MAb may significantly be hampered by the potential absence or modification of its target epitope in a mutant or subtype of the infectious agent. These limitations of individual neutralizing MAbs can be overcome by using oligoclonal combinations of several MAbs with different specificities to the target antigen. Studies conducted in our lab and by others show that such combined MAb preparation may present substantial synergy in its potency over the calculated additive potency of its individual MAb components. Moreover, oligoclonal preparation is expected to be better suited to compensating for reduced efficacy due to epitope variation. In this review, the synergistic neutralization properties of combined oligoclonal Ab preparations are described. The effect of Ab affinity, autologous Fc fraction, and targeting a critical number of epitopes, as well as the unexpected contribution of non-neutralizing clones to the synergistic neutralizing effect are presented and discussed.

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Comparativein vitroandin vivoassessment of toxin neutralization by anti-tetanus toxin monoclonal antibodies

Cited by 24 publications

References 29 publications

Identification of a Tetanus Toxin Specific Epitope in Single Amino Acid Resolution

Identification of a Tetanus Toxin Specific Epitope in Single Amino Acid Resolution

Comparative human and mouse antibody responses against tetanus toxin at clonal level

Monoclonal Antibody Combinations that Present Synergistic Neutralizing Activity: A Platform for Next-Generation Anti-Toxin Drugs

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