Monoclonal Antibody to Shiga Toxin 1, Which Blocks Receptor Binding and Neutralizes Cytotoxicity

Nakao, Hiroshi; Kataoka, Chiwa; Kiyokawa, Nobutaka; Fujimoto, Junichiro; Yamasaki, Shinji; Takeda, Tae

doi:10.1111/j.1348-0421.2002.tb02764.x

Cited by 20 publications

(31 citation statements)

References 8 publications

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“…The predominance of A-subunit-specific HuMAbs is consistent with previous findings in which the majority of murine Stx2-specific MAbs were also specific for the A subunit (6,25,28,29). Isolation of Stx2-specific human IgG1 and IgG3 HuMAbs with differential epitope specificity confirms previous findings that HuMAb___Mouse contains a sufficiently diverse repertoire of human heavy chain immunoglobulin loci capable of responding to a variety of antigens and undergoing isotype switching and affinity maturation (12).…”

Section: Discussionsupporting

confidence: 78%

“…Similarly, passively administered Stx2e antiserum has been shown to prevent edema disease in swine (18). Several murine Stx2-specific monoclonal antibodies (MAbs) have been developed, and many have been shown to neutralize the activity of Stx2 in vitro and/or in vivo in mice (5,9,25,30,35). Here we describe development of a panel of Stx2 A-and B-subunit-specific human MAbs (HuMAbs), several of which similarly neutralize Stx2-mediated activity in vitro and in vivo.…”

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confidence: 99%

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Human Stx2-Specific Monoclonal Antibodies Prevent Systemic Complications of Escherichia coli O157:H7 Infection

Mukherjee

Chios

Fishwild³

et al. 2002

Infect Immun

103

118

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Section: Discussionsupporting

confidence: 78%

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confidence: 99%

Human Stx2-Specific Monoclonal Antibodies Prevent Systemic Complications of Escherichia coli O157:H7 Infection

Mukherjee

Chios

Fishwild³

et al. 2002

Infect Immun

103

118

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“…Prediction of conformational B-cell epitopes using Elipro was resulted to identify strong epitopes that can be used in immunodiagnostic tests and antibody production. The most probable Stx1A and Stx2A Stx1 A T290, I291, S292, S293 0.976 G25, T26, P27, L28, Q29, T30, I31, S32, S33, G34, G35, T36, S37, L39, M40, P211, D212, Y213, H214, G215, Q216, D217, S218, R220, G222, G227, S228, I229, N230, H245, A246, S247, R248, V249, A250, R251, M252, A253, S254, D255, E256, S259, P262, A263, D264, G265, R266, V267, R268, G269, I270, T271, H272, N273, K274, I275, L276, W277, S279, S280, T281, L282, G283, A284, I285, L286, M287, R288, R289 0.704 F7, S8, T9, A10, K11, T12, D15, G56, I57, D58, P59, E60, E61, G62, R63, F64, N65, N66, N83, R84, T85, N86, N87, V88, Y90, R91, F92, A93, S96, H97, V98, F100, P101, G102, T103, T104, A105, V106, T107, L108, S109, G110, V120, A121, G122, I123, S124, T126, G127, M128, Q129, I130, N131, H133, T136, T137, L140, D141, M143, S144, H145, S146, G147, T148, S149, L150, T151, Q152, S153, R179, T180, T181, D183, D184, L185, S186, G187, R188, S189, Y190, V191, M192 (Nakao et al 1999). Their findings indicated that three segments of 13C4 monoclonal antibody epitope are amino acids from 21-26, 45-52 and 74-81 with critical asparagine residue at position 55 that are necessary for binding of the 13C4 monoclonal antibody.…”

Section: Discussionmentioning

confidence: 99%

In silico analysis of Shiga toxins (Stxs) to identify new potential vaccine targets for Shiga toxin-producing Escherichia coli

Golshani

Oloomi

Bouzari

2017

In Silico Pharmacol.

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Shiga toxins belong to a family of structurally and functionally related toxins serving as the main virulence factors for pathogenicity of the Shiga toxin-producing Escherichia coli (STEC) associating with Hemolytic uremic syndrome (HUS). At present, there is no effective treatment or prevention for HUS. The aim of the present study was to find conserved regions within the amino acid sequences of Stx1, Stx2 (Shiga toxin) and their variants. In this regard, In-silico identification of conformational continuous B cell and T-cell epitopes was performed in order to introduce new potential vaccine candidates. 93-100% Homology was observed in Stx1 and its variants. In Stx2 and its variants, 69-100% homology was shown. By sequence alignment with Stx1 and Stx2, 54% homology was detected. T-cell epitope identification in Stx1A and Stx2A epitopes with highest binding affinity for each HLA (human leukocyte antigen) was demonstrated with 100% identity among all Stxs. B-cell epitope prediction was resulted in finding of four common epitopes between Stxs. In silico analysis of Stxs was resulted to identification of new peptide targets that could be used in development of new epitope vaccine candidates or in immunodiagnostic tests.

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“…The 13C4 MAb did not bind to StxB1 with the N55T mutation, nor did the antibody neutralize the Stx1 with the N55T mutation. The asparagine at the 55th residue of StxB1 is also a critical amino acid for the binding of another Stx1-neutralizing monoclonal antibody (5-5B) that recognizes the Stx1 B subunit but fails to recognize Stx1d (21). Additionally, a third MAb (2H3) that recognizes StxB1, but not StxB1d, has been described, and residue 55 may play a role in that difference as well (3).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, a third MAb (2H3) that recognizes StxB1, but not StxB1d, has been described, and residue 55 may play a role in that difference as well (3). Finally, another MAb, VTm1.1 (later humanized and called TMA-15), recognizes StxB2 and neutralizes Stx2 (12,22) but fails to recognize StxB2 when the 56th amino acid is mutated (E56H). The 55th residue of StxB1 and the 56th residue of StxB2 are both located on the outside of the B monomers in approximately the same location.…”

Section: Discussionmentioning

confidence: 99%

The 13C4 Monoclonal Antibody That Neutralizes Shiga Toxin Type 1 (Stx1) Recognizes Three Regions on the Stx1 B Subunit and Prevents Stx1 from Binding to Its Eukaryotic Receptor Globotriaosylceramide

et al. 2006

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The 13C4 monoclonal antibody (MAb) recognizes the B subunit of Stx1 (StxB1) and neutralizes the cytotoxic and lethal activities of Stx1. However, this MAb does not bind to the B polypeptide of Stx2, despite the 73% amino acid sequence similarity between StxB1 and StxB2. When we compared the amino acid sequences of StxB1 and StxB2, we noted three regions of dissimilarity (amino acids 1 to 6, 25 to 32, and 54 to 61) located near each other on the crystal structure of StxB1. To identify the 13C4 epitope, we generated seven Stx1/Stx2 B chimeric polypeptides that contained one, two, or three of the dissimilar StxB1 regions. The 13C4 MAb reacted strongly with StxB1 and the triple-chimeric B subunit but not with the other chimeras. Mice immunized with the triple-chimeric B subunit survived a lethal challenge with Stx1 but not Stx2, substantiating the identified regions as the 13C4 MAb epitope and suggesting that the incorporation of this epitope into StxB2 altered sites necessary for anti-Stx2-neutralizing Ab production. Next, single amino acid substitutions were made in StxB1 to mimic Stx1d, a variant not recognized by the 13C4 MAb. The 13C4 MAb reacted strongly to StxB1 with the T1A or G25A mutations but not with the N55T change. Finally, we found that the 13C4 MAb blocked the binding of Stx1 to its receptor, globotriaosyl ceramide. Taken together, these results indicate that the 13C4 MAb prevents the interaction of Stx1 with its receptor by binding three nonlinear regions of the molecule that span receptor recognition sites on StxB1, one of which includes the essential residue 55N.In the United States, Shiga toxin-producing Escherichia coli (STEC) strains account for about 110,000 infections per year (16). Enterohemorrhagic E. coli (EHEC) strains are a subset of STEC that contain a large pathogenicity island called the locus of enterocyte effacement and carry a 90-kb plasmid (13,30,32). Enterohemorrhagic E. coli serotype O157:H7 in particular is noted for it association with food-, water-, or petting zoo-linked outbreaks of Stx-mediated disease (4,23,28). A possible complication from an infection with an Stx-producing organism is the hemolytic uremic syndrome (HUS), a syndrome that is characterized by hemolytic anemia, thrombic thrombocytopenia, and renal failure. The majority of patients with HUS are children (5, 23), and there is a 5 to 10% fatality rate for those individuals. Furthermore, HUS survivors may have lasting kidney damage. Currently, there are no FDA-approved therapies or vaccines in the United States to combat or prevent illness from STEC, but several promising options for the future are under investigation. These options include receptor mimics and active and passive immunization strategies (reviewed in references 17 and 31). Several recent vaccine candidates not described in the above-mentioned reviews include Stx1 and Stx2 genetic toxoids, a plantbased Stx2 toxoid, and a chimeric StxA2/StxB1 toxoid that elicits a neutralizing antibody response and provides protection against a lethal challenge of b...

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Monoclonal Antibody to Shiga Toxin 1, Which Blocks Receptor Binding and Neutralizes Cytotoxicity

Cited by 20 publications

References 8 publications

Human Stx2-Specific Monoclonal Antibodies Prevent Systemic Complications of Escherichia coli O157:H7 Infection

Human Stx2-Specific Monoclonal Antibodies Prevent Systemic Complications of Escherichia coli O157:H7 Infection

In silico analysis of Shiga toxins (Stxs) to identify new potential vaccine targets for Shiga toxin-producing Escherichia coli

The 13C4 Monoclonal Antibody That Neutralizes Shiga Toxin Type 1 (Stx1) Recognizes Three Regions on the Stx1 B Subunit and Prevents Stx1 from Binding to Its Eukaryotic Receptor Globotriaosylceramide

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