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Antibody therapy in the management of shiga toxin-induced hemolytic uremic syndrome - PubMed

Review

Antibody therapy in the management of shiga toxin-induced hemolytic uremic syndrome

Saul Tzipori et al. Clin Microbiol Rev. 2004 Oct.

Abstract

Hemolytic uremic syndrome (HUS) is a disease that can lead to acute renal failure and often to other serious sequelae, including death. The majority of cases are attributed to infections with Escherichia coli, serotype O157:H7 strains in particular, which cause bloody diarrhea and liberate one or two toxins known as Shiga toxins 1 and 2. These toxins are thought to directly be responsible for the manifestations of HUS. Currently, supportive nonspecific treatment is the only available option for the management of individuals presenting with HUS. The benefit of antimicrobial therapy remains uncertain because of several reports which claim that such intervention can in fact exacerbate the syndrome. There have been only a few specific therapies directed against neutralizing the activities of these toxins, but none so far has been shown to be effective. This article reviews the literature on the mechanism of action of these toxins and the clinical manifestations and current management and treatment of HUS. The major focus of the article, however, is the development and rationale for using neutralizing human antibodies to combat this toxin-induced disease. Several groups are currently pursuing this approach with either humanized, chimeric, or human antitoxin antibodies produced in transgenic mice. They are at different phases of development, ranging from preclinical evaluation to human clinical trials. The information available from preclinical studies indicates that neutralizing specific antibodies directed against the A subunit of the toxin can be highly protective. Such antibodies, even when administered well after exposure to bacterial infection and onset of diarrhea, can prevent the occurrence of systemic complications.

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Figures

FIG. 1.
FIG. 1.

Technologies used to produce antibodies for human therapy. Chimeric antibodies are made by combining the antigen-binding variable heavy- and light-chain domains (VL and VH) of the mouse antigen-specific monoclonal antibody with human constant region domains (CH1, CH2, and CH3). Humanized antibodies are made by replacing the complementarity-determining regions (CDRs) (regions within the antigen-binding variable domains which react with the antigen) of human IgG molecule with the complementarity-determining regions of mouse antigen-specific monoclonal antibody. Transfer of one or more amino acid residues from the framework regions (FRs) is often required to create high-affinity humanized antibodies. Human antibodies are produced by conventional hybridoma technology with transgenic mice which bear human heavy- and light-chain immunoglobulin gene loci. Human antibodies are also obtained from single-chain variable fragments or Fab phage display libraries combined with a prefabricated human constant region.

FIG. 2.
FIG. 2.

Histological sections of the cerebellum of a 2-year-old patient who died of HUS and profound neurological complications (left) and a piglet challenged orally with the same Stx2-producing STEC isolated from the child (right). Both sections show various degrees of petechial hemorrhages in the molecular layer (human and piglet) and in the cortex layer (piglet). Extensive infarction in the granular layer with extremely shrunken nuclei can be seen under higher magnification (hematoxylin and eosin stain).

FIG. 3.
FIG. 3.

Recombinant and engineered antibody molecules used in therapy. Antibodies of interest can be engineered in a number of ways to modify function and antigen specificity (lower right) or modulate binding affinity by affinity maturation (lower left; asterisks represent specific amino acid substitutions). Smaller Fab molecules (upper left), which lack the effector functions associated with the Fc regions, can be generated either by treatment with papain or by production of recombinant Fab molecules. Recombinant single-chain antibodies (scFv, upper right) can be produced once the nucleotide sequences of the variable regions of the light chain (VL) and heavy chain (VH) have been determined. The VL and VH regions are then cloned into an expression vector so that the VL region is linked to the VH region through a flexible glycine-serine peptide linker. This flexible linker permits the VH and VL regions to fold properly to form a functional antigen binding domain. Isotype variants of an IgG molecule can be created by replacement of the constant region (Fc) of one isotype with the constant region of one of the other isotypes. If the antibodies are recombinant, the constant regions can be readily swapped if a modular approach is taken in the design of the expression vector.

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