Antibody recognition of carbohydrate epitopes

Haji-Ghassemi, O.; Blackler, R.J.; Young, N. Martin; Evans, Stephen V.

doi:10.1093/glycob/cwv037

Cited by 120 publications

(126 citation statements)

References 280 publications

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“…Adaptable protection against carbohydrate Ags using small numbers of germline genes (49) and an example of cross-reactivity between carbohydrate and single-strand DNA with limited paratope overlap (50) have been reported. We now add data that support a mechanism whereby the IGHV3-30 and IGKV3-11 V genes provide an innate foundation for protection to two divergent pathogens by their ability to generate neutralizing mAbs targeting an invariant site on a viral protein necessary for viral infectivity as well as neutralizing mAbs directed at a pneumococcal capsular polysaccharide.…”

Section: Discussionmentioning

confidence: 99%

“…These residues include Tyr Specificity for the AD-2S1 peptide is dictated primarily by these germline-encoded residues. The Tyr side chain of peptide residue P4 sits in a hydrophobic pocket formed by germline-encoded CDRL2 residue Tyr 49 (L), the CDRH3 backbone, and junctional residue Leu In KE5, the junctional residue Glu 95 (H) is critical for CDRH3 stabilization, forming hydrogen bonds with the backbone nitrogen atoms of Thr 100 E(H) and Gly 100 F(H), which are part of an opposing junctional Ser/Thr-Gly-Leu-Leu/Ile motif, encoded by stochastically generated DNA, conserved in the anti-AD2-S1 Abs, and located at the C-terminal base of the CDRH3 (Fig. 1) (15, 24).…”

Section: Interactions Between Fab Ke5 and Its Ad-2s1 Agmentioning

confidence: 99%

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Structures of Preferred Human IgV Genes–Based Protective Antibodies Identify How Conserved Residues Contact Diverse Antigens and Assign Source of Specificity to CDR3 Loop Variation

Bryson

Thomson

Risnes

et al. 2016

The Journal of Immunology

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The human Ab response to certain pathogens is oligoclonal, with preferred IgV genes being used more frequently than others. A pair of such preferred genes, IGVK3-11 and IGVH3-30, contributes to the generation of protective Abs directed against the 23F serotype of the pneumonococcal capsular polysaccharide of Streptococcus pneumoniae and against the AD-2S1 peptide of the gB membrane protein of human CMV. Structural analyses of Fab fragments of mAbs 023.102 and pn132p2C05 in complex with portions of the 23F polysaccharide revealed five germline-encoded residues in contact with the key component, l-rhamnose. In the case of the AD-2S1 peptide, the KE5 Fab fragment complex identified nine germline-encoded contact residues. Two of these germline-encoded residues, Arg91L and Trp94L, contact both the l-rhamnose and the AD-2S1 peptide. Comparison of the respective paratopes that bind to carbohydrate and protein reveals that stochastic diversity in both CDR3 loops alone almost exclusively accounts for their divergent specificity. Combined evolutionary pressure by human CMV and the 23F serotype of S. pneumoniae acted on the IGVK3-11 and IGVH3-30 genes as demonstrated by the multiple germline-encoded amino acids that contact both l-rhamnose and AD-2S1 peptide.

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Section: Discussionmentioning

confidence: 99%

Section: Interactions Between Fab Ke5 and Its Ad-2s1 Agmentioning

confidence: 99%

Structures of Preferred Human IgV Genes–Based Protective Antibodies Identify How Conserved Residues Contact Diverse Antigens and Assign Source of Specificity to CDR3 Loop Variation

Bryson

Thomson

Risnes

et al. 2016

The Journal of Immunology

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“…Due to wide antigenic variation of microbial carbohydrates, an immune response is often restricted to a particular species or subgroup (serotype) of bacteria (10). This serotype specificity is reflected in the majority of carbohydrate-binding monoclonal antibodies (mAbs) with known structures where binding involves a particular carbohydrate epitope often located at the ends of polysaccharide chains (11). Although a number of carbohydratebinding antibodies have been identified and evaluated in clinical trials, there are currently no carbohydrate-specific therapeutic mAbs that have been approved for the treatment of bacterial infections (12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Structural basis for antibody targeting of the broadly expressed microbial polysaccharide poly-N-acetylglucosamine

Soliman

Walduck

Yuriev

et al. 2018

Journal of Biological Chemistry

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“…Furthermore, an antibody-combining site can form a pocket or groove as originally predicted by Kabat (77) or a combination of both depending on the nature of the antigen (24). B-cell receptors often select groove combining site architecture for larger antigens such as proteins, although pocket-type antibod- Numbering is based on the Kabat scheme.…”

Section: S55-3 Cdr H2 Possesses a Different ␤-Turnmentioning

confidence: 99%

“…Although antibodies specific for the various LPS components have been reported (15)(16)(17)(18)(19)(20)(21)(22)(23)(24), the structural variation in the core and O-polysaccharide regions together with the rapid onset of septic shock have hindered their introduction into clinical use (4,12,(25)(26)(27). To date, only the inner core binding mAb WN1 222-5 has been reported successful in neutralizing a wide range of Gram-negative bacteria, including Escherichia, Salmonella, Shigella, and Citrobacter (15,28,29).…”

mentioning

confidence: 99%

The Combining Sites of Anti-lipid A Antibodies Reveal a Widely Utilized Motif Specific for Negatively Charged Groups

Haji-Ghassemi

Müller‐Loennies

Rodrı́guez

et al. 2016

Journal of Biological Chemistry

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Lipopolysaccharide dispersed in the blood by Gram-negative bacteria can be a potent inducer of septic shock. One research focus has been based on antibody sequestration of lipid A (the endotoxic principle of LPS); however, none have been successfully developed into a clinical treatment. Comparison of a panel of anti-lipid A antibodies reveals highly specific antibodies produced through distinct germ line precursors. The structures of antigen-binding fragments for two homologous mAbs specific for lipid A, S55-3 and S55-5, have been determined both in complex with lipid A disaccharide backbone and unliganded. These high resolution structures reveal a conserved positively charged pocket formed within the complementarity determining region H2 loops that binds the terminal phosphates of lipid A. Significantly, this motif occurs in unrelated antibodies where it mediates binding to negatively charged moieties through a range of epitopes, including phosphorylated peptides used in diagnostics and therapeutics. S55-3 and S55-5 have combining sites distinct from anti-lipid A antibodies previously described (as a result of their separate germ line origin), which are nevertheless complementary both in shape and charge to the antigen. S55-3 and S55-5 display similar avidity toward lipid A despite possessing a number of different amino acid residues in their combining sites. Binding of lipid A occurs independent of the acyl chains, although the GlcN-O6 attachment point for the core oligosaccharide is buried in the combining site, which explains their inability to recognize LPS. Despite their lack of therapeutic potential, the observed motif may have significant immunological implications as a tool for engineering recombinant antibodies.Bacterial Gram-positive and Gram-negative infections can lead to septic shock, with estimates as high as one million annual cases in the United States with a mortality rate as high as 50% (1-3). The amphipathic lipopolysaccharide (LPS) responsible for Gram-negative-induced septic shock is normally shed from the bacterial outer membrane but can be released in great amounts upon cell death (4). Lipid A, the endotoxic principle of LPS, is an acylated glucosamine phosphate disaccharide that anchors the LPS molecule to the bacterial outer membrane (5, 6). The presence of intact LPS (or lipid A) in blood can induce a potentially fatal inflammatory cascade in humans (7), initiated by the formation of a signaling complex of the lipid A with Toll-like receptor 4 (TLR4) and co-receptor myeloid differentiation factor 2 (MD-2) (8 -11).Efforts to develop therapeutic antibodies to inhibit the formation of the LPS⅐TLR4⅐MD-2 complex by sequestering LPS have proved challenging (12)(13)(14). Although antibodies specific for the various LPS components have been reported (15-24), the structural variation in the core and O-polysaccharide regions together with the rapid onset of septic shock have hindered their introduction into clinical use (4, 12, 25-27). To date, only the inner core binding mAb WN1 222-5 has been ...

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Antibody recognition of carbohydrate epitopes

Cited by 120 publications

References 280 publications

Structures of Preferred Human IgV Genes–Based Protective Antibodies Identify How Conserved Residues Contact Diverse Antigens and Assign Source of Specificity to CDR3 Loop Variation

Structures of Preferred Human IgV Genes–Based Protective Antibodies Identify How Conserved Residues Contact Diverse Antigens and Assign Source of Specificity to CDR3 Loop Variation

Structural basis for antibody targeting of the broadly expressed microbial polysaccharide poly-N-acetylglucosamine

The Combining Sites of Anti-lipid A Antibodies Reveal a Widely Utilized Motif Specific for Negatively Charged Groups

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