Antigenic Properties of Peptide Mimotopes of HIV-1-associated Carbohydrate Antigens

Pashov, Anastas; Canziani, Gabriela; Monzavi‐Karbassi, Behjatolah; Kaveri, Srini V.; MacLeod, Stewart L.; Saha, Rinku; Perry, Marty; VanCott, Thomas C.; Kieber‐Emmons, Thomas

doi:10.1074/jbc.m502964200

Cited by 25 publications

(25 citation statements)

References 32 publications

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“…In the first and second case, the peptides resembled the high-molecularweight melanoma-associated antigen epitope recognized by mAb 763.74 27 and by 225.28s, 28 respectively, whereas in the last case the synthetic peptide resembled the HER-2 epitope recognized by the mAb trastuzumab. 29 Altogether, these findings are not surprising, since peptides have been shown to mimic antigens with a completely different structure, namely the polysaccharide capsule of Cryptococcus neoformans, 30 the glycan shield of HIV, 31 or the pneumococcal capsular polysaccharide. 32 The specific reactivity with CD20 ϩ cells of anti-Rp5-L and -Rp15-C immune sera and their cytotoxic effects similar to those observed with rituximab paralleled our own observation with phagotope R10-L-derived Rp10-L 33 and suggest that these peptides could potentially be used to target CD20 in an active immunotherapy setting, once the immunization protocol has been optimized.…”

Section: Discussionmentioning

confidence: 93%

Generation of biologically active linear and cyclic peptides has revealed a unique fine specificity of rituximab and its possible cross-reactivity with acid sphingomyelinase-like phosphodiesterase 3b precursor

Perosa

Favoino

Caragnano

et al. 2006

Blood

113

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Heterogeneity of the effector functions displayed by rituximab and other anti-CD20 monoclonal antibodies (mAbs) apparently recognizing the same CD20 epitope suggests that additional mechanisms, probably related to mAb fine specificity, are responsible for B-cell depletion. To improve our understanding of rituximab's function, its fine specificity was investigated by means of phage display peptide library (PDPL)-expressing 7-mer cyclic (c7c) or 7-/12-mer linear peptides. Rituximab-specific c7c PDPL-derived clone insert sequences expressed the motif A(S)NPS overlapping the human CD20 170 ANPS 173 . P 172 was the most critical for rituximab binding, since its replacement with S 172 (of mouse CD20) abolished the reactivity. The WPXWLE motif expressed by the linear PDPL-derived clone insert sequences could only be aligned to the reverse-oriented 161 WPXWLE 156 of acid sphingomyelinase-like phosphodiesterase 3b precursor (ASMLPD), though linear peptides bearing WPXWLE competed with cyclic ones for rituximab-paratope binding. Anti-CD20 mAb 1F5 only displayed a reactivity profile similar to that of rituximab, which also reacted with ASMLPD-derived peptides. Peptides induced antibodies with specificity and effector functions similar to those of rituximab. Our results show a unique fine specificity of rituximab, define the molecular basis for the lack of rituximab reactivity with mouse CD20 (mCD20), and the potential of targeting CD20 in an active immunotherapy setting. A possible rituximab interaction with ASMLPD is sug-

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Section: Discussionmentioning

confidence: 93%

Generation of biologically active linear and cyclic peptides has revealed a unique fine specificity of rituximab and its possible cross-reactivity with acid sphingomyelinase-like phosphodiesterase 3b precursor

Perosa

Favoino

Caragnano

et al. 2006

Blood

113

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“…Mimotope-The reactivity of the mannose mimotope peptide RYRY (also known as D002) with ConA has been studied previously (27). To determine the degree of specificity of the mimicry, we further tested the reactivity of RYRY with a panel of lectins ( Fig.…”

Section: Ryry Is a Polyreactivementioning

confidence: 99%

“…Cross-blot-A dot-blot technique was used to analyze the binding of antibody fractions to gp120 and peptides (27,33). Polyvinylidene difluoride membrane (Millipore) was pre-wetted and inserted in a miniblotter (Immunetics, Cambridge, MA).…”

Section: Reagents-biotinylatedmentioning

confidence: 99%

“…in peptide 911 YRYRYGRYRSGSYRYRYGRYRSGS), in terms of binding to concanavalin A (ConA) and eliciting anti-mannose antibodies (22,23). Recently, we demonstrated that the YRY containing cyclic peptide D002 (RGGLCYCRYRYCVCVGR) is a mimic of oligomannose antigens that elicit antibodies reactive to oligomannose-9, and serum of D002 immunized mice was able to suppress the binding of HIV gp120 to human dendritic cells (27). At the same time, the peptides 105 (GGIYYPYDIYYPY-DIYYPYD) and 107 (GGIYYRYDIYYRYDIYYRYD) have been found to mimic a large variety of fucosylated lactosamines (16,23,24).…”

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confidence: 99%

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Multiple Antigenic Mimotopes of HIV Carbohydrate Antigens

Pashov

Plaxco

Kaveri

et al. 2006

Journal of Biological Chemistry

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Carbohydrate mimetic peptides are designable, and they can carry T-cell epitopes and circumvent tolerance. A mimic-based human immunodeficiency virus (HIV) vaccine can be a viable alternative to carbohydrate-based antigens if the diversity of epitopes found on gp120 can be recapitulated. To improve existing mimics, an attempt was made to study the structural correlates of the observed polyspecificity of carbohydrate mimetic peptides based on the Y(P/R)Y motif in more detail. A carbohydrate mimetic peptide, D002 (RGGLCYCRYRYCVCVGR), bound a number of lectins with different specificities. Although this peptide reacted strongly with both lotus and concanavalin A (ConA) lectins, it bound to lotus stronger than ConA. By varying the central motif RYRY, five versions were produced in multiple antigen peptide format, and their avidity for lotus and ConA lectins was tested by surface plasmon resonance. Although the kinetic parameters were similar, the version based on the sequence YPYRY had an optimal affinity for both lectins as well as improved avidity for wheat germ agglutinin and phytohemagglutinin. Thus, as far as lectin specificity is concerned, YPYRY had improved multiple antigenic properties. Both RYRY and YPYRY precipitated antibodies from human IgG for intravenous use that bound to gp120 in vitro and immunoprecipitated gp120 from transfected CHO-PI cells. Thus, Y(P/R)Y motifs mimic multiple carbohydrate epitopes, many of which are found on HIV, and preimmune human IgG antibodies that bind to HIV carbohydrates cross-react to a comparable extent with both RYRY and YPYRY carbohydrate mimetic peptides.Glycosylation accounts for roughly 50% of the molecular mass of the major envelope (Env) 2 protein of human immunodeficiency virus type 1 (HIV-1) (1). In its native quaternary conformation Env exposes mostly its glycosylated surface. The latter represents a diverse array of glycans, dominated by N-linked structures (high mannose, complex, or hybrid structures) and sialosyl residues (2-4). Early observations that lectins and carbohydrate-reactive antibodies inhibit virus entry into cells (5-9) highlight the potential importance of targeting Env-associated glycans in vaccine strategies. This notion is further supported by the existence of a human neutralizing monoclonal antibody 2G12 with protective activity against viral challenge in animal models (10), which binds a virus-specific conformational epitope in the cluster of oligomannose glycans of gp120 Env (11).Such an antibody response could be a viable strategy for a vaccine if it could induce broadly reactive anti-HIV responses (12). However, targeting a set of carbohydrate structures as diverse and variable as the ones found on Env of HIV maybe daunting. It will require a multivalent vaccine approach to induce antibodies with polyreactivity for the diverse glycoforms of Env (13-15). An alternative approach to induce polyreactive antibodies is based upon carbohydrate mimetic peptides (16). Using peptide mimics of carbohydrates as immunogens offers the possibility of ...

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“…Epitope mapping of the polyclonal antibodies in the sera of immunized animals is used as a tool for discovering the antigenic moieties of pathogens, and it provides important information for the development of vaccines (18)(19)(20)(21)(22)). Yet, the few studies that have sought to map the polyclonal response toward ricin have used only RTA as the immunogenic entity (23,24).…”

mentioning

confidence: 99%

Characterization and Epitope Mapping of the Polyclonal Antibody Repertoire Elicited by Ricin Holotoxin-Based Vaccination

Cohen¹,

Mechaly²,

Sabo³

et al. 2014

Clin. Vaccine Immunol.

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Ricin, one of the most potent and lethal toxins known, is classified by the Centers for Disease Control and Prevention (CDC) as a select agent. Currently, there is no available antidote against ricin exposure, and the most promising therapy is based on neutralizing antibodies elicited by active vaccination or that are given passively. The aim of this study was to characterize the repertoire of anti-ricin antibodies generated in rabbits immunized with ricin toxoid. These anti-ricin antibodies exhibit an exceptionally high avidity (thiocyanate-based avidity index, 9 M) toward ricin and an apparent affinity of 1 nM. Utilizing a novel tissue culture-based assay that enables the determination of ricin activity within a short time period, we found that the anti-ricin antibodies also possess a very high neutralizing titer. In line with these findings, these antibodies conferred mice with full protection against pulmonary ricinosis when administered as a passive vaccination. Epitope mapping analysis using phage display random peptide libraries revealed that the polyclonal serum contains four immunodominant epitopes, three of which are located on the A subunit and one on the B subunit of ricin. Only two of the four epitopes were found to have a significant role in ricin neutralization. To the best of our knowledge, this is the first work that characterizes these immunological aspects of the polyclonal response to ricin holotoxin-based vaccination. These findings provide useful information and a possible strategy for the development and design of an improved ricin holotoxin-based vaccine. R icin, derived from the plant Ricinus communis, is one of the most lethal toxins known. The toxin consists of two covalently linked subunits: the A subunit (RTA) is an N-glycosidase that irreversibly inactivates the 28S rRNA of the mammalian 60S ribosome subunit, and the B subunit (RTB) is a galactose-specific lectin that mediates the binding of the toxin to the cell membrane (1). The high toxicity, availability, and ease of production and dissemination of ricin render it an attractive tool for bioterrorism, and ricin was therefore classified as a category B select agent by the Centers for Disease Control and Prevention (CDC). Currently, there is no available antidote against ricin exposure, underlining the need to develop effective countermeasures. Numerous efforts have been made to identify small molecules that inhibit the catalytic activity of RTA (2, 3) in order to develop aptamers or sugar analogs that prevent the binding of ricin to the cell membrane (4, 5) or to inhibit the intracellular trafficking of the toxin (6). While several of these studies demonstrated an inhibitory effect of ricin activity in vitro, they were not as effective in vivo. To date, the most promising antiricin therapy is based on neutralizing antibodies elicited by active vaccination or that are given passively. Over a decade ago, several research programs were initiated that aimed to develop an effective RTA-based vaccine (7). However, the prophylactic immun...

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Antigenic Properties of Peptide Mimotopes of HIV-1-associated Carbohydrate Antigens

Cited by 25 publications

References 32 publications

Generation of biologically active linear and cyclic peptides has revealed a unique fine specificity of rituximab and its possible cross-reactivity with acid sphingomyelinase-like phosphodiesterase 3b precursor

Generation of biologically active linear and cyclic peptides has revealed a unique fine specificity of rituximab and its possible cross-reactivity with acid sphingomyelinase-like phosphodiesterase 3b precursor

Multiple Antigenic Mimotopes of HIV Carbohydrate Antigens

Characterization and Epitope Mapping of the Polyclonal Antibody Repertoire Elicited by Ricin Holotoxin-Based Vaccination

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