J. Med. Microbiol. Ð Vol. 50 )2001), 937±939 # 2001 The Pathological Society of Great Britain and Ireland ISSN 0022-2615

EDITORIAL

Mimotope

Many microbial pathogens and tumour cells evade elicited an effective IgG response against the ganglio- immune surveillance by possessing polysaccharides or side. Small but favourable therapeutic responses were carbohydrates on their surfaces; this can lead to observed and further studies are required to determine severe disease and death of the host. This strategy is its ef®cacy. Peptide mimotopes have also been devel- effective because glycans are poorly immunogenic oped from amino acid sequences within the comple- and fail to elicit immunological memory responses mentarity determining region 3 )CDR 3) of anti- due to the absence of T-cell processing. However, [10]. successful vaccines that elicit protection in infants as well as adults against major bacterial pathogens, Recent advances in molecular techniques have made it including Haemophilus in¯uenzae [1], Neisseria possible for further developments to take place in this meningitidis serogroup C [2]and Streptococcus area. Peptide mimotopes have been identi®ed from pneumoniae [3]have been developed by conjugation libraries displaying random linear or structurally of the polysaccharide to a carrier protein. Some constrained peptides on the surface of coliphage by polysaccharides cannot be converted into effective direct interaction with antibodies of the required by conjugation, because of similarities to carbohydrate speci®city. These include mimotopes of host cell structures. The polysialic acid meningococ- bacterial carbohydrates [11±13], capsular polysacchar- cal group B capsular polysaccharide, for example, ides [14, 15]and HIV envelope glycoproteins [16]. appears to mimic sialylated on the surface of Furthermore, combinatorial solid-phase peptide lib- human cells [4]. Alternative outer-membrane bacterial raries have provided an alternative peptide approach carbohydrates such as lipopolysaccharides are also for the identi®cation of mimotopes [17]. toxic or may elicit autoimmune antibodies because they mimic human antigens. Molecular mimics Until recently the identi®cation of peptide mimics has )mimotopes) of immunogenic of carbo- been based empirically on either amino acid sequences hydrate antigens that do not include regions of host present in the CDR 3 regions of anti-idiotype anti- cell mimicry represent an attractive alternative that bodies, or by screening peptide libraries with mono- can avoid these problems yet induce protective clonal antibodies. Very little is understood about the . They can be produced relatively easily nature and degree of mimicry, and how these translate and cheaply, with the potential for production as into the immunological responses observed. To exploit polyvalent formulations. The use of surrogate antigens more rational approaches, recent studies have been as immunogens that substitute sugars with amino designed to elucidate this mimicry and to establish acids requires that their antigenic mimicry elicits a objective methods for predicting immunogenicity speci®c response to the nominal . Three levels [18, 19]. The development of a peptide that of molecular similarity may exist between antigen and mimics the immunogenic regions of meningococcal mimic that may or may not be inter-related; the lipo-oligosaccharide )LOS) has included the determina- conformation or three-dimensional structure, the tion of binding af®nities of peptide mimics to the binding con®guration to antibodies and other ligands, used for their identi®cation by real time and their immunogenicity. kinetic measurements on a resonant mirror biosensor [11, 18]and competition assays to determine the ef- The idiotype network hypothesis of Lindenmann [5] fectiveness of these mimics to compete with the and Jerne [6]provides an elegant approach to mim- nominal carbohydrate antibody in binding to the icking the structure of an antigen by an antibody. Structurally constrained peptide mimics of idiotypic determinant on the surface of an antibody. meningococcal LOS had higher binding af- Anti-idiotypic antibodies with surrogate images of ®nities than ¯exible, linear peptide mimics, and their carbohydrate antigens that can elicit immunological binding af®nities were directly correlated to their responses against carbohydrates have been described; ability to compete for binding with the nominal e.g., to capsular polysaccharides of N. meningitidis carbohydrate antigen [18]. Remarkably, structurally serogroup C [7]and to human tumour cells [8].Anti- constrained peptides had binding af®nities similar to idiotype antibodies of disialoganglioside have recently the nominal meningococcal antigen. Modi®cations to been used in clinical trials of patients with advanced the peptide mimic revealed that structural features of melanoma [9]. This antibody was minimally toxic and the peptides are critical for their antigenicity [18]. 938 EDITORIAL Solution structure analysis of the peptides is beginning structures have enormous potential as safe and cheap to reveal the details of the three-dimensional structure vaccine components. Their main applications are likely [20]. We postulate that the level of mimicry, as to include new vaccines for which capsular conjugates determined by binding and competition assays, would have failed, and for making mass vaccination pro- re¯ect their ability to elicit cross-reactive antibody grammes a reality for resource-limited developing responses to the nominal antigen. Using a more countries where the burden of infectious disease is empirical approach, c. 100 putative peptide mimics greatest. were tested for immunogenicity by immunising mice, but only two peptides were found to elicit cross- B. M. CHARALAMBOUS and I. M. FEAVERSÃ reactive antibodies to the nominal antigen [13]. Both Department of Medical Microbiology, Royal Free & University these peptides are likely to have a constrained three- College Medical School, University College London, Royal Free Campus, Rowland Hill, London NW3 2PF and dimensional structure, as they contained two internal ÃBacteriology Division National Institute for Biological cysteines that could form a disulphide bridge. Standardisation and Control Blanche Lane, Potters Bar, South Mimms, Herts. EN6 3QG The induction of a relevant anti-peptide immune Corresponding author: B. M. Charalambous response, a key issue for all peptide-based vaccination )e-mail: [email protected]) strategies, may prove to be a critical obstacle in the development of a mimotope vaccine. Also, the intensity References of immune response may be unpredictable among individuals of different HLA types. The immunogeni- 1. Deck MD, Edwards KM. Haemophilus in¯uenzae type b city of small peptides is invariably dependent upon T- vaccines: history, choice and comparisons. Pediatr Infect Dis J cell help [21], typically requiring conjugation to a 1998; 17 )9 Suppl): S113±S116. 2. Ramsay ME, Andrews N, Kaczmarski EB, Miller E. Ef®cacy carrier protein, and often needs to be enhanced by the of meningococcal serogroup C conjugate vaccine in teenagers co-administration of an adjuvant. By their nature, such and toddlers in England. Lancet 2001; 357: 195±196. modi®cations or formulations themselves have implica- 3. Goldblatt D. Recent developments in bacterial conjugate vaccines. J Med Microbiol 1998; 47: 563±567. tions for structural integrity of the peptide epitope. For 4. 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Infect Immun 1988; 56: 1120±1127. principle to be extended by genetically fusing and 8. Kieber-Emmons T, Luo P, Qiu J et al. Vaccination with expressing c. 270 peptide mimotopes to the coliphage carbohydrate peptide mimotopes promotes anti-tumor re- major coat protein pVIII on the surface of the sponses. Nat Biotechnol 1999; 17: 660±665. 9. Foon KA, Lutzky J, Baral RN et al. Clinical and immune ®lamentous coliphage fd [22]. responses in advanced melanoma patients immunized with an anti-idiotype antibody mimicking disialoganglioside GD2. A further problem may arise from the polyclonal nature J Clin Oncol 2000; 18: 376±384. 10. Hutchins WA, Kieber-Emmons T, Carlone GM, Westerink of the antibody response. Assuming that the peptide MAJ. Human immune response to a peptide mimic of antigen is likely to adopt multiple conformations, only Neisseria meningitidis serogroup C in hu-PBMC-SCID mice. one of which mimics the carbohydrate, then only a Hybridoma 1999; 18: 121±129. 11. Charalambous BM, Feavers IM. Peptide mimics elicit antibody subset of antibodies can be expected to cross-react with responses against the outer-membrane lipooligosaccharide of the nominal carbohydrate antigen. Thus one might group B Neisseria meningitidis FEMS Microbiol Lett 2000; predict that by constraining the peptides we would limit 191: 45±50. 12. Luo P, Canziani G, Cunto-Amesty G, Kieber-Emmons T. A the number of conformations that can be adopted and molecular basis for functional peptide mimicry of a carbo- this will improve the carbohydrate-speci®c humoral hydrate antigen. J Biol Chem 2000; 275: 16146±16154. response. This prediction is supported by evidence 13. Phalipon A, Folgori A, Arondel J et al. Induction of anti- carbohydrate antibodies by phage library-selected peptide from immunogenicity studies in which potentially con- mimics. Eur J Immunol 1997; 27: 2620±2625. strained peptides elicited a better cross-reactive anti- 14. Pincus SH, Smith MJ, Jennings HJ, Burritt JB, Glee PM. carbohydrate response [13]. Alternatively, peptide Peptides that mimic the group B streptococcal type III capsular polysaccharide antigen. J Immunol 1998; 160: 293±298. mimics might be used to prime the immune system 15. Moe GR, Tan S, Granoff DM. Molecular mimetics of to mount an effective response on subsequent exposure polysaccharide epitopes as vaccine candidates for prevention to the carbohydrate, but this possibility has not been of Neisseria meningitidis serogroup B disease. FEMS Immunol Med Microbiol 1999; 26: 209±226. tested experimentally. 16. Agadjanyan M, Luo P, Westerink MAJ et al. Peptide mimicry of carbohydrate epitopes on human immunode®ciency virus. We can expect that many of the problems associated Nat Biotechnol 1997; 15: 547±551. 17. Chargelegue D, Obeid OE, Hsu SC et al. A peptide mimic of with the use of peptides as effective immunogens can a protective epitope of respiratory syncytial virus selected from be overcome, thus peptide mimics of carbohydrate a combinatorial library induces virus-neutralizing antibodies EDITORIAL 939

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