Immunologic Research

, 17:95 | Cite as

Peptide mimotopes of carbohydrate antigens

  • Thomas Kieber-Emmons


Carbohydrate structures have been identified as significant antigens for bacterial, viral, and fungal pathogens as well as targets on human tumor cells. Many of these antigens are poorly immunogenic in humans, requiring extensive adjuvant sublimation. Although conjugate carbohydrate vaccines appear promising, there are limitations of using carbohydrate formulations. An alternative approach is to use surrogate antigens for some carbohydrates. We are developing peptides that mimic carbohydrates which might be further manipulated to induce responses that target biologically important carbohydrates expressed on pathogens and on tumor cells. We have shown that peptide mimotopes of carbohydrates induce immune responses to carbohydrate structures with in vivo and vitro functionality. Model systems include the Neisseria group C meningococcal polysaccharide; the histo-blood group-related antigens expressed on tumor cells; and mannose, sialyl, and histo-blood group-related carbohydrate epitopes expressed on human immunodeficiency virus.

Key words

Peptide mimotopes Carbohydrate antigens Lewis Y Vaccine Adjuvants 


  1. 1.
    Hakomori S: Aberrant glycosylation in tumors and tumorassociated carbohydrate antigens. Adv Cancer Res 1989;52:257–331.PubMedGoogle Scholar
  2. 2.
    Hakomori S: Possible functions of tumor-associated carbohydrate antigens. Curr Opinion Immunol 1991;3:646–653.CrossRefGoogle Scholar
  3. 3.
    Mond JJ, Lees A, Snapper CM: T cell-independent antigens type 2 [Review]. Annu Rev Immunol 1995;13(655):655–692.PubMedCrossRefGoogle Scholar
  4. 4.
    Zhang S, Walberg LA, Ogata S, Itzkowitz SH, Koganty RR, Reddish M, Gandhi SS, Longenecker BM, Lloyd KO, Livingston PO: Immune sera and monoclonal antibodies define two configurations for the sialyl Tn tumor antigen. Cancer Res 1995;55(15):3364–3368.PubMedGoogle Scholar
  5. 5.
    Livingston PO: Approaches to augmenting the immunogenicity of melanoma gangliosides: from whole melanoma cells to ganglioside-KLH conjugate vaccines. [Review]. Immunol Rev 1995; 145(147):147–166.PubMedCrossRefGoogle Scholar
  6. 6.
    Westerink MA, Apicella MA: Antiidiotypic antibodies as vaccines against carbohydrate antigens [Review]. Springer Semin Immunopathol 1993;15(2-3):227–234.PubMedCrossRefGoogle Scholar
  7. 7.
    Berzofsky JA: Antigenic peptide interaction with MHC molecules: implications for the design of artificial vaccines [Review]. Semin Immunol 1991;3(4):203–16.PubMedGoogle Scholar
  8. 8.
    Westerink MAJ, Giardina PC, Apicella MA, Kieber-Emmons T: Peptide mimicry of the meningococcal group C capsular polysaccharide. Proc Natl Acad Sci USA 1995;92:4021–4025.PubMedCrossRefGoogle Scholar
  9. 9.
    Kieber-Emmons T, Luo P, Agadjanyan M, Hutchins W, Westreink M, Steplewski Z: Peptide mimicry of tumor associated carbohydrate antigens. Hybridoma 1996;16:3–10.Google Scholar
  10. 10.
    Agadjanyan M, Lou P, Westerink MAJ, Carey LA, Hutchins W, Steplewski Z, et al.: Peptide mimicry of carbohydrate epitopes on human immunodeficiency virus. Nat Biotechnol 1997;15:547–551.PubMedCrossRefGoogle Scholar
  11. 11.
    Saleh MN, Stapleton JD, Khazaeli MB, LoBuglio AF: Generation of a human anti-idiotypic antibody that mimics the GD2 antigen. J Immunol 1993;151(6):3390–3398.PubMedGoogle Scholar
  12. 12.
    Hoess R, Brinkmann U, Handel T, Pastan I: Identification of a peptide which binds to the carbohydrate-specific monoclonal antibody B3. Gene 1993;128(1):43–49.PubMedCrossRefGoogle Scholar
  13. 13.
    Scott JK, Loganathan D, Easley RB, Gong X, Goldstein IJ: A family of concanavalin A-binding peptides from a hexapeptide epitope library. Proc Natl Acad Sci USA 1992;89(12): 5398–5402.PubMedCrossRefGoogle Scholar
  14. 14.
    Oldenburg KR, Loganathan D, Goldstein IJ, Schultz PG, Gallop MA: Peptide ligands for a sugar-binding protein isolated from a random peptide library. Proc Natl Acad Sci USA 1992;89(12):5393–5397.PubMedCrossRefGoogle Scholar
  15. 15.
    Thurin-Blaszczyk M, Murali R, Westerink MAJ, Steplewski Z, Co M-S, Kieber-Emmons T: Molecular recognition of the Lewis Y antigen by monoclonal antibodies. Protein Engin 1996;9:101–113.CrossRefGoogle Scholar
  16. 16.
    Yamada N, Chung YS, Maeda K, Sawada T, Ikehara T, Nishino H, Okuno M, Sowa M: Increased expression of sialyl Lewis A and sialyl Lewis X in liver metastases of human colorectal carcinoma. Invasion & Metastasis 1995;15(3-4):95–102.Google Scholar
  17. 17.
    Ikeda Y, Mori M, Kajiyama K, Haraguchi Y, Sasaki O, Sugimachi K: Immunohistochemical expression of sialyl Tn, sialyl Lewis a, sialyl Lewis a-b-, and sialyl Lewis x in primary tumor and metastatic lymph nodes in human gastric cancer. J Sur Oncol 1996;62(3):171–176.CrossRefGoogle Scholar
  18. 18.
    Dennis JW, Laferte S: Oncodevelopmental expression of Glc NAcb 1,6 Mana l,6 Manal-branched asparagine-linked oligosaccharides in murine tissues and human breast carcinoma. Cancer Res 1989;49: 945–950.PubMedGoogle Scholar
  19. 19.
    Hiraizumi S, Takasaki S, Ochuchi N, Harada Y, Nose M, Mori S, et al.: Altered glycosylation of membrane glycoproteins associated with human mammary carcinoma. Jpn J Cancer Res 1992;83:1063–1072.PubMedGoogle Scholar
  20. 20.
    MacLean GD, Reddish M, Koganty RR, Wong T, Gandhi S, Smolenski M, et al.: Immunization of breast cancer patients using a synthetic sialyl-Tn glycoconjugate plus Detox adjuvant. Cancer Immunol Immunother 1993;36(4):215–222.PubMedCrossRefGoogle Scholar
  21. 21.
    Springer GF, Desai PR, Tegtmeyer H, Carlstedt SC, Scanion EF: T/Tn antigen vaccine is effective and safe in preventing recurrence of advanced human breast carcinoma. Cancer Biother 1994;9(1):7–15.PubMedGoogle Scholar
  22. 22.
    Toyokuni T, Hakomori S, Singhal AK: Synthetic carbohydrate vaccines: synthesis and immunogenicity of Tn antigen conjugates. Bioorganic Med Chem 1994;2(11):1119–1132.CrossRefGoogle Scholar
  23. 23.
    Bremer EG, Levery SB, Sonnino S, Ghidoni R, Canevari S, Kannagi R, et al.: Characterization of a glycosphingolipid antigen defined by the monoclonal antibody MBR1 expressed in normal and neoplastic epithelial cells of human mammary gland. J Biol Chem 1984;259: 14, 773–14,777.Google Scholar
  24. 24.
    Nakagoe T, Fukushima K, Hirota M, Kusano H, Kawahara K, Ayabe H, et al.: Immunohistochemical expression of blood group substances and related carbohydrate antigens in breast carcinoma. Jpn J Cancer Res 1991;82:559–568.PubMedGoogle Scholar
  25. 25.
    Hoff SD, Matsushita Y, Ota DM, Cleary KR, Yamori T, Hakomori S, et al.: Increased expression of sialyl-dimeric LeX antigen in liver metastases of human colorectal carcinoma. Cancer Res 1989;49 (24Pt1):6883–6888.PubMedGoogle Scholar
  26. 26.
    Hoff SD, Irimura T, Matsushita Y, Ota DM, Cleary KR, Hakomori S: Metastatic potential of colon carcinoma. Expression of ABO/ Lewis-related antigens. Arch Surg 1990;125(2):206–209.PubMedGoogle Scholar
  27. 27.
    Blaszczyk-Thurin M, Thurin J, Hindsgaul O, Karlsson KA, Steplewski Z, Koprowski H: Y and blood group B type 2 glycolipid antigens accumulate in a human gastric carcinoma cell line as detected by monoclonal antibody. Isolation and characterization by mass spectrometry and NMR spectroscopy. J Biol Chem 1987;262(l):372–379.PubMedGoogle Scholar
  28. 28.
    Rodeck U, Herlyn M, Leander K, Borlinghaus P, Koprowski H: A mucin containing the X, Y, and H type 2 carbohydrate determinants is shed by carcinoma cells. Hybridoma 1987;6:389–401.PubMedGoogle Scholar
  29. 29.
    Miyake M, Taki T, Hitomi S, Hakomori S: The correlation of expression of H/Ley/Leb antigens with survival of patients with carcinoma of the lung. Biochemistry 1992;327:14–18.Google Scholar
  30. 30.
    Shimizu T, Yonezawa S, Tanaka S, Sato E: Expression of Lewis X-related antigens in adenocarcinomas of lung. Histopathology 1993;22(6):549–555.PubMedCrossRefGoogle Scholar
  31. 31.
    Sun J, Thurin J, Cooper HS, Wang P, Mackiewicz M, Steplewski Z, et al.: Elevated expression of H type GDP-L-fucose:beta-D-galactoside alpha-2-L-fucosyltransferase is associated with human colon adenocarcinoma progression. Proc Natl Acad Sci USA 1995;92(12):5724–5728.PubMedCrossRefGoogle Scholar
  32. 32.
    Yazawa S, Nakamura J, Asao T, Nagamachi Y, Sagi M, Matta KL, et al.: Aberrant alpha 1→2 fucosyltransferases found in human colorectal carcinoma involved in the accumulation of Leb and Y antigens in colorectal tumors. Jpn J Cancer Res 1993;84(9):989–995.PubMedGoogle Scholar
  33. 33.
    Livingston PO: Construction of cancer vaccines with carbohydrate and protein (peptide) tumor antigens [Review]. Curr Opinion Immunol 1992;4(5):624–629.CrossRefGoogle Scholar
  34. 34.
    Livingston PO, Calves MJ, Helling F, Zollanger WD, Blake MS, Lowell GH: GD3/proteosome vaccines induce consistent IgM antibodies against the gangiioside GD3. Vaccine 1993;11(12):1199–1204.PubMedCrossRefGoogle Scholar
  35. 35.
    Livingston PO, Adluri S, Helling F, Yao TJ, Kensil CR, Newman MJ, Marciani D: Phase 1 trial of immunological adjuvant QS-21 with a GM2 ganglioside-keyhole limpet haemocyanin conjugate vaccine in patients with malignant melanoma. Vaccine 1994;12(14): 1275–1280.PubMedCrossRefGoogle Scholar
  36. 36.
    Longenecker BM, Reddish M, Koganty R, MacLean GD: Immune responses of mice and human breast cancer patients following immunization with synthetic sialyl-Tn conjugated to KLH plus detox adjuvant. Ann NY Acad Sci 1993;690(276):276–291.PubMedCrossRefGoogle Scholar
  37. 37.
    Longenecker BM, Reddish M, Koganty R, MacLean GD: Specificity of the IgG response in mice and human breast cancer patients following immunization against synthetic sialyl-Tn, an epitope with possible functional significance in metastasis. Adv Exp Med Biol 1994;353(105):105–124.PubMedGoogle Scholar
  38. 38.
    Ravindranath MH, Morton DL: Role of gangliosides in active immunotherapy with melanoma vaccine [Review]. Int Rev Immunol 1991;7(4):303–329.PubMedCrossRefGoogle Scholar
  39. 39.
    Helling F, Shang A, Calves M, Zhang S, Ren S, Yur K, et al.: GD3 vaccines for melanoma: superior immunogenicity of keyhole limpet hemocyanin conjugate vaccines. Cancer Res 1994;54(1): 197–203.PubMedGoogle Scholar
  40. 40.
    Helling F, Zhang S, Shang A, Adluri S, Calves M, Koganty R, et al.: GM2-KLH conjugate vaccine: increased immunogenicity in melanoma patients after administration with immunological adjuvant QS-21. Cancer Res 1995;55 (13):2783–2788.PubMedGoogle Scholar
  41. 41.
    Kitamura K, Livingston PO, Fortunato SR, Stocken E, Helling F, Ritter G, et al.: Serological response patterns of melanoma patients immunized with a GM2 gangiioside conjugate vaccine. Proc Natl Acad Sci USA 1995; 92(7):2805–2809.PubMedCrossRefGoogle Scholar
  42. 42.
    Adluri S, Helling F, Ogata S, Zhang S, Itzkowski SH, Lloyd KO, et al.: Immunogenicity of synthetic TF-KLH (keyhole limpet hemocyanin) and sTn-KLH conjugates in colorectal carcinoma patients. Cancer Immunol Immunother 1995;41(3):185–192.PubMedCrossRefGoogle Scholar
  43. 43.
    Kitamura K, Stocken E, Garin CP, Chesa P, Welt S, Lloyd KO, et al.: Specificity analysis of blood group Lewis-y (Le(y)) antibodies generatedagainst synthetic and natural Le(y) determinants. Proc Natl Acad Sci USA 1994;91(26):12,957-12,961.CrossRefGoogle Scholar
  44. 44.
    Kieber-Emmons T, Ward RE, Raychaudhuri S, Rein R, Kohler H: Rational design and application of idiotope vaccines. Int Rev Immunol 1986;1(1):1–26.PubMedCrossRefGoogle Scholar
  45. 45.
    Diakun KR, Matta KL: Synthetic antigens as immunogens: Part III. Specificity analysis of an antianti-idiotypic antibody to a carbohydrate tumor-associated antigen. J Immunol 1989;142(6): 2037–2040.PubMedGoogle Scholar
  46. 46.
    Sugiyama T, Imai K, Ono A, et al.: Conformational structure of a monoclonal anti-idiotypic antibody to the monoclonal antiadenocarcinoma-associated carbohydrate antibody YH206. J Immunol 1991;146(9):3097–3101.PubMedGoogle Scholar
  47. 47.
    Cheung NK, Cheung IY, Canete A, Yeh SJ, Kushner B, Bonilla MA, et al.: Antibody response to murine anti-GD2 monoclonal antibodies: correlation with patient survival. Cancer Res 1994;54(8):2228–2233.PubMedGoogle Scholar
  48. 48.
    Zanetti M, Lenert G, Springer GF: Idiotypes of pre-existing human anti-carcinoma anti-T and anti-Tn antibodies. Int Immunol 1993; 5(2):113–119.PubMedCrossRefGoogle Scholar
  49. 49.
    Schmolling J, Reinsberg J, Wagner U, Krebs D: Antiidiotypic antibodies in ovarian cancer patients treated with the monoclonal antibody B72.3. Hybridoma 1995;14(2):183–186.PubMedGoogle Scholar
  50. 50.
    Fagerberg J, Frodin JE, Ragnhammar P, Steinitz M, Wigzell H, Mellstedt H: Induction of an immune network cascade in cancer patients treated with monoclonal antibodies (ab1). II. Is induction of anti-idiotype reactive T-cells (T3) of importance for tumor response to mAb therapy? Cancer Immunol Immunother 1994;38(3):149–159.PubMedGoogle Scholar
  51. 51.
    Fagerberg J, Hjelm AL, Ragnhammar P, Frodin JE, Wigzell H, Mellstedt H: Tumor regression in monoclonal antibodytreated patients correlates with the presence of anti-idiotypereactive T lymphocytes. Cancer Res 1995;55(9):1824–1827.PubMedGoogle Scholar
  52. 52.
    Fagerberg J, Steinitz M, Wigzell H, Askelof P, Mellstedt H: Human anti-idiotypic antibodies induced a humoral and cellular immune response against a colorectal carcinoma-associated antigen in patients. Proc Natl Acad Sci USA 1995;92(11):4773–4777.PubMedCrossRefGoogle Scholar
  53. 53.
    Ioannides CG, Freedman RS: T-cell responses to ovarian tumor vaccines: identification and significance for future immunotherapy [Review]. Int Rev Immunol 1991;7(4):349–364.PubMedCrossRefGoogle Scholar
  54. 54.
    Tsuyuoka K, Yago K, Hirashima K, Ando S, Hanai N, Saito H, et al.: Characterization of a T-cell line specific to an anti-Id antibody related to the carbohydrate antigen, sialyl ssea-1, and the immunodominant T-cell antigenic site of the antibody. J Immunol 1996;157:661–669.PubMedGoogle Scholar
  55. 55.
    Apostolopoulos V, McKenzie IF: Cellular mucins: targets for immunotherapy [Review]. Crit Rev Immunol 1994;14(3,4):293–309.PubMedGoogle Scholar
  56. 56.
    Shattil SJ, Weisel JW, Kieber-Emmons T: Use of monoclonal antibodies to study the interaction between an integrin adhesion receptor, GPIIa-IIIb, and its physiological ligand, fibrinogen. Immun Meth 1993;l:53–63.Google Scholar
  57. 57.
    Prammer KV, Boyer J, Ugen K, Shattil SJ, Kieber-Emmons T: Bioactive Arg-Gly-Asp conformations in anti-integrin GPiibiiia antibodies. Receptor 1994; 4:93–108.PubMedGoogle Scholar
  58. 58.
    Hansen JE, Clausen H, Hu SL, Nielsen JO, Olofsson S: An O-linked carbohydrate neutralization epitopeof HIV-1 gp l20 is expressed by HIV-1 env gene recombinant vaccinia virus. Arch Virol 1992;126(l-4):11–20.PubMedCrossRefGoogle Scholar
  59. 59.
    Hansen JE, Nielsen C, Arendrup M, Olofsson S, Mathiesen L, Nielsen J, et al.: Broadly neutralizing antibodies targeted to mucintype carbohydrate epitopes of human immunodeficiency virus. J Virol 1991;65(12):6461–6467.PubMedGoogle Scholar
  60. 60.
    Bernstein HB, Tucker SP, Hunter E, Schutzbach JS, Compans RW: Human immunodeficiency virus type 1 envelope glycoprotein is modified by O-linked oligosaccharides. J Virol 1994;68(1):463–468.PubMedGoogle Scholar
  61. 61.
    Adachi M, Hayami M, Kashiwagi N, Mizuta T, Ohta Y, Gill MJ, et al.: Expression of LeY antigen in human immunodeficiency virusinfected human T-cell lines and in peripheral lymphocytes of patients with acquired immune deficiency syndrome (AIDS) and AIDS-related complex (ARC). J Exp Med 1988;167:323–331.PubMedCrossRefGoogle Scholar
  62. 62.
    Lefebvre JC, Giordanengo V, Doglio A, Cagnon L, Breittmayer JP, Peyron JF, et al.: Altered sialylation of CD45 in HIV-1 -infected T lymphocytes. Virology 1994; 199(2):265–274.PubMedCrossRefGoogle Scholar
  63. 63.
    Arendrup M, Hansen JE, Clausen H, Nielsen C, Mathiesen LR, Nielsen JO: Antibody to histoblood group A antigen neutralizes HIV produced by lymphocytes from blood group A donors but not from blood group B or O donors. AIDS 1991;5(4):441–444.PubMedCrossRefGoogle Scholar
  64. 64.
    Gattegno L, Ramdani A, Jouault T, Saffar L, Gluckman JC: Lectincarbohydrate interactions and infectivity of human immunodeficiency virus type 1 (HIV-1). AIDS Res Hum Retroviruses 1992;8(l):27–37.PubMedCrossRefGoogle Scholar
  65. 65.
    Hansen JE, Sorensen AM, Arendrup M, Olofsson S, Nielson, JO, Janzek E, et al.: Enhancement of retroviral infection in vitro by anti-Le(y) IgG: reversal by humanization of monoclonal mouse antibody. Apmis 1993;101(9):711–718.PubMedCrossRefGoogle Scholar
  66. 66.
    Furukawa K, Akagi T, Nagata Y, Yamada Y, Shimotohno K, Cheung N, et al.: GD2 ganglioside on human T-lymphotropic virus type I-infected T-cells: possible activation of beta-l,4-N-acetylgalactosaminyltransferase gene by p40tax. Proc Natl Acad Sci USA 1993;90(5): 1972–1976.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 1998

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory MedicineUniversity of PennsylvaniaPhiladelphia

Personalised recommendations