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Vaccination with carbohydrate peptide mimotopes promotes anti-tumor responses

Nature Biotechnology volume 17, pages 660–665 (1999)Cite this article

Abstract

Tumor-associated carbohydrate (TAC) antigens are important targets in cancer vaccine efforts. Carbohydrates are, however, frequently poor immunogens, in that they are T-cell–independent antigens. Molecular mimicry of TAC by peptides is an alternative approach to generating anti-carbohydrate immune responses. Here we demonstrate that peptide mimotopes can elicit antibody responses that cross-react with representative human TAC antigens. Primary immunization with such a multiple antigenic peptide, along with QS-21 as adjuvant, elicits cytotoxic antibodies reactive with naturally occurring forms of TAC expressed on tumor cells, and vaccination of mice with peptide mimotopes reduced tumor growth and prolonged host survival in a murine tumor model.

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Figure 1: Serum binding to synthetic LeY and sLeX.
Figure 2: Complement-dependent cytotoxicity (CDC) assay.
Figure 3: Priming responses to peptide mimotopes.
Figure 4: Tumor growth of peptide-immunized mice.

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References

  1. Hakomori, S. Aberrant glycosylation in tumors and tumor-associated carbohydrate antigens. Adv. Cancer Rres. 52, 257– 331 (1989).

    Article  CAS  Google Scholar 

  2. Livingston, P.O. & Ragupathi, G. Carbohydrate vaccines that induce antibodies against cancer. 2. Previous experience and future plans. Cancer Immunol. Immunother. 45, 10–19 (1997).

    Article  CAS  Google Scholar 

  3. Mond, J.J., Lees, A. & Snapper, C.M. T cell-independent antigens type 2. [Review]. Annu. Rev. Immunol. 13, 655–692 (1995).

    Article  CAS  Google Scholar 

  4. Livingston, P.O., Zhang, S. & Lloyd, K.O. Carbohydrate vaccines that induce antibodies against cancer. 1. Rationale. Cancer Immunol., Immunother. 45, 1–9 (1997).

    Article  CAS  Google Scholar 

  5. Chapman, P.B. Anti-idiotypic monoclonal antibody cancer vaccines. Semin. Cancer Biol. 6, 367–374 ( 1995).

    Article  CAS  Google Scholar 

  6. Hoess, R., Brinkmann, U., Handel, T. & Pastan, I. Identification of a peptide which binds to the carbohydrate-specific monoclonal antibody B3. Gene 128, 43– 49 (1993).

    Article  CAS  Google Scholar 

  7. Luo, P. et al. Antigenic and immunological mimicry of peptide mimotopes of adenocarcinoma associated carbohydrate antigens. Mol. Immunol. 13, 865–879 (1998).

    Article  Google Scholar 

  8. Qiu, J., Luo, P., Wasmund, K., Steplewski, Z. & Kieber-Emmons, T. Towards the development of peptide mimotopes of carbohydrate antigens as cancer vaccines. Hybridoma 18, 103–112 (1999).

    Article  CAS  Google Scholar 

  9. Taki, T., Ishikawa, D., Hamasaki, H. & Handa, S. Preparation of peptides which mimic glycosphingolipids by using phage peptide library and their modulation on beta-galactosidase activity. FEBS Lett. 418, 219–223 ( 1997).

    Article  CAS  Google Scholar 

  10. Oldenburg, K.R., Loganathan, D., Goldstein, I.J., Schultz, P.G. & Gallop, M.A. Peptide ligands for a sugar-binding protein isolated from a random peptide library. Proc. Natl. Acad. Sci. USA 89, 5393–5397 ( 1992).

    Article  CAS  Google Scholar 

  11. Scott, J.K., Loganathan, D., Easley, R.B., Gong, X. & Goldstein, I.J. A family of concanavalin A-binding peptides from a hexapeptide epitope library. Proc. Natl. Acad. Sci. USA 89, 5398–5402 ( 1992).

    Article  CAS  Google Scholar 

  12. Murai, H. et al. Amino acid sequence of protein alpha-amylase inhibitor from Streptomyces griseosporeus YM-25. J. Biochem. 97 , 1129–1133 (1985).

    Article  CAS  Google Scholar 

  13. Westerink, M.A.J., Giardina, P.C., Apicella, M.A. & Kieber-Emmons, T. Peptide mimicry of the meningococcal group C capsular polysaccharide. Proc. Natl. Acad. Sci. USA 92, 4021– 4025 (1995).

    Article  CAS  Google Scholar 

  14. Imberty, A. et al. Computer simulation of histo-blood group oligosaccharides: energy maps of all constituting disaccharides and potential energy surfaces of 14 ABH and Lewis carbohydrate antigens. Glycoconjugate J. 12, 331–349 (1995).

    Article  CAS  Google Scholar 

  15. Agadjanyan, M. et al. Peptide mimicry of carbohydrate epitopes on human immunodeficiency virus. Nat. Biotechnol. 15, 547– 551 (1997).

    Article  CAS  Google Scholar 

  16. Fehr, T. et al. Role of repetitive antigen patterns for induction of antibodies against antibodies. J. Exp. Med. 185, 1785 –1792 (1997).

    Article  CAS  Google Scholar 

  17. Zhang, S. et al. Immune sera and monoclonal antibodies define two configurations for the sialyl Tn tumor antigen. Cancer Res. 55, 3364–3368 (1995).

    CAS  PubMed  Google Scholar 

  18. Kudryashov, V. et al. Immunogenicity of synthetic conjugates of Lewis(y) oligosaccharide with proteins in mice: towards the design of anticancer vaccines. Cancer Immunol. Immunother. 45, 281– 286 (1998).

    Article  CAS  Google Scholar 

  19. Steplewski, Z. et al. Tumor cell lysis and tumor growth inhibition by the isotype variants of MAb BR55-2 directed against Y oligosaccharide. In Vivo 5, 79–83 (1991 ).

    CAS  PubMed  Google Scholar 

  20. Noguchi, Y., Richards, E.C., Chen, Y.T. & Old, L.J. Influence of interleukin 12 on p53 peptide vaccination against established Meth A sarcoma. Proc. Natl. Acad. Sci..USA 92, 2219–2223 (1995).

    Article  CAS  Google Scholar 

  21. Jiao, Y. & Fujimoto, S. Sequential T cell response involved in tumor rejection of sarcoma, Meth A, in syngeneic mice. Jpn. J. Cancer Res. 89, 657–665 (1998).

    Article  CAS  Google Scholar 

  22. Tsuyuoka, K. 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. 157, 661–669 (1996).

    CAS  PubMed  Google Scholar 

  23. Helling, F. et al. GM2-KLH conjugate vaccine: increased immunogenicity in melanoma patients after administration with immunological adjuvant QS-21. Cancer Res. 55, 2783–2788 (1995).

    CAS  PubMed  Google Scholar 

  24. Kitamura, K. et al. Serological response patterns of melanoma patients immunized with a GM2 ganglioside conjugate vaccine. Proc. Natl. Acad. Sci. USA 92, 2805–2809 ( 1995).

    Article  CAS  Google Scholar 

  25. Longenecker, B.M., Reddish, M., Koganty, R. & MacLean, G.D. 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. 353, 105–124 (1994).

    Article  CAS  Google Scholar 

  26. Jones, R.C. et al. Immune response to polyvalent melanoma cell vaccine in AJCC stage III melanoma: an immunologic survival model. Ann. Surg. Oncol. 3, 437–445 ( 1996).

    Article  CAS  Google Scholar 

  27. Pantel, K. et al. Frequency and prognostic significance of isolated tumour cells in bone marrow of patients with non-small-cell lung cancer without overt metastases. Lancet 347, 649–653 (1996).

    Article  CAS  Google Scholar 

  28. Houghton, A.N. & Lloyd, K.O. Stuck in the MUC on the long and winding road. Nat. Med. 4, 270–271 (1998).

    Article  CAS  Google Scholar 

  29. Ravindranath, M.H. et al. Ratio of IgG:IgM antibodies to sialyl Lewis(x) and GM3 correlates with tumor growth after immunization with melanoma-cell vaccine with different adjuvants in mice. Int. J. Cancer 75 , 117–124 (1998).

    Article  CAS  Google Scholar 

  30. Putterman, C. & Diamond, B. Immunization with a peptide surrogate for double-stranded DNA (dsDNA) induces autoantibody production and renal immunoglobulin deposition. J. Exp. Med. 188, 29–38 (1998).

    Article  CAS  Google Scholar 

  31. Frassanito, M.A. et al. Identification of Meth A sarcoma-derived class I major histocompatibility complex-associated peptides recognized by a specific CD8+ cytotoxic T lymphocyte. Cancer Res. 55, 124–128 (1995).

    CAS  PubMed  Google Scholar 

  32. Abdel, M.U. et al. Immunization with glycosylated Kb-binding peptides generates carbohydrate-specific, unrestricted cytotoxic T cells. Eur. J. Immunol. 26, 544–551 ( 1996).

    Article  Google Scholar 

  33. Bohm, C.M. et al. Carbohydrate recognition on MUC1-expressing targets enhances cytotoxicity of a T cell subpopulation. Scand. J. Immunol. 46, 27–34 (1997).

    Article  CAS  Google Scholar 

  34. Dabelsteen, E. Cell surface carbohydrates as prognostic markers in human carcinomas. [Review] [141 refs]. J. Pathol. 179, 358– 369 (1996).

    Article  CAS  Google Scholar 

  35. Ravindranath, M.H. et al. Endothelial-selectin ligands sialyl Lewis(x) and sialyl Lewis(a) are differentiation antigens immunogenic in human melanoma. Cancer 79, 1686–1697 ( 1997).

    Article  CAS  Google Scholar 

  36. Zhang, S. et al. Selection of tumor antigens as targets for immune attack using immunohistochemistry: II. Blood group-related antigens. Int. J. Cancer 73, 50–56 ( 1997).

    Article  CAS  Google Scholar 

  37. Livingston, P.O. Approaches to augmenting the immunogenicity of melanoma gangliosides: from whole melanoma cells to ganglioside–KLH conjugate vaccines. [Review]. Immunol. Rev. 145, 147– 166 (1995).

    Article  CAS  Google Scholar 

  38. Kitamura, K. et al. Specificity analysis of blood group Lewis-y (Le(y)) antibodies generatedagainst synthetic and natural Le(y) determinants. Proc. Natl. Acad. Sci. USA 91, 12957–12961 (1994).

    Article  CAS  Google Scholar 

  39. Adluri, S. et al. Immunogenicity of synthetic TF-KLH (keyhole limpet hemocyanin) and sTn-KLH conjugates in colorectal carcinoma patients. Cancer Immunol. Immunother. 41, 185–192 (1995).

    Article  CAS  Google Scholar 

  40. Phalipon, A. et al. Induction of anti-carbohydrate antibodies by phage library-selected peptide mimics. Eur. J. Immunol. 27, 2620 –2625 (1997).

    Article  CAS  Google Scholar 

  41. Harris, S.L. et al. Exploring the basis of peptide–carbohydrate crossreactivity: evidence for discrimination by peptides between closely related anti-carbohydrate antibodies. Proc. Natl. Acad. Sci. USA 94, 2454–2459 (1997).

    Article  CAS  Google Scholar 

  42. Pincus, S.H., Smith, M.J., Jennings, H.J., Burritt, J.B. & Glee, P.M. Peptides that mimic the group B streptococcal type III capsular polysaccharide antigen. J. Immunol. 160, 293–298 (1998).

    CAS  PubMed  Google Scholar 

  43. Valadon, P., Nussbaum, G., Boyd, L.F., Margulies, D.H. & Scharff, M.D. Peptide libraries define the fine specificity of anti-polysaccharide antibodies to Cryptococcus neoformans. J. Mol. Biol. 261, 11–22 (1996).

    Article  CAS  Google Scholar 

  44. Zhang, H., Zhong, Z. & Pirofski, L.A. Peptide epitopes recognized by a human anti-cryptococcal glucuronoxylomannan antibody. Infect. Immun. 65, 1158–1164 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Ishikawa, D. et al. GD1α-replica peptides functionally mimic GD1α, an adhesion molecule of metastatic tumor cells, and suppress the tumor metastasis. FEBS Lett. 441, 20–24 (1998).

    Article  CAS  Google Scholar 

  46. Kundu, N., Beaty, T.L., Jackson, M.J. & Fulton, A.M. Antimetastatic and antitumor activities of interleukin 10 in a murine model of breast cancer. J. Natl. Cancer Inst. 88, 536–541 (1996).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the USAMRMC (DAMD17-94-J-4310) Breast Cancer Program (T.K.E.) and NIH grant AI 45133 (T.K.E.). We thank Charlotte Read Kensil of Aquila Pharmaceuticals (Worcester, MA.) for supplying the QS-21. We also thank Dr. A. DeLeo (University of Pittsburgh) for the Meth A cell line and Dr. A Fulton (University of Maryland Cancer Center) for the murine breast lines.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, 19104, PA.

    Thomas Kieber-Emmons, Ping Luo, Jianping Qiu & Tylis Y. Chang

  2. The Wistar Institute, Philadelphia, 19104, PA

    Insug O & Magdalena Blaszczyk-Thurin

  3. Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, 19104, PA

    Zenon Steplewski

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Correspondence to Thomas Kieber-Emmons.

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Kieber-Emmons, T., Luo, P., Qiu, J. et al. Vaccination with carbohydrate peptide mimotopes promotes anti-tumor responses . Nat Biotechnol 17, 660–665 (1999). https://doi.org/10.1038/10870

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