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Increased Efficacy of NKT Cell-Adjuvanted Peptide Vaccines Through Chemical Conjugation

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Book cover Coupling and Decoupling of Diverse Molecular Units in Glycosciences

Abstract

Through vaccination infectious diseases such as smallpox, polio, measles, and tetanus have either been eradicated or significantly restricted. However, there remain many diseases for which no effective vaccine exists, and therefore new vaccine approaches are still needed. Current vaccine approaches that generate strong immune responses are often based on ill-defined immunogens such as heat-killed or live-attenuated biological products that suffer from concerns related to safety, stability, and lengthy or complex manufacturing processes. For these reasons, there is a strong push toward vaccines that elicit immune responses to defined structures within the targeted pathogen or tissue, which can be achieved by injecting defined antigenic proteins or peptides. On their own, proteins or peptides are generally poorly immunogenic and they must be combined with immune stimulants known as adjuvants to drive antigen-specific immune responses. Recent studies have shown that the direct conjugation of adjuvant compounds to protein or peptide antigens can enhance the magnitude and quality of induced immune responses. In this chapter, we will discuss the chemical approaches our group has used to synthesize a new class of vaccines based on conjugation of peptides with lipid structures that activate innate-like T cells. The stimulatory milieu created by these structures helps drive potent T cell-mediated immune responses that can prevent infectious disease, or can act therapeutically in noncommunicable conditions as diverse as cancer and allergy.

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References

  1. van Rijt LS, Jung S, Kleinjan A, Vos N, Willart M, Duez C, Hoogsteden HC, Lambrecht BN (2005) In vivo depletion of lung CD11c + dendritic cells during allergen challenge abrogates the characteristic features of asthma. J Exp Med 201(6):981–991. doi:10.1084/jem.20042311

    Article  Google Scholar 

  2. Silverman E (2012) Can we afford the war on cancer? Biotechnol Healthc 9(4):13–16

    Google Scholar 

  3. Jones LH (2015) Recent advances in the molecular design of synthetic vaccines. Nat Chem 7(12):952–960. doi:10.1038/nchem.2396

    Article  CAS  Google Scholar 

  4. Reed SG, Orr MT, Fox CB (2013) Key roles of adjuvants in modern vaccines. Nat Med 19(12):1597–1608. doi:10.1038/nm.3409

    Article  CAS  Google Scholar 

  5. Zom GG, Khan S, Britten CM, Sommandas V, Camps MG, Loof NM, Budden CF, Meeuwenoord NJ, Filippov DV, van der Marel GA, Overkleeft HS, Melief CJ, Ossendorp F (2014) Efficient induction of antitumor immunity by synthetic toll-like receptor ligand-peptide conjugates. Cancer Immunol Res 2(8):756–764. doi:10.1158/2326-6066.CIR-13-0223

    Article  CAS  Google Scholar 

  6. Ingale S, Wolfert MA, Gaekwad J, Buskas T, Boons GJ (2007) Robust immune responses elicited by a fully synthetic three-component vaccine. Nat Chem Biol 3(10):663–667. doi:10.1038/nchembio.2007.25

    Article  CAS  Google Scholar 

  7. Zom GG, Filippov DV, van der Marel GA, Overkleeft HS, Melief CJ, Ossendorp F (2014) Two in one: improving synthetic long peptide vaccines by combining antigen and adjuvant in one molecule. Oncoimmunology 3(7):e947892. doi:10.4161/21624011.2014.947892

    Article  Google Scholar 

  8. Wright TH, Brooks AES, Didsbury AJ, MacIntosh JD, Williams GM, Harris PWR, Dunbar PR, Brimble MA (2013) Direct peptide lipidation through thiol-ene coupling enables rapid synthesis and evaluation of self-adjuvanting vaccine candidates (vol 52, pg 10616. Angew Chem Int Edit 52(45):11686. doi:10.1002/anie.201305620

    Article  CAS  Google Scholar 

  9. Khan S, Bijker MS, Weterings JJ, Tanke HJ, Adema GJ, van Hall T, Drijfhout JW, Melief CJM, Overkleeft HS, van der Marel GA, Filippov DV, van der Burg SH, Ossendorp F (2007) Distinct uptake mechanisms but similar intracellular processing of two different Toll-like receptor ligand-peptide conjugates in dendritic cells. J Biol Chem 282(29):21145–21159. doi:10.1074/jbc.M701705200

    Article  CAS  Google Scholar 

  10. Vecchi S, Bufali S, Uno T, Wu T, Arcidiacono L, Filippini S, Rigat F, O’Hagan D (2014) Conjugation of a TLR7 agonist and antigen enhances protection in the S. pneumoniae murine infection model. Eur J Pharm Biopharm 87(2):310–317. doi:10.1016/j.ejpb.2014.01.002

    Article  CAS  Google Scholar 

  11. Jackson DC, Lau YF, Le T, Suhrbier A, Deliyannis G, Cheers C, Smith C, Zeng WG, Brown LE (2004) A totally synthetic vaccine of generic structure that targets Toll-like receptor 2 on dendritic cells and promotes antibody or cytotoxic T cell responses. Proc Natl Acad Sci USA 101(43):15440–15445. doi:10.1073/pnas.0406740101

    Article  CAS  Google Scholar 

  12. Oh JZ, Kedl RM (2010) The capacity to induce cross-presentation dictates the success of a TLR7 agonist-conjugate vaccine for eliciting cellular immunity. J Immunol 185(8):4602–4608. doi:10.4049/jimmunol.1001892

    Article  CAS  Google Scholar 

  13. Tighe H, Takabayashi K, Schwartz D, Marsden R, Beck L, Corbeil J, Richman DD, Eiden JJ Jr, Spiegelberg HL, Raz E (2000) Conjugation of protein to immunostimulatory DNA results in a rapid, long-lasting and potent induction of cell-mediated and humoral immunity. Eur J Immunol 30(7):1939–1947. doi:10.1002/1521-4141(200007)30:7<1939:AID-IMMU1939>3.0.CO;2-#

    Article  CAS  Google Scholar 

  14. Hermans IF, Silk JD, Gileadi U, Salio M, Mathew B, Ritter G, Schmidt R, Harris AL, Old L, Cerundolo V (2003) NKT cells enhance CD4 + and CD8 + T cell responses to soluble antigen in vivo through direct interaction with dendritic cells. J Immunol 171(10):5140–5147

    Article  CAS  Google Scholar 

  15. Banchet-Cadeddu A, Henon E, Dauchez M, Renault JH, Monneaux F, Haudrechy A (2011) The stimulating adventure of KRN 7000. Org Biomol Chem 9(9):3080–3104. doi:10.1039/c0ob00975j

    Article  CAS  Google Scholar 

  16. Morita M, Motoki K, Akimoto K, Natori T, Sakai T, Sawa E, Yamaji K, Koezuka Y, Kobayashi E, Fukushima H (1995) Structure-activity relationship of alpha-galactosylceramides against B16-bearing mice. J Med Chem 38(12):2176–2187

    Article  CAS  Google Scholar 

  17. Borg NA, Wun KS, Kjer-Nielsen L, Wilce MC, Pellicci DG, Koh R, Besra GS, Bharadwaj M, Godfrey DI, McCluskey J, Rossjohn J (2007) CD1d-lipid-antigen recognition by the semi-invariant NKT T-cell receptor. Nature 448(7149):44–49. doi:10.1038/nature05907

    Article  CAS  Google Scholar 

  18. Hermans IF, Silk JD, Gileadi U, Masri SH, Shepherd D, Farrand KJ, Salio M, Cerundolo V (2007) Dendritic cell function can be modulated through cooperative actions of TLR ligands and invariant NKT cells. J Immunol 178(5):2721–2729

    Article  CAS  Google Scholar 

  19. Li X, Fujio M, Imamura M, Wu D, Vasan S, Wong CH, Ho DD, Tsuji M (2010) Design of a potent CD1d-binding NKT cell ligand as a vaccine adjuvant. Proc Natl Acad Sci USA 107(29):13010–13015. doi:10.1073/pnas.1006662107

    Article  CAS  Google Scholar 

  20. Tefit JN, Crabe S, Orlandini B, Nell H, Bendelac A, Deng SL, Savage PB, Teyton L, Serra V (2014) Efficacy of ABX196, a new NKT agonist, in prophylactic human vaccination. Vaccine 32(46):6138–6145. doi:10.1016/j.vaccine.2014.08.070

    Article  CAS  Google Scholar 

  21. Giaccone G, Punt CJ, Ando Y, Ruijter R, Nishi N, Peters M, von Blomberg BM, Scheper RJ, van der Vliet HJ, van den Eertwegh AJ, Roelvink M, Beijnen J, Zwierzina H, Pinedo HM (2002) A phase I study of the natural killer T-cell ligand alpha-galactosylceramide (KRN7000) in patients with solid tumors. Clin Cancer Res Official J Am Assoc Cancer Res 8(12):3702–3709

    CAS  Google Scholar 

  22. Liu Y, Goff RD, Zhou D, Mattner J, Sullivan BA, Khurana A, Cantu C 3rd, Ravkov EV, Ibegbu CC, Altman JD, Teyton L, Bendelac A, Savage PB (2006) A modified alpha-galactosyl ceramide for staining and stimulating natural killer T cells. J Immunol Methods 312(1–2):34–39. doi:10.1016/j.jim.2006.02.009

    Article  CAS  Google Scholar 

  23. Zhou XT, Forestier C, Goff RD, Li C, Teyton L, Bendelac A, Savage PB (2002) Synthesis and NKT cell stimulating properties of fluorophore- and biotin-appended 6″-amino-6″-deoxy-galactosylceramides. Org Lett 4(8):1267–1270

    Article  CAS  Google Scholar 

  24. Pauwels N, Aspeslagh S, Vanhoenacker G, Sandra K, Yu ED, Zajonc DM, Elewaut D, Linclau B, Van Calenbergh S (2011) Divergent synthetic approach to 6’’-modified alpha-GalCer analogues. Org Biomol Chem 9(24):8413–8421. doi:10.1039/c1ob06235b

    Article  CAS  Google Scholar 

  25. Du W, Kulkarni SS, Gervay-Hague J (2007) Efficient, one-pot syntheses of biologically active alpha-linked glycolipids. Chem Commun 23:2336–2338. doi:10.1039/b702551c

    Article  Google Scholar 

  26. Anderson RJ, Tang CW, Daniels NJ, Compton BJ, Hayman CM, Johnston KA, Knight DA, Gasser O, Poyntz HC, Ferguson PM, Larsen DS, Ronchese F, Painter GF, Hermans IF (2014) A self-adjuvanting vaccine induces cytotoxic T lymphocytes that suppress allergy. Nat Chem Biol 10(11):943–949. doi:10.1038/Nchembio.1640

    Article  CAS  Google Scholar 

  27. Bertozzi CR (2011) A decade of bioorthogonal chemistry. Acc Chem Res 44(9):651–653. doi:10.1021/ar200193f

    Article  CAS  Google Scholar 

  28. Sun XC, Zeckner DJ, Current WL, Boyer R, McMillian C, Yumibe N, Chen SH (2001) N-Acyloxymethyl carbamate linked prodrugs of pseudomycins are novel antifungal agents. Bioorg Med Chem Lett 11(14):1875–1879. doi:10.1016/S0960-894x(01)00333-X

    Article  CAS  Google Scholar 

  29. Dinkel C, Moody M, Traynor-Kaplan A, Schultz C (2001) Membrane-Permeant 3-OH-Phosphorylated Phosphoinositide Derivatives. Angew Chem Int Ed Engl 40(16):3004–3008. doi:10.1002/1521-3773(20010817)40:16<3004:AID-ANIE3004>3.0.CO;2-O

    Article  CAS  Google Scholar 

  30. Ulrich S, Boturyn D, Marra A, Renaudet O, Dumy P (2014) Oxime ligation: a chemoselective click-type reaction for accessing multifunctional biomolecular constructs. Chem-Eur J 20(1):34–41. doi:10.1002/chem.201302426

    Article  CAS  Google Scholar 

  31. Wills-Karp M (1999) Immunologic basis of antigen-induced airway hyperresponsiveness. Annu Rev Immunol 17:255–281. doi:10.1146/annurev.immunol.17.1.255

    Article  CAS  Google Scholar 

  32. Wells JW, Cowled CJ, Giorgini A, Kemeny DM, Noble A (2007) Regulation of allergic airway inflammation by class I-restricted allergen presentation and CD8 T-cell infiltration. J Allergy Clin Immunol 119(1):226–234. doi:10.1016/j.jaci.2006.09.004

    Article  CAS  Google Scholar 

  33. Perez HL, Cardarelli PM, Deshpande S, Gangwar S, Schroeder GM, Vite GD, Borzilleri RM (2014) Antibody-drug conjugates: current status and future directions. Drug Discov Today 19(7):869–881. doi:10.1016/j.drudis.2013.11.004

    Article  CAS  Google Scholar 

  34. Anderson RJ, Compton BJ, Tang CW, Authier-Hall A, Hayman CM, Swinerd GW, Kowalczyk R, Harris P, Brimble MA, Larsen DS, Gasser O, Weinkove R, Hermans IF, Painter GF (2015) NKT cell-dependent glycolipid-peptide vaccines with potent anti-tumour activity. Chem Sci 6(9):5120–5127. doi:10.1039/c4sc03599b

    Article  CAS  Google Scholar 

  35. Yang M, Yang Y, Chen PR (2016) Transition-metal-catalyzed bioorthogonal cycloaddition reactions. Top Curr Chem 374(1):1–29. doi:10.1007/s41061-015-0001-3

    Article  Google Scholar 

  36. Godfrey DI, Hammond KJ, Poulton LD, Smyth MJ, Baxter AG (2000) NKT cells: facts, functions and fallacies. Immunol Today 21(11):573–583

    Article  CAS  Google Scholar 

  37. Weinkove R, Brooks CR, Carter JM, Hermans IF, Ronchese F (2013) Functional invariant natural killer T-cell and CD1d axis in chronic lymphocytic leukemia: implications for immunotherapy. Haematologica 98(3):376–384. doi:10.3324/haematol.2012.072835

    Article  CAS  Google Scholar 

  38. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M (2013) Nivolumab plus ipilimumab in advanced melanoma. N Eng J Med 369(2):122–133. doi:10.1056/NEJMoa1302369

    Article  CAS  Google Scholar 

  39. Beatty PL, Finn OJ (2013) Preventing cancer by targeting abnormally expressed self-antigens: MUC1 vaccines for prevention of epithelial adenocarcinomas. Ann N Y Acad Sci 1284. doi:10.1111/nyas.12108

  40. van der Burg SH, Arens R, Ossendorp F, van Hall T, Melief CJ (2016) Vaccines for established cancer: overcoming the challenges posed by immune evasion. Nat Rev Cancer 16(4):219–233. doi:10.1038/nrc.2016.16

    Article  Google Scholar 

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Correspondence to Colin M. Hayman .

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Hayman, C.M., Hermans, I.F., Painter, G.F. (2018). Increased Efficacy of NKT Cell-Adjuvanted Peptide Vaccines Through Chemical Conjugation. In: Witczak, Z., Bielski, R. (eds) Coupling and Decoupling of Diverse Molecular Units in Glycosciences. Springer, Cham. https://doi.org/10.1007/978-3-319-65587-1_14

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