Self-Adjuvanting Peptide Vaccines Against Cervical Cancer

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Authors

  • Hannah Hanh-Hong Truong School of Chemistry and Molecular Biosciences,The University of Queensland, St. Lucia, QLD 4072, Australia
  • Waleed M. Hussein School of Chemistry and Molecular Biosciences,The University of Queensland, St. Lucia, QLD 4072, Australia; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Helwan University, Helwan, Egypt
  • Tzu-Yu Liu School of Chemistry and Molecular Biosciences,The University of Queensland, St. Lucia, QLD 4072, Australia
  • Zhongfan Jia Australian Institute for Bioengineering and Nanotechnology,The University of Queensland, Brisbane, QLD 4072, Australia
  • James W. Wells The University of Queensland Diamantina Institute,The University of Queensland,Translational Research Institute, Brisbane, QLD 4072, Australia
  • Michael J. Monteiro Australian Institute for Bioengineering and Nanotechnology,The University of Queensland, Brisbane, QLD 4072, Australia
  • Mariusz Skwarczynski School of Chemistry and Molecular Biosciences,The University of Queensland, St. Lucia, QLD 4072, Australia
  • Istvan Toth School of Chemistry and Molecular Biosciences,The University of Queensland, St. Lucia, QLD 4072, Australia; Institute for Molecular Bioscience,The University of Queensland, St. Lucia, QLD 4072, Australia; School of Pharmacy,Woolloongabba,The University of Queensland, QLD 4072, Australia

DOI:

https://doi.org/10.17140/VROJ-4-114

Keywords:

Peptide-based subunit vaccine, Human papillomavirus, Polyglutamic acid, Therapeutic cancer vaccine, Polymer-peptide conjugate, Self-adjuvanting, Cervical cancer

Abstract

Background
Cervical cancer is a common cause of cancer-related deaths in women worldwide, with a fatality rate second only to breast cancer.
Human papillomaviruses (HPVs) are the main causative agents of cervical cancer, and are therefore obvious targets for vaccine
development. Although two prophylactic HPV vaccines have been commercialized, therapeutic vaccines against HPVs have not
been developed yet. Current vaccine technologies emphasize the power of small particles in targeting immune cells, and particles
of 20-50 nm have been reported to induce optimal immune responses against a variety of pathogens and cancers.
Methods
We synthesized new nanoparticle-based vaccines against cervical cancer by using antigenic 8Qmin peptide epitope derived from
HPV-16 E7 protein, a hydrophilic poly-(L-glutamic acid) (PGA) linker, and an 8-arm poly (tert-butyl acrylate) dendrimer-based
delivery system (D8).
Results
Four different peptides containing 8Qmin and PGA of different lengths were successfully synthesized with high yield and purity.
These were then conjugated to alkyne-functionalized D8 by copper-catalyzed alkyne-azide cycloaddition “click” reaction. The
conjugates self-assembled into nanoparticles, with decreased particle size corresponding to a greater number of Glu units. The
four vaccine candidates were tested in C57 black 6 (C57BL/6) mice bearing well-established (7-day-old) tumors to examine their
therapeutic effects.
Conclusion
Interestingly, only one conjugate delayed tumor growth, and montanide adjuvanted antigen, used as a positive control, failed to
demonstrate any therapeutic effect.

References

Burd EM. Human papillomavirus and cervical cancer. Clin Mi-crobiol Rev. 2003; 16(1): 1-17. doi: 10.1128/Cmr.16.1.1-17.2003

Cardone G, Moyer AL, Cheng NQ, et al. Maturation of the human papillomavirus 16 capsid. MBio. 2014; 5(4): 1-11. doi: 10.1128/mBio.01104-14

Chapman R, Soldan K, Jit M. Modelling borderline and mild dysplasia associated with HPV 6 and 11 infection. Vaccine. 2011; 29(16): 2881-2886. doi: 10.1016/j.vaccine.2011.02.008

Pinto LA, Castle PE, Roden RB, et al. HPV-16 L1 VLP vaccine elicits a broad-spectrum of cytokine responses in whole blood. Vac-cine. 2005; 23(27): 3555-3564. doi: 10.1016/j.vaccine.2005.01.146

Munoz, N, Bosch, FX, de Sanjose, S, et al. Epidemiologic clas-sification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003; 348(6): 518-527. doi: 10.1056/NEJ-Moa021641

Kirby T. FDA approves new upgraded Gardasil 9. Lancet Oncol. 2015; 16(2): e56-e56. doi: 10.1016/S1470-2045(14)71191-X

Liu TY, Hussein WM, Toth I, Skwarczynski M. Advances in pep-tide-based human papillomavirus therapeutic vaccines. Curr Top Med Chem. 2012; 12(14): 1581-1592. doi: 10.2174/156802612802652402

Purcell AW, McCluskey J, Rossjohn J. More than one reason to rethink the use of peptides in vaccine design. Nat Rev Drug Discov. 2007; 6(5): 404-414. doi: 10.1038/nrd2224

Khongkow M, Liu T-Y, Bartlett S, et al. Liposomal formula-tion of polyacrylate-peptide conjugate as a new vaccine candidate against cervical cancer. Prec Nanomed. 2018; 1(3): 186-196. doi:

33218/prnano1(3).181003.1 10. Hussein WM, Liu TY, Maruthayanar P, et al. Double conju-gation strategy to incorporate lipid adjuvants into multiantigenic vaccines. Chem Sci. 2016; 7(3): 2308-2321. doi: 10.1039/c5sc03859f

Hussein WM, Liu TY, Jia ZF, et al. Multiantigenic peptide-polymer conjugates as therapeutic vaccines against cervical can-cer. Bioorgan Med Chem. 2016; 24(18): 4372-4380. doi: 10.1016/j. bmc.2016.07.036

Liu TY, Hussein WM, Giddam AK, et al. Polyacrylate-based delivery system for self-adjuvanting anticancer peptide vaccine. J Med Chem. 2015; 58(2): 888-896. doi: 10.1021/jm501514h

Liu TY, Giddam AK, Hussein WM, et al. Self-adjuvanting therapeutic peptide-based vaccine induce CD8(+) cytotoxic T Lymphocyte responses in a murine human papillomavirus tumor model. Curr Drug Delivery. 2015; 12(1): 3-8. doi: 10.2174/15672018

Liu TY, Hussein WM, Jia Z, et al. Self-adjuvanting polymer-peptide conjugates as therapeutic vaccine candidates against cervi-cal cancer. Biomacromolecules. 2013; 14(8): 2798-2806. doi: 10.1021/ bm400626w

Skwarczynski M, Toth I. Recent advances in peptide-based subunit nanovaccines. Nanomedicine (Lond). 2014; 9(17): 2657-2669. doi: 10.2217/Nnm.14.187

Skwarczynski M, Zaman M, Urbani CN, et al. Polyacrylate den-drimer nanoparticles: A self-adjuvanting vaccine delivery system. Angew Chem Int Ed Engl. 2010; 49(33): 5742-5745. doi: 10.1002/ anie.201002221

Ahmad Fuaad AA, Jia Z, Zaman M, et al. Polymer-peptide hy-brids as a highly immunogenic single-dose nanovaccine. Nanomedi-cine (Lond). 2014; 9(1): 35-43. doi: 10.2217/nnm.13.7

Zaman M, Skwarczynski M, Malcolm JM, et al. Self-adjuvant-ing polyacrylic nanoparticulate delivery system for group A strep-tococcus (GAS) vaccine. Nanomedicine. 2011; 7(2): 168-173. doi: 10.1016/j.nano.2010.10.002

Chandrudu, S, Bartlett, S, Khalil, ZG, et al. Linear and branched polyacrylates as a delivery platform for peptide-based vaccines. Ther Deliv. 2016; 7(9): 601-609. doi: 10.4155/tde-2016-0037

Zhao, GZ, Chandrudu, S, Skwarczynski, M, Toth I. The ap-plication of self-assembled nanostructures in peptide-based sub-unit vaccine development. Eur Polym J. 2017; 93: 670-681. doi: 10.1016/j.eurpolymj.2017.02.014

Hilgers LA, Ghenne L, Nicolas I, Fochesato M, Lejeune G, Boon B. Alkyl-polyacrylate esters are strong mucosal adjuvants. Vaccine. 2000; 18(28): 3319-3325. doi: S0264-410X(00)00114-6

Hilgers LA, Nicolas I, Lejeune G, Dewil E, Strebelle M, Boon B. Alkyl-esters of polyacrylic acid as vaccine adjuvants. Vaccine. 1998; 16(16): 1575-1581. doi: S0264410X98000474 28 Hussein WM et al

Leak LV. Studies on the permeability of lymphatic capillaries. J Cell Bio. 1971; 50(2): 300-323. doi: 10.1083/jcb.50.2.300

Manolova V, Flace A, Bauer M, Schwarz K, Saudan P, Bach-mann MF. Nanoparticles target distinct dendritic cell populations according to their size. Eur J Immunol. 2008; 38(5): 1404-1413. doi: 10.1002/eji.200737984

Li YL, Ma ZL, Zhao Y, Zhang J. Immunization with mutant HPV16 E7 protein inhibits the growth of TC-1 cells in tumor-bearing mice. Oncol Lett. 2015; 9(4): 1851-1856. doi: 10.3892/ ol.2015.2911

Munger K, Phelps WC, Bubb V, Howley PM, Schlegel R. The E6-gene and E7-gene of the human papillomavirus type-16 to-gether are necessary and sufficient for transformation of primary human keratinocytes. J Virol. 1989; 63(10): 4417-4421.

Greenhalgh K, Turos E. In vivo studies of polyacrylate nanoparticle emulsions for topical and systemic applications. Nano-medicine. 2009; 5(1): 46-54. doi: 10.1016/j.nano.2008.07.004

Zaman M, Simerska P, Toth I. Synthetic polyacrylate polymers as particulate intranasal vaccine delivery systems for the induction of mucosal immune response. Curr Drug Deliv. 2010; 7(2): 118-124. doi: 10.2174/156720110791011846

Stanley MA. Progress in prophylactic and therapeutic vaccines for human papillomavirus infection. Expert Rev Vaccines. 2003; 2(3): 381-389. doi: 10.1586/14760584.2.3.381

Zwaveling S, Ferreira Mota SC, Nouta J, et al. Established hu-man papillomavirus type 16-expressing tumors are effectively erad-icated following vaccination with long peptides. J Immunol. 2002; 169(1): 350-358. doi: 10.4049/jimmunol.169.1.350

Chu NR, Wu HB, Wu TC, et al. Immunotherapy of a human papillomavirus (HPV) type 16 E7-expressing tumour by adminis-tration of fusion protein comprising Mycobacterium bovis bacille Calmette-Guerin (BCG) hsp65 and HPV16 E7. Clin Exp Immunol. 2000; 121(2): 216-225. doi: 10.1046/j.1365-2249.2000.01293.x

Hariharan K, Braslawsky G, Barnett RS, et al. Tumor regres-sion in mice following vaccination with human papillomavirus E7 recombinant protein in PROVAX. Int J Oncol. 1998; 12(6): 1229- 1235. doi: 10.3892/ijo.12.6.1229

Cui ZG, Han SJ, Huang L. Coating of mannan on LPD par-ticles containing HPV E7 peptide significantly enhances immunity against HPV-positive tumor. Pharm Res. 2004; 21(6): 1018-1025. doi: 10.1023/B:PHAM.0000029292.66792.4f

Daftarian PM, Mansour M, Pohajdak B, et al. Rejection of large HPV-16 expressing tumors in aged mice by a single immunization of VacciMax encapsulated CTL/T helper peptides. J Transl Med. 2007; 5: 26. doi: 10.1186/1479-5876-5-26 Original Research | Volume 1 | Number 1|

Wu CY, Monie A, Pang X, Hung CF, Wu TC. Improving thera-peutic HPV peptide-based vaccine potency by enhancing CD4+ T help and dendritic cell activation. J Biomed Sci. 2010; 17: 88. doi: 10.1186/1423-0127-17-88

Bergot AS, Durgeau A, Levacher B, Colombo BM, Cohen JL, Klatzmann D. Antigen quality determines the efficiency of anti-tumor immune responses generated in the absence of regulato-ry T cells. Cancer Gene Ther. 2010; 17(9): 645-654. doi: 10.1038/ cgt.2010.21

Shimizu, J, Yamazaki, S, Sakaguchi, S Induction of tumor im-munity by removing CD25(+)CD4(+) T cells: A common basis between tumor immunity and autoimmunity. J Immunol. 1999; 163(10): 5211-5218.

Hoffmann C, Stanke J, Kaufmann AM, Loddenkemper C, Schneider A, Cichon G. Combining T-cell vaccination and appli-Submit your article to this journal | https://openventio.org/submit-manuscript/ Original Research | Volume 4 | Number 1| Hussein WM et al cation of agonistic Anti-GITR mAb (DTA-1) induces complete eradication of HPV oncogene expressing tumors in mice. J Immu-nother. 2010; 33(2): 136-145. doi: 10.1097/CJI.0b013e3181badc46

Loddenkemper, C, Hoffmann, C, Stanke, J, et al. Regulatory (FOXP3(+)) T cells as target for immune therapy of cervical in-traepithelial neoplasia and cervical cancer. Cancer Sci. 2009; 100(6): 1112-1117. doi: 10.1111/j.1349-7006.2009.01153.x

Chuang CM, Hoory T, Monie A, Wu A, Wang MC, Hung CF. Enhancing therapeutic HPV DNA vaccine potency through deple-tion of CD4(+)CD25(+) T regulatory cells. Vaccine. 2009; 27(5): 684-689. doi: 10.1016/j.vaccine.2008.11.042

Piersma SJ. Immunosuppressive tumor microenvironment in cervical cancer patients. Cancer Microenviron. 2011; 4(3): 361-375. doi: 10.1007/s12307-011-0066-7

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Published

2019-08-27

How to Cite

Hannah Hanh-Hong Truong, Waleed M. Hussein, Tzu-Yu Liu, Zhongfan Jia, James W. Wells, Michael J. Monteiro, … Istvan Toth. (2019). Self-Adjuvanting Peptide Vaccines Against Cervical Cancer. Vaccination Research, 4(1), 21–29. https://doi.org/10.17140/VROJ-4-114

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Vol. 4 No. 1 (2019): Volume 4 Issue 1 2019

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