Combined synthetic and recombinant techniques for the development of lipoprotein-based, self-adjuvanting vaccines targeting human papillomavirus type-16 associated tumors

Peter M Moyle; Wei Dai; Tzu-Yu Liu; Waleed M Hussein; Pirashanthini Maruthayanar; James W Wells; Nigel A J McMillan; Mariusz Skwarczynski; Istvan Toth

doi:10.1016/j.bmcl.2015.10.049

Combined synthetic and recombinant techniques for the development of lipoprotein-based, self-adjuvanting vaccines targeting human papillomavirus type-16 associated tumors

Bioorg Med Chem Lett. 2015 Dec 1;25(23):5570-5. doi: 10.1016/j.bmcl.2015.10.049. Epub 2015 Oct 19.

Authors

Peter M Moyle¹, Wei Dai², Tzu-Yu Liu², Waleed M Hussein³, Pirashanthini Maruthayanar⁴, James W Wells⁴, Nigel A J McMillan⁵, Mariusz Skwarczynski², Istvan Toth⁶

Affiliations

¹ School of Pharmacy, The University of Queensland, 20 Cornwall St, Woolloongabba, QLD 4102, Australia. Electronic address: [email protected].
² School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia.
³ 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, Ein Helwan, Helwan, Egypt.
⁴ The University of Queensland Diamantina Institute, Translational Research Institute (TRI), Woolloongabba, QLD 4102, Australia.
⁵ Griffith Health Institute and School of Medical Sciences, Griffith University, Southport, QLD 4222, Australia.
⁶ School of Pharmacy, The University of Queensland, 20 Cornwall St, Woolloongabba, QLD 4102, Australia; 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.

PMID: 26514746
DOI: 10.1016/j.bmcl.2015.10.049

Abstract

Human papillomaviruses (HPVs) are associated with various cancers, with HPV16 linked to more than half of cervical cancer cases. Vaccines to prevent HPV infection and cancer development have proven effective, but are not useful in individuals with prior HPV exposure. Treatment vaccines to eradicate or control HPV-associated lesions are therefore desirable for these patients. Herein we describe the development of a process to enable the production of semisynthetic vaccines based on the site-specific attachment of synthetic bacterial lipid analogs (e.g., Pam2Cys) to a non-oncogenic mutant HPV16 E7 protein to generate molecularly defined vaccines. Many cytotoxic lymphocyte (CTL) epitopes from E7 are delivered by this approach; potentially ensuring that large numbers of immunized individuals can generate CTLs to clear HPV infected cells. Delivery of this construct reduced the growth of HPV16-associated tumors in a TC1 mouse model, the effects of which were better than the potent CTL epitope HPV16 E7(44-57) administered with Montanide ISA51 adjuvant.

Keywords: Cancer; Human papillomavirus; Pam2Cys; Protein engineering; Vaccine.

MeSH terms

Adjuvants, Immunologic / chemical synthesis
Adjuvants, Immunologic / therapeutic use*
Amino Acid Sequence
Animals
Cancer Vaccines / chemical synthesis
Cancer Vaccines / therapeutic use*
Chemistry Techniques, Synthetic
Electrophoresis, Polyacrylamide Gel
Female
Humans
Lipopeptides / chemical synthesis
Lipopeptides / chemistry*
Lipopeptides / genetics
Mice
Molecular Sequence Data
Neoplasms / drug therapy*
Papillomavirus E7 Proteins / drug effects*
Papillomavirus Infections / therapy*
Recombinant Proteins* / chemistry
Recombinant Proteins* / genetics

Substances

Adjuvants, Immunologic
Cancer Vaccines
Lipopeptides
Papillomavirus E7 Proteins
Recombinant Proteins
oncogene protein E7, Human papillomavirus type 16