title: Synthesis and evaluation of monophosphoryl lipid A derivatives as fully synthetic self-adjuvanting glycoconjugate cancer vaccine carriers.
abstract: A fully synthetic carbohydrate-based cancer vaccine is an attractive concept, but an important topic in the area is to develop proper vaccine carriers that can improve the immunogenicity and other immunological properties of tumor-associated carbohydrate antigens (TACAs). In this context, four monophosphoryl derivatives of Neisseria meningitidis lipid A were synthesized via a highly convergent and effective strategy and evaluated as vaccine carriers and adjuvants. The conjugates of these monophosphoryl lipid A (MPLA) derivatives with a modified form of the sTn antigen were found to elicit high titers of antigen-specific IgG antibodies, indicating a T cell-dependent immune response, in the absence of an external adjuvant. It was concluded that MPLAs could be utilized as potent vaccine carriers and built-in adjuvants to create fully synthetic self-adjuvanting carbohydrate-based cancer vaccines. The lipid composition and structure of MPLA were shown to have a significant influence on its immunological activity, and among the MPLAs examined, natural N. meningitidis MPLA exhibited the most promising properties. Moreover, Titermax Gold, a conventional vaccine adjuvant, was shown to inhibit, rather than promote, the immunological activity of MPLA conjugates, maybe via interacting with MPLA.
authors.affiliation: Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202, USA. zwguo@chem.wayne.edu.
authors.forename: Zhifang
authors.initials: Z
authors.lastname: Zhou
authors.forename: Mohabul
authors.initials: M
authors.lastname: Mondal
authors.forename: Guochao
authors.initials: G
authors.lastname: Liao
authors.forename: Zhongwu
authors.initials: Z
authors.lastname: Guo
mesh_terms: D000276:Adjuvants, Immunologic / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000276:immunology; D019496:Cancer Vaccines / Q000138:chemical synthesis* / Q000737:chemistry / Q000276:immunology*; D004337:Drug Carriers / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D006001:Glycoconjugates / Q000276:immunology*; D007106:Immune Sera; D008050:Lipid A / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology; D051379:Mice; D009343:Neisseria; D014614:Vaccines, Synthetic / Q000276:immunology*
chemical_list: C533688:5'-N-phenylacetyl siayl Tn antigen; D000276:Adjuvants, Immunologic; D015295:Antigens, Tumor-Associated, Carbohydrate; D019496:Cancer Vaccines; D004337:Drug Carriers; D006001:Glycoconjugates; D007106:Immune Sera; D008050:Lipid A; D014614:Vaccines, Synthetic; C048436:monophosphoryl lipid A
references.citation: Chemistry. 2004 Oct 4;10(19):4798-807
references.pmid: 15372693
references.citation: Carbohydr Res. 2003 Jan 2;338(1):47-54
references.pmid: 12504380
references.citation: Rev Infect Dis. 1984 Jul-Aug;6(4):439-43
references.pmid: 6474003
references.citation: Carbohydr Res. 2000 Mar 10;324(4):225-30
references.pmid: 10744331
references.citation: J Biochem. 1986 Apr;99(4):1203-10
references.pmid: 2423510
references.citation: Angew Chem Int Ed Engl. 2005 Sep 19;44(37):5985-8
references.pmid: 16108081
references.citation: FASEB J. 1994 Feb;8(2):217-25
references.pmid: 8119492
references.citation: Proc Natl Acad Sci U S A. 2012 Jan 3;109(1):261-6
references.pmid: 22171012
references.citation: ACS Chem Biol. 2012 Jan 20;7(1):235-40
references.pmid: 22013921
references.citation: Microbes Infect. 2002 Jul;4(8):837-51
references.pmid: 12270731
references.citation: J Med Chem. 2012 Aug 9;55(15):6968-74
references.pmid: 22800462
references.citation: Bioconjug Chem. 2006 Nov-Dec;17(6):1537-44
references.pmid: 17105234
references.citation: J Am Chem Soc. 2003 May 21;125(20):6103-12
references.pmid: 12785841
references.citation: J Med Chem. 2005 Feb 10;48(3):875-83
references.pmid: 15689172
references.citation: J Med Chem. 1999 Nov 4;42(22):4640-9
references.pmid: 10579826
references.citation: Immunol Rev. 1997 Apr;156:199-209
references.pmid: 9176709
references.citation: J Am Chem Soc. 2012 May 30;134(21):8730-3
references.pmid: 22587010
references.citation: Chem Soc Rev. 2013 Jun 7;42(11):4543-56
references.pmid: 23250562
references.citation: Chemistry. 2013 Feb 4;19(6):1962-70
references.pmid: 23280874
references.citation: Carbohydr Res. 2007 May 7;342(6):784-96
references.pmid: 17300769
references.citation: ACS Med Chem Lett. 2011 May 12;2(5):373-378
references.pmid: 21691430
references.citation: Infect Immun. 1992 Aug;60(8):3309-14
references.pmid: 1639498
references.citation: J Immunol. 1991 Jan 1;146(1):316-20
references.pmid: 1898604
references.citation: Trends Microbiol. 2002;10(10 Suppl):S32-7
references.pmid: 12377566
references.citation: J Immunol. 1998 Jan 1;160(1):20-3
references.pmid: 9551950
references.citation: Clin Microbiol Rev. 2003 Jul;16(3):379-414
references.pmid: 12857774
references.citation: J Biol Chem. 2004 Feb 6;279(6):4440-9
references.pmid: 14570885
references.citation: Microbes Infect. 2002 Jul;4(9):903-14
references.pmid: 12106783
references.citation: Curr Opin Chem Biol. 2009 Dec;13(5-6):608-17
references.pmid: 19766052
references.citation: Vaccine. 1999 Aug 20;18(1-2):190-7
references.pmid: 10501249
references.citation: Eur J Biochem. 1985 Apr 1;148(1):1-5
references.pmid: 2579812
references.citation: J Bacteriol. 1992 Mar;174(6):1793-800
references.pmid: 1548229
references.citation: Cell Mol Life Sci. 2008 Oct;65(20):3231-40
references.pmid: 18668203
references.citation: Chem Commun (Camb). 2009 Oct 7;(37):5536-7
references.pmid: 19753348
references.citation: Bioconjug Chem. 2008 Oct;19(10):2060-7
references.pmid: 18816108
references.citation: Angew Chem Int Ed Engl. 2010 May 10;49(21):3688-92
references.pmid: 20449837
references.citation: Biomol Eng. 2001 Oct 15;18(3):69-85
references.pmid: 11566599
references.citation: Vaccine. 2008 Jun 6;26(24):3036-45
references.pmid: 18226433