Sulfavants, a new class of molecular vaccine adjuvants: development in immunotherapy and correlation of the colloidal self-assembly with immune cell response

Session: 
S1.3 Glycolipid immunology
Code: 
OL1.3.4
Location (hall): 
Galactose
Start/end time: 
Monday, July 1, 2019 - 12:30 to 12:45
Emiliano
Manzo

Emiliano Manzo1, Laura Fioretto1,3, Carmela Gallo1, Marcello Ziaco2, Genoveffa Nuzzo1, Marina Della Greca3, Luigi Paduano3, Raffaele De Palma4, Angelo Fontana1

1Bio-Organic Chemistry Unit, CNR-Istituto di Chimica Biomolecolare (CNR-Italy), Pozzuoli (Naples), Italy, 2BioSEARCH  c/o R&D Site-Istituto Chimica Biomolecolare – CNR-Italy, Pozzuoli (naples), Italy, 3Department of Chemical Sciences, University of Naples Federico II, Naples, Italy, 4Second University of Naples, Dept. of Precision Medicine, c/o II Policlinico , Naples, Italy

Adjuvants are components of vaccine that enhance the specific immune response against co-inoculated antigens. Recently, we reported the characterization of a synthetic sulfolipid named Sulfavant A (1) as a promising candidate of a novel class of molecular adjuvants based on the sulfoquinovosyl-diacylglycerol skeleton [1].  Sulfavant A is able to prime human dendritic cells (DC) by a TLR2/TLR4-independent mechanism inducing maturation of DC with expression of high levels of MHC II molecules and upregulation of costimulatory proteins (CD83, CD86) and proinflammatory cytokines (IL-12 and INF-γ) [1]. Moreover 1 triggers an efficient immune response in vivo; in fact mice immunized with OVA associated to Sulfavant A (1:500) produced a titer of anti-OVA Ig comparable to traditional adjuvants. In an experimental model of melanoma, vaccination of C57BL/6 mice by Sulfavant A-adjuvanted hgp10 peptide elicited a protective response with reduction of tumour growth and increase of survival.

Improved synthesis of the sulfolipid scaffold, the preparation of two epimeric analogs named Sulfavant-S (2) and Sulfavant-R (3), as well as a study of self-aggregation of these molecule in water and the effect of this aggregation on biological response will be the object of this communication [2]. In the new synthetic approach, the strategy for Sulfavant A is reduced from 14 to 11 steps with approximately triplication of the overall yield (11%) permitting the preparation of the analogs 2-3 [2]. The new members Sulfavant R and S elicit DC maturation at a concentration of 10 nM, which is 1000 times lower than that of the parent molecule 1. Analysis by Dynamic Light Scattering (DLS) indicates self-assembly of Sulfavants and formation of colloidal particles with a small hydrodynamic radius (Rh~60 nm) for the epimers 2 and 3, and a larger radius (Rh~150 nm) for 1. Further studies on these aggregates were led by Small Angle Neutron Scattering (SANS) and Zeta potential analysis. The formation of colloidal aggregates is responsible for the different immunomodulant behavior of these molecules; it’s possible that the particle size can influence the equilibrium with free monomers thus determining the effective concentration of the sulfolipid molecule at the cellular targets and the different immunological efficacy of 1-3. Sulfavants do not show in vitro cytotoxicity at concentrations 105 higher than the dose that triggers maximal immune response, thus predicting a low level of toxicological risk in their formulation in vaccines. 

Figure 1. Sulfavants (1-3); (A) hydrodynamic radius of 1-3; (B) biological activity of 1-3

References: 
  1. (a) Manzo E. et al. Marine-derived sulfoglycolipid triggers dendritic cell activation and immune adjuvant response Scientific Reports 2017, 7(1), 6286; (b) Fontana A.; Manzo E. et al. Use and preparation of glycolipids as adjuvants in vaccines. Italian patent IT1417828 2015; International extension of the italian patent: application number: PCT/IB2014/062098; (c) Manzo E. et al. Chemical synthesis of marine-derived sulfoglycolipids, a new class of molecular adjuvants Marine Drugs 2017, 15 (9), 288.
  2. Manzo E. et al. Diasteroselective colloidal self-assembly affects the immunological response of the molecular adjuvant Sulfavant ACS Omega 2019, in press.

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