Adjuvants
Inventors
HILGERS, Lucas A. Th. • PLATENBURG, Peter Paul L. I. • Van Den Bosch, Johannes F.
Assignees
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Publication Number
US-10342867-B2
Publication Date
2019-07-09
Expiration Date
Abstract
The present invention relates to a family of carbohydrate monosulphate fatty acid esters, which contain less than 10 mole % of carbohydrate polysulphate fatty acid esters, and to a method of preparation thereof. The monosulphate carbohydrate esters according to the invention comprise one sulphate ester and at least one fatty acid and are among others useful as adjuvants for immunological products such as vaccines.
Core Innovation
The invention relates to vaccine adjuvants based on carbohydrate monosulphate fatty acid esters (MONO) enriched from sulpholipid-carbohydrate mixtures. The approach uses fractionation to remove carbohydrate polysulphate esters (POLY), thereby leaving less than 10 mol% multi-sulphated species, where multi-sulphated species are carbohydrate esters substituted with more than one sulphate group.
The document characterizes MONO structures as comprising a carbohydrate selected from mono-/di-/trisaccharides or cyclodextrins, substituted with one sulphate group and with fatty acids such that substantially all non-sulphated hydroxyls are fatty-acylated. Prior random synthesis is described as producing a ZERO/MONO/POLY composition, with a mixture including carbohydrate ester species with zero, one, or more than one sulphate group.
The core teaching is that substantially reducing POLY improves the E/T ratio of the adjuvant while maintaining strong immune responses. The document reports that MONO enriched formulations show minimal or no POLY-associated toxicity, including reduced body temperature rise and reduced local reactogenicity and tissue damage such as granuloma/necrosis, while yielding strong or comparable immune responses versus prior SL-carbohydrate mixtures and improved performance relative to alum.
Claims Coverage
Across the provided independent claims, there are four inventive claim categories. The inventive features center on using a carbohydrate ester mixture in which less than 10 mole% has more than one sulphate group.
Immune response enhancement with monosulphate-enriched sulpholipid-carbohydrate adjuvant
A method for increasing an immune response evoked by an antigenic component comprising administering the antigenic component with an adjuvant comprising a carbohydrate ester mixture comprising a sulpholipid-carbohydrate, which is a carbohydrate substituted with at least one sulphate group and with at least one fatty acid, wherein less than 10 mole % of the carbohydrate ester mixture is substituted with more than one sulphate group, and a pharmaceutically acceptable carrier.
Vaccine with monosulphate-enriched sulpholipid-carbohydrate adjuvant
A vaccine comprising an adjuvant comprising a carbohydrate ester mixture comprising a sulpholipid-carbohydrate, which is a carbohydrate substituted with at least one sulphate group and with at least one fatty acid, wherein less than 10 mole % of the carbohydrate ester mixture is substituted with more than one sulphate group, and a pharmaceutically acceptable carrier, and an antigenic component.
Kit of parts with monosulphate-enriched sulpholipid-carbohydrate adjuvant
A kit of parts comprising an adjuvant comprising a carbohydrate ester mixture comprising a sulpholipid-carbohydrate, which is a carbohydrate substituted with at least one sulphate group and with at least one fatty acid, wherein less than 10 mole % of the carbohydrate ester mixture is substituted with more than one sulphate group, and a pharmaceutically acceptable carrier, and an antigenic component.
Monosulphate carbohydrate fatty acid ester mixture prepared by esterification and fractionation to remove multi-sulphated species
A process for preparing a carbohydrate ester mixture comprising a monosulphate carbohydrate fatty acid ester, wherein less than 10 mole % of the carbohydrate ester mixture is substituted with more than one sulphate group, the method comprising esterifying a carbohydrate with a sulfonating agent and a reactive fatty acid acyl compound to obtain the carbohydrate ester mixture, and fractionating the mixture to remove the carbohydrate esters with more than one sulphate group from the carbohydrate ester mixture to obtain the mixture comprising a monosulphate carbohydrate fatty acid ester.
The claims are anchored in carbohydrate ester mixtures derived from sulpholipid-carbohydrate adjuvants where multi-sulphated carbohydrate esters are limited to less than 10 mole%. The claims cover immune response enhancement, vaccine formulations, kits comprising adjuvant and antigenic component, and a manufacturing process that esterifies carbohydrates and then fractionates to remove more-than-one sulphate substituted species.
Stated Advantages
Improved efficacy/toxicity (E/T) ratio by substantially reducing POLY.
Minimal or no POLY-associated toxicity, including reduced body temperature rise and reduced local reactogenicity such as granuloma/necrosis.
Strong or comparable immune responses versus prior SL-carbohydrate mixtures.
Improved performance relative to alum.
POLY reduced antigen epitope damage associated with worse antibody responses in the influenza model.
Documented Applications
Rabbit immunization studies evaluating MONO enriched formulations, including outcomes such as body temperature rise, local reaction scoring, and immune response measurements.
Influenza model application described for H5N1, including effects on antibody responses and relative E/T performance.
Comparative immune response evaluation versus prior SL-carbohydrate mixtures and benchmark adjuvant alum.
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