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Globo h and related anti-cancer vaccines with novel glycolipid adjuvants

A cancer vaccine and adjuvant technology, applied in the field of cancer vaccines, can solve problems such as the difficulty in the precise determination of glycocomplexation

Active Publication Date: 2011-10-12
ACAD SINIC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the precise determination of this glycocomplexation is extremely difficult

Method used

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  • Globo h and related anti-cancer vaccines with novel glycolipid adjuvants
  • Globo h and related anti-cancer vaccines with novel glycolipid adjuvants
  • Globo h and related anti-cancer vaccines with novel glycolipid adjuvants

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0182] Example 1: Synthesis of Globo H complexed with different carrier proteins

[0183] Using a programmable one-pot strategy with process control, Globo H was synthesized (1; see Figure 11) and its fragment 2-10 (Huang C-Y, et al. (2006) Proc Natl Acad Sci USA103: 15-20). The reaction of 1 is carried out with sufficient homobifunctional (homobifunctional) linkers in anhydrous DMF solution at room temperature (Wu X, et al. (2004) Org Lett 6:4407-4410; Wu X, Bundle DR (2005) J Org Chem 70:7381-7388). The reaction can be easily monitored by TLC. Once the free amine disappeared and the larger Rf product appeared, the reaction mixture was evaporated to remove DMF and washed with dichloromethane and water to remove excess linker. Finally, the product was purified by reverse-phase (C18) column chromatography and gradually eluted with water containing 1% acetic acid to 40% methanol in water. The solution was then lyophilized to yield the pale yellow product 12. Finally, for p...

example 2

[0186] Example 2: Fabrication and Validation of Glycan Microarrays

[0187] Make the synthetic Globo H and cut fragment ( figure 1 ) was attached to the reducing end with a pentylamine linker and covalently immobilized on NHS-coated glass slides. Of the eleven oligosaccharides, nine were selected to be imprinted on the microarray. A series of oligosaccharide concentrations (1, 5, 10, 20, 40, 50, 80, 100 [mu]M) were tested to optimize binding affinity and fluorescence intensity. Each microarray slide was spotted with 12 replicates of nine Globo H analogs (SSEA-4, GH, Gb5, Gb4, Gb3, Gb2, BB4, BB3, and BB2) at 50 μM each. After reacting in an 80% humidity atmosphere, the slides were stored in a desiccator at room temperature until use.

[0188] To validate the carbohydrates on the microarray, use mouse monoclonal antibodies (VK9 and Mbr1 against Globo H, and anti-SSEA-3) and corresponding secondary antibodies (goat anti-mouse IgG and IgM) to test the pool specificity, and the...

example 3

[0189] Example 3: Mouse Immunization

[0190] In this experiment, a group of mice were immunized subcutaneously with 1 μg of the synthetic Globo H(GH)-complex in the presence or absence of the glycolipid adjuvant α-GalCer(C1). After 10 days of three immunizations at weekly intervals, mouse sera were collected and subsequently introduced into glycan microarrays to assess antibody levels. It is found that GH-KLH, GH-DT, and GH-BV are the most effective immunogens induced by IgM, followed by GH-TT and GH-BSA, such as Figure 3A Abstract, and α-GalCer can stimulate the immune response to induce high levels of IgM antibodies. A similar tendency was also observed for mouse IgG antibodies ( Figure 3B ), and the relative IgG content is higher than the IgM content. In brief, despite the lower sugar density of the synthetic glycoconjugate, GH-DT has similar immunogenicity to GH-KLH, and α-GalCer adjuvant was shown to enhance the immune response.

[0191] Since C1 has been shown to ...

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Abstract

Immunogenic compositions, cancer vaccines and methods for treating cancer are provided. Compositions comprising: (a) a glycan such as Globo H or an immunogenic fragment thereof, wherein the glycan is conjugated with a carrier protein by a linker such as para-nitrophenyl; and (b) an adjuvant comprising glycolipid capable of binding CDId on a dendritic cell, such as an a-galactosyl-ceramide derivative, wherein the immunogenic composition induces an immune response that induces a higher relative level of IgG isotype antibodies as compared to IgM isotype antibodies, are provided. Immunogenic compositions comprising the carrier protein diphtheria toxin cross-reacting material 197 (DT-CRM 197) and the adjuvant C34 are provided. Antibodies generated by immunogenic compositions disclosed herein further neutralize at least one of the antigens Globo H, stage-specific embryonic antigen-3 (SSEA-3) and stage-specific embryonic antigen-4 (SSEA-4). Therapeutics against breast cancer stem cells comprising immunogenic compositions comprising Globo H, SSEA-3 or SSEA-4 conjugated with DT-CRM 197.

Description

[0001] Cross References to Related Applications [0002] This application is the U.S. Patent Application Serial No. 12 / 485,546 (invention name "Compositions for inducing immune responses specific to Globo H and SSEA-3 and uses thereof in cancer treatment", filed on June 16, 2009) under examination A continuation-in-part application claiming priority to US Provisional Patent Application Serial No. 61 / 061,968 (filed June 16, 2008). The contents of these patent applications are incorporated in this specification by reference data in their entirety. [0003] technical field of invention [0004] The present invention relates to the field of cancer vaccines. In particular, the application relates to a sugar-based vaccine containing the B-cell epitope Globo H complexed with the immunogenic carrier DT-CRM197. More specifically, the present invention relates to anti-cancer Globo H-DT vaccines co-administered with novel glycolipid adjuvants such as C34. Background of the invention ...

Claims

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Application Information

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IPC IPC(8): A61K39/00A61K39/385
CPCA61K39/0011A61K39/385A61K39/39A61K2039/55511A61K2039/6081A61K2039/627C12N15/1137C12N2310/14A61K39/02A61K39/095A61K39/395
Inventor 志辉·王忠义·吴爱丽丝·于约翰·于
Owner ACAD SINIC
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