Chemoenzymatic Synthesis of 9NHAc-GD2 Antigen to Overcome the Hydrolytic Instability of O-Acetylated-GD2 for Anticancer Conjugate Vaccine Development

Xuanjun Wu; Jinfeng Ye; Andrew T DeLaitsch; Zahra Rashidijahanabad; Shuyao Lang; Tayeb Kakeshpour; Yuetao Zhao; Sherif Ramadan; Paulo Vilar Saavedra; Vilma Yuzbasiyan-Gurkan; Herbert Kavunja; Hongzhi Cao; Jeffrey C Gildersleeve; Xuefei Huang

doi:10.1002/anie.202108610

Chemoenzymatic Synthesis of 9NHAc-GD2 Antigen to Overcome the Hydrolytic Instability of O-Acetylated-GD2 for Anticancer Conjugate Vaccine Development

Angew Chem Int Ed Engl. 2021 Nov 2;60(45):24179-24188. doi: 10.1002/anie.202108610. Epub 2021 Oct 4.

Authors

Xuanjun Wu^{1

2

3}, Jinfeng Ye¹, Andrew T DeLaitsch⁴, Zahra Rashidijahanabad^{2

3}, Shuyao Lang^{2

3}, Tayeb Kakeshpour², Yuetao Zhao^{2

3

5}, Sherif Ramadan^{2

3

6}, Paulo Vilar Saavedra⁷, Vilma Yuzbasiyan-Gurkan⁸, Herbert Kavunja^{2

9}, Hongzhi Cao¹, Jeffrey C Gildersleeve⁴, Xuefei Huang^{2

3

10}

Affiliations

¹ National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, Shandong University, Qingdao, Shandong, 266237, China.
² Department of Chemistry, Michigan State University, East Lansing, MI, 48824, USA.
³ Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, 48824, USA.
⁴ Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
⁵ School of Life Sciences, Central South University, Changsha, Hunan, 410013, China.
⁶ Chemistry Department, Faculty of Science, Benha University, Benha, Qaliobiya, 13518, Egypt.
⁷ Department of Small Animal Clinical Sciences, Michigan State University, East Lansing, MI, 48824, USA.
⁸ Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, 48824, USA.
⁹ Iaso Therapeutics, 4942 Dawn Avenue, East Lansing, MI, 48823, USA.
¹⁰ Department of Biomedical Engineering, Michigan State University, East Lansing, MI, 48824, USA.

Abstract

Ganglioside GD2 is an attractive tumor-associated carbohydrate antigen for anti-cancer vaccine development. However, its low immunogenicity and the significant side effects observed with anti-GD2 antibodies present significant obstacles for vaccines. To overcome these, a new GD2 derivative bearing an N-acetamide (NHAc) at its non-reducing end neuraminic acid (9NHAc-GD2) has been designed to mimic the 9-O-acetylated-GD2 (9OAc-GD2), a GD2 based antigen with a restricted expression on tumor cells. 9NHAc-GD2 was synthesized efficiently via a chemoenzymatic method and subsequently conjugated with a powerful carrier bacteriophage Qβ. Mouse immunization with the Qβ-9NHAc-GD2 conjugate elicited strong and long-lasting IgG antibodies, which were highly selective toward 9NHAc-GD2 with little cross-recognition of GD2. Immunization of canines with Qβ-9NHAc-GD2 showed the construct was immunogenic in canines with little adverse effects, paving the way for future clinical translation to humans.

Keywords: 9NHAc-GD2; cancer; glycoconjugates; synthesis design; vaccine.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Acetamides / chemistry
Acetamides / immunology
Acetylation
Animals
Cancer Vaccines / chemistry*
Cancer Vaccines / immunology
Carbohydrate Conformation
Gangliosides / chemical synthesis*
Gangliosides / chemistry
Gangliosides / immunology
Hydrolysis
Mice
Neuraminic Acids / chemistry
Neuraminic Acids / immunology
Vaccine Development
Vaccines, Conjugate / chemistry*
Vaccines, Conjugate / immunology

Substances

Acetamides
Cancer Vaccines
Gangliosides
Neuraminic Acids
Vaccines, Conjugate
ganglioside, GD2
acetamide

Abstract

Publication types

MeSH terms

Substances

Grants and funding