Aberrant glycosylation is the hallmark of malignant transformation of normal healthy cells. These altered patterns on the glycocalyx of cancer cells are called tumor-associated carbohydrate antigens (TACAs). TACAs are poorly immunogenic i.e., they elicit T-cell independent immune responses on their own and hence once they are conjugated to carrier proteins like KLH, CRM197 they can elicit T-cell dependent immune responses. Due to the self-immunogenicity of the carrier proteins, capsular polysaccharides, such as PS A1, can be used as an alternative approach to carrier proteins. PS A1, isolated from B.fragilis ATCC 25285/NCTC 9343, is a T-cell immune stimulating immunogen on its own and we conjugate TACAs synthesized in our lab to PS A1 to overcome T-cell independence. Previously, we have reported on TACA-PS A1 conjugates such as Tn-PS A1, STn-PS A1 and others, that can elicit robust MHC II dependent immune responses which leads to CD4+ T-cell proliferation and antibody production. Inspired by these results, we are currently working on GD2-PS A1 conjugate. GD2 is a disialoganglioside and TACA for neuroblastomas (NB), a cancer which starts in early nerve cells i.e., neuroblasts of the sympathetic nervous system. Approximately 700 children under the age of five, are diagnosed in the United States every year and it accounts for 6% of all childhood cancers. 99% of the NB cells have GD2 expressed on their cell surface and approximately 5-10 million molecules of GD2/cell. Over past two decades there has been immense demand for anti-GD2 mAbs to treat high risk neuroblastomas. Unituxin®, the first ever FDA approved anti-GD2 monoclonal antibody (mAb) against NB has been proven positive as an immuno-therapeutic but has many limitations such as infusion reactions, bone marrow suppression, electrolyte abnormalities, etc. In an attempt to validate our entirely carbohydrate-based immunogens and seek to overcome some setbacks of Unituxin, we envisaged a strategy to chemically prepare a linker-free construct by synthesizing an aminooxy derivative of GD2 and then conjugating it to PS A1. GD2-PS A1 can be used in mice immunizations to produce GD2 specific mAbs, which will be tested for their in vitro and in vivo tumor killing efficiency against various NB cancer cell lines.

Synthesis of Entirely Carbohydrate Immunogen GD2-PS A1 and Production of Anti-GD2 mAbs

ACS Spring Meeting 2021

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