Antibodies against sialoglycolipids two sides of the same coin

FERNANDO M. RUGGIERO; ALDO A. VILCAES; VANINA TORRES DEMICHELIS; JOSÉ L. DANIOTTI

San Pablo

Workshop; Sao Paulo School for Advanced Science in Cell Biology; 2018

Faculdade de Ciências Farmacêuticas, Universidade de São Paulo

Sialoglycolipids are a sialic acid bearing family of glycolipids ubiquitously distributed on the outer leaflet of vertebrate plasma membranes (PM). Most of them are known as gangliosides. Ganglioside expression is tightly regulated in a tissue and development fashion and changes under several physiological and pathological conditions. A wide spectrum of pathological processes are associated with gangliosides, being receptors for viruses, toxins and antibodies. Antibodies to gangliosides (AGAbs) have been associated with a wide range of neuropathological syndromes. AGAbs GM1 and GD1a are key mediators of peripheral nerve damage in Guillain-Barre syndrome and the endocytosis of these AGAbs is critical to mitigate injury. On the other hand, the abnormal glycosylation of gangliosides on the surface of different cancer cells has received considerable attention as a convenient immunotherapeutic target for cancer treatment through AGAbs. In this scenario, it is essential to understand the mechanisms by which AGAbs, recognize their epitopes, the cellular fate and the physiopathological consequences. This information has important translational implications for the understanding of clinical characteristics of AGAb mediated neuropathies and for the development of novel therapeutics targeting. In our laboratory, we are interested in understanding the molecular mechanisms involved in ganglioside expression as well as the internalization and intracellular trafficking of AGAbs after binding their target gangliosides at the PM. The kinetics of cellular internalization and fate of AGAbs are quite different and seem to be unique for each cell type-AGAbs system. This knowledge allows us to selectively target and to potentially ablate the cell population that express the target ganglioside. Those AGAbs that are internalized could be used to selectively deliver cytotoxic agents into the target cells. On the other hand, AGAbs that are not actively internalized but remain associated to the PM could potentially be used to engage cellular/humoral responses against those target cells. We took advantage of the internalization feature of an antibody that recognizes GD3 to selectively deliver saporin toxin (a protein synthesis inhibitor) into GD3-expressing melanoma cells, which caused a drastic growth inhibition. Now, we are characterizing the cellular behavior of an antibody to SSEA4, an upregulated sialoglycolipid in triple negative breast cancer cells that constitute a promising antigen to specifically target this cancer subtype.